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Geographic tongue, also known by several other terms, is a condition of the mucous membrane of the tongue, usually on the dorsal surface. It is a common condition, affecting approximately 2–3% of the general population. It is characterized by areas of smooth, red depapillation (loss of lingual papillae) which migrate over time. The name comes from the map-like appearance of the tongue, with the patches resembling the islands of an archipelago. The cause is unknown, but the condition is entirely benign (importantly, it does not represent oral cancer), and there is no curative treatment. Uncommonly, geographic tongue may cause a burning sensation on the tongue, for which various treatments have been described with little formal evidence of efficacy. == Signs and symptoms == In health, the dorsal surface of the tongue is covered in tuft-like projections called lingual papillae (some of which are associated with taste buds), which give the tongue an irregular surface texture and a white-pink color. Geographic tongue is characterized by areas of atrophy and depapillation (loss of papillae), leaving an erythematous (darker red) and smoother surface than the unaffected areas. The depapillated areas are usually well-demarcated, and bordered by a slightly raised, white, yellow or grey, serpiginous (snaking) peripheral zone. A lesion of geographic tongue may start as a white patch before the depapillation occurs. In certain cases there may be only one lesion, but this is uncommon; the lesions will typically occur in multiple locations on the tongue and coalesce over time to form the typical map-like appearance. The lesions usually change in shape and size, and migrate to other areas, sometimes within hours. The condition may affect only part of the tongue, with a predilection for the tip and the sides of the tongue, or the entire dorsal surface at any one time. The condition goes through periods of remission and relapse. Loss of the white peripheral zone is thought to signify periods of mucosal healing. There are usually no symptoms other than the unusual appearance of the tongue, but in some cases persons may experience pain or burning, e.g. when eating hot, acidic, spicy or other kinds of foods (e.g. cheese, tomatoes, fruit). Where there is a burning symptom, other causes of a burning sensation on the tongue are considered, such as oral candidiasis. == Causes == The cause is unknown. Geographic tongue does not usually cause any symptoms, and in those cases where there are symptoms, an oral parafunctional habit may be a contributory factor. Persons with parafunctional habits related to the tongue may show scalloping on the sides of the tongue (crenated tongue). Some suggest that hormonal factors may be involved, because one reported case in a female appeared to vary in severity in correlation with oral contraceptive use. People with geographic tongue frequently claim that their condition worsens during periods of psychological stress. Geographic tongue is inversely associated with smoking and tobacco use. Sometimes geographic tongue is said to run in families, and it is reported to be associated with several different genes, though studies show family association may also be caused by similar diets. Some have reported links with various human leukocyte antigens, such as increased incidence of HLA-DR5, HLA-DRW6 and HLA-Cw6 and decreased incidence in HLA-B51. Vitamin B2 deficiency (ariboflavinosis) can cause several signs in the mouth, possibly including geographic tongue, although other sources state that geographic tongue is not related to nutritional deficiency. Fissured tongue often occurs simultaneously with geographic tongue, and some consider fissured tongue to be an end stage of geographic tongue. In the past, some research suggested that geographic tongue was associated with diabetes, seborrheic dermatitis and atopy, however newer research does not corroborate these findings. Others suggest allergy as a major factor, e.g. to nickel sulphate. Some studies have reported a link between geographic tongue and psoriasis, although 90% of children who are diagnosed with geographic tongue do not develop psoriasis. Again however, modern research studies do not support any link between psoriasis and geographic tongue. Lesions that are histologically indistinguishable from geographic tongue may also be diagnosed in reactive arthritis (arthritis, uveitis/conjunctivitis and urethritis). == Predisposing factors == Geographic tongue (GT) is a lesion with an unknown origin. However, it has been reported more frequently in people with psoriasis, history of allergies, asthma and rhinitis. Studies have also suggested that psychological/psychiatric factors, diabetes, gastrointestinal diseases and haematological disorders may predispose to GT however, more studies with a larger cohort are needed to determine if GT could be an oral manifestation of a systemic disease. There is strong evidence to support a high prevalence of celiac disease and iron-deficiency anaemia in patients with GT. Oral candidiasis and caries are commonly reported in patients with GT, however this can be explained by saliva of a lower pH which will promote the cariogenic process. Most common areas in which GT can be found include; the lateral border of the tongue, followed by the anterior dorsum of the tongue and ventral surface. == Diagnosis == Diagnosis of geographic tongue (GT) mainly relies on clinical, intraoral findings. As GT is usually asymptomatic in the mouth it does not require treatment. A differential diagnosis between oral candidiasis and GT, two similar looking conditions, can be established through a careful and thorough examination. GT is a keratotic lesion which can be described as a round or irregular shaped white plaque, cannot be scraped off and is normally self-resolving. These lesions are known to reoccur within variable periods. Although rare, cytological techniques and biopsies can be done to aid in a clinical diagnosis. The cytological description can define the disease due to its inflammatory characteristics, with its main characteristic being nuclear demarcation. Furthermore, it is important to be aware that GT may be related to other extraoral and intraoral conditions. The differential diagnosis includes oral lichen planus, erythematous candidiasis, leukoplakia, lupus erythematosus, glossitis, and chemical burns. Atrophic glossitis is usually distinguished from benign migratory glossitis on the basis of the migrating pattern of the lesions and the presence of a whitish border, features which are not present in atrophic glossitis, which instead shows lesions which enlarge rather than migrate. Rarely, blood tests may be required to distinguish from glossitis associated with anemia or other nutritional deficiencies. Since the appearance and the history of the condition (i.e. migrating areas of depapillation) are so striking, there is rarely any need for biopsy. When biopsy is taken, the histopathologic appearance is quite similar to psoriasis: Hyperparakeratosis. Acanthosis. Subepithelial T lymphocyte inflammatory infiltrate. Migration of neutrophilic granulocytes into the epithelial layer, which may create superficial microabscesses, similar to the Munro's microabscesses described in pustular psoriasis. === Classification === Geographic tongue could be considered to be a type of glossitis. It usually presents only on the dorsal 2/3 and lateral surfaces of the tongue, but less commonly an identical condition can occur on other mucosal sites in the mouth, such as the ventral surface (undersurface) of the tongue, mucosa of the cheeks or lips, soft palate or floor of mouth; usually in addition to tongue involvement. In such cases, terms such as stomatitis erythema migrans, ectopic geographic tongue, areata migrans, geographic stomatitis, or migratory stomatitis are used instead of geographic tongue. Beside the differences in locations of presentation inside the oral cavity and prevalence among the general population, in all other aspects of clinical significance, symptoms, treatment, and histopathologic appearance, these two forms are identical. This condition is sometimes termed (oral) erythema migrans, but this has no relation to the more common use of the term erythema migrans (erythema chronicum migrans), to describe the appearance of skin lesions in Lyme disease and southern tick-associated rash illness. == Treatment == Geographic tongue (GT), also termed benign migratory glossitis, usually presents without symptoms, and due to a lack of reliable evidence researchers can not identify a specific treatment for the condition. It is currently suggested that patients are given reassurance that the condition is entirely benign and self-resolving. Although there is no established gold standard treatment confirmed by current evidence, patients with symptomatic GT can be advised on several treatment options prescribed by the clinician on a case-by-case basis. This includes possible prescriptions of antihistamines, anxiolytics, corticosteroids and topical anaesthetics. It is recommended that patients avoid spicy and acidic foods. Research has not shown high levels of evidence for the treatment of symptomatic GT and larger study sizes are needed to come to a reliable recommendation. == Prognosis == The condition may disappear over time, but it is impossible to predict if or when this may happen. == Epidemiology == Geographic tongue is a common condition, affecting 2-3% of the adult general population, although other sources report a prevalence of up to 14%. It is one of the most common tongue disorders that occurs in children. The condition often starts in childhood, sometimes at an early age, but others report that the highest incidence occurs in the over 40 age group. Females are sometimes reported to be more commonly affected than males, in a 2:1 ratio, although others report that the gender distribution is equal. == Psoriasis == A recent study has proven the link between geographic tongue (GT) and psoriasis - the presence of geographic tongue can be a predictor of psoriasis. Clinical manifestation of GT and psoriasis can be histologically similar, however a genetic link between the two has been pathogenically identified. Patients with generalised pustular psoriasis and GT both exhibit the c.115 +6T >C mutation in the IL36RN gene. Patients who have GT have been shown to experience a greater severity of psoriasis and have a less positive response to treatment. == Manifestations in COVID-19 infection == Many articles including case reports, case-series and cross-sectional studies have been done since the 2020 outbreak of COVID-19, causing a global pandemic. These studies have shown that approximately 20% of people with COVID-19 can present with mucosal manifestations in their oral cavities, including geographic tongue. Geographic tongue may appear alongside the onset of the regular symptoms of COVID-19. Interleukin-6 (IL-6) is known to be an important biomarker in people with COVID-19 in relation to a cytokine storm where too many inflammatory cells which have a detrimental effect on organ systems throughout the body. Geographic tongue is associated with elevated levels of IL-6, which possibly helps explain the presentation in confirmed COVID-19 cases. This evidence is minimal and requires more studies and research to confirm these claims. == Notes == == References == == External links ==	Wikipedia/Geographic_tongue
Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a type of chronic liver disease. This condition is diagnosed when there is excessive fat build-up in the liver (hepatic steatosis), and at least one metabolic risk factor. When there is also increased alcohol intake, the term MetALD, or metabolic dysfunction and alcohol associated/related liver disease is used, and differentiated from alcohol-related liver disease (ALD) where alcohol is the predominant cause of the steatotic liver disease. The terms non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH, now MASH) have been used to describe different severities, the latter indicating the presence of further liver inflammation. NAFL is less dangerous than NASH and usually does not progress to it, but this progression may eventually lead to complications, such as cirrhosis, liver cancer, liver failure, and cardiovascular disease. Obesity and type 2 diabetes are strong risk factors for MASLD. Other risks include being overweight, metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum HDL cholesterol), a diet high in fructose, and older age. Obtaining a sample of the liver after excluding other potential causes of fatty liver can confirm the diagnosis. Treatment for MASLD is weight loss by dietary changes and exercise; bariatric surgery can improve or resolve severe cases. There is some evidence for SGLT-2 inhibitors, GLP-1 agonists, pioglitazone, and vitamin E in the treatment of MASLD. In March 2024, resmetirom was the first drug approved by the FDA for MASH. Those with MASH have a 2.6% increased risk of dying per year. MASLD is the most common liver disorder in the world; about 25% of people have it. It is very common in developed nations, such as the United States, and affected about 75 to 100 million Americans in 2017. Over 90% of obese, 60% of diabetic, and up to 20% of normal-weight people develop MASLD. MASLD was the leading cause of chronic liver disease and the second most common reason for liver transplantation in the United States and Europe in 2017. MASLD affects about 20 to 25% of people in Europe. In the United States, estimates suggest that 30% to 40% of adults have MASLD, and about 3% to 12% of adults have MASH. The annual economic burden was about US$103 billion in the United States in 2016. == Definition == An abnormal accumulation of fat in the liver in the absence of secondary causes of fatty liver, such as significant alcohol use, viral hepatitis, or medications that can induce fatty liver, was the definition of NAFLD. However, the term MASLD accepts there may be other conditions present, but focuses on the metabolic abnormalities contributing to the disorder. MASLD encompasses a continuum of liver abnormalities, from metabolic dysfunction–associated steatotic liver (MASL, simple steatosis) to Metabolic dysfunction-associated steatohepatitis (MASH). These diseases begin with fatty accumulation in the liver (hepatic steatosis). A liver can remain fatty without disturbing liver function (MASL), but by various mechanisms and possible insults to the liver, it may also progress into steatohepatitis (MASH), a state in which steatosis is combined with inflammation and sometimes fibrosis. MASH can then lead to complications such as cirrhosis and hepatocellular carcinoma. The new name, metabolic dysfunction-associated steatotic liver disease (MASLD), was proposed after 70% of a panel of experts expressed support for this name. This new name was adopted in 2023. == Signs and symptoms == People with MASLD often have no noticeable symptoms, and it is often only detected during routine blood tests or unrelated abdominal imaging or liver biopsy. In some cases, it can cause symptoms related to liver dysfunction such as fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild yellow discoloration of the skin may occur, although this is rare. MASH can severely impair liver function, leading to cirrhosis, liver failure, and liver cancer. === Comorbidities === The condition is strongly associated with or caused by type 2 diabetes, insulin resistance, and metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein). It is also associated with hormonal disorders (panhypopituitarism, hypothyroidism, hypogonadism, polycystic ovary syndrome), persistently elevated transaminases, increasing age, and hypoxia caused by obstructive sleep apnea; some of these conditions predict disease progression. Most normal-weight people with MASLD ("lean MASLD") have impaired insulin sensitivity, are sedentary, and have increased cardiovascular disease risk and increased liver lipid levels. These are the consequences of a decreased capacity for storing fat and reduced mitochondrial function in fat and increased hepatic de novo lipogenesis. A recent systematic review reported an increased risk of severe COVID-19 infection in MASLD patients, but no difference in mortality was observed between MASLD and non-MASLD patients. == Risk factors == === Genetics === Two-thirds of families with a history of diabetes type 2 report more than one family member having MASLD. There is a higher risk of fibrosis for family members where someone was diagnosed with MASH. Asian populations are more susceptible to metabolic syndrome and MASLD than their western counterparts. Hispanic persons have a higher prevalence of MASLD than white individuals, whereas the lowest prevalence is observed in black individuals. MASLD is twice as prevalent in men as in women, which might be explained by lower levels of estrogen in men. Genetic variations in two genes are associated with MASLD: non-synonymous single-nucleotide polymorphisms (SNPs) in PNPLA3 and TM6SF2. Both correlate with MASLD presence and severity, but their roles for diagnosis remain unclear. Although NAFLD has a genetic component, the American Association for the Study of Liver Diseases (AASLD) does not recommend screening family members as there is not enough confirmation of heritability, although there is some evidence from familial aggregation and twin studies. === From diet === According to the Asia-Pacific Working Group (APWG) on MASLD, overnutrition is a major factor of MASLD and MASH, particularly for lean MASLD. Diet composition and quantity, in particular omega-6 fatty acid and fructose, have important roles in disease progression from MASL to MASH and fibrosis. Choline deficiency can lead to the development of MASLD. Higher consumption of processed, red, and organ meats have been associated with higher risk of developing MASLD. Some research also suggests eggs are also associated with developing MASLD. On the other hand, studies have found healthful plant foods such as legumes and nuts, to be associated with a lower risk of developing MASLD. Two different studies have found healthy plant-based diets rich in healthy plant foods and low in animal foods to be associated with a lower risk of developing MASLD, even after adjusting for BMI. === From lifestyle === Habitual snoring may be a risk factor for MASLD. Severe snoring often signals the presence of obstructive sleep apnea (OSAS), a much more serious breathing condition. Blockage or narrowing of the airways, even temporarily, can cause the body to experience lowered oxygen levels in the blood. This in turn may cause a variety of changes within the body such as tissue inflammation, increased insulin resistance, and liver injury. A prospective cohort study found the association between habitual snoring and MASLD development to be significant, and the trend was noted to be most prominent in lean individuals. == Pathophysiology == The primary characteristic of MASLD is the accumulation of lipids in the liver, largely in the form of triglycerides. However, the mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to liver dysfunction are complex and incompletely understood. MASLD can include steatosis along with varied signs of liver injury: either lobular or portal inflammation (a form of liver injury) or ballooning degeneration. Similarly, NASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, megamitochondria, and perisinusoidal fibrosis. Hepatocyte death via apoptosis or necroptosis is increased in MASH compared with simple steatosis, and inflammation is a hallmark of MASH. The degree of inflammation can be correlated to the number of inflammatory foci. Various definitions exist for an inflammatory focus, but one defines it as the presence of more than four mononuclear cells in close proximity inside the hepatic parenchyma. One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends the second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence NAFLD and NASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the NAFLD pathology. Many researchers describe NAFLD as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than the liver. The accumulation of senescent cells in the liver is seen in persons with NAFLD. In mice, liver senescent hepatocytes result in increased liver fat deposition. Treatment of NAFLD mice with senolytic agents has been shown to reduce hepatic steatosis. Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting the progression of NASH. === Fructose consumption === Non-alcoholic and alcoholic fatty liver disease share similar histological features, which suggests that they might share common pathogenic pathways. Fructose can cause liver inflammation and addiction similarly to ethanol by using similar metabolic pathways, unlike glucose. Therefore, some researchers argue that non-alcoholic and alcoholic fatty liver diseases are more alike than previously thought. Furthermore, high fructose consumption promotes fat accumulation in the liver by stimulating de novo lipogenesis in the liver and reducing the beta-oxidation of fat. Unlike the sugar glucose, the enzyme fructokinase rapidly metabolizes fructose. This leads to a decreased level of intracellular adenosine triphosphate (ATP). The decrease in ATP increases oxidative stress and impairments in proper protein synthesis and mitochondrial function in the liver. === Insulin resistance === Insulin resistance contributes to the accumulation of toxic fat in the liver in several ways. First, it promotes the release of free fatty acids (FFAs) from adipose tissue into the blood. Typically, adipose tissue stores lipids in the form of triglycerides, slowly releasing them into the bloodstream when insulin is low. In insulin-resistant adipose tissue, such as in people with obesity and type 2 diabetes, more triglycerides are broken down into FFAs and released into the bloodstream, promoting uptake by the liver. Second, insulin promotes the production of new FFAs in the liver via de novo lipogenesis; this production of liver fats continues to be stimulated by insulin, even when other tissues are insulin-resistant. These FFAs are combined back into triglycerides in the liver, forming the major constituent of the accumulated fat in the liver. The three sources of free fatty acids that contribute to liver triglyceride accumulation include FFAs circulating in the bloodstream (59%), FFAs derived from carbohydrates such as fructose and glucose (26%), and diet (14%). Despite the accumulation of triglycerides in the liver, they are not directly toxic to liver tissue. Instead, alteration of the profile of the other lipid subtypes present in the liver, such as diacylglycerols, phospholipids, ceramides, and free cholesterol, have a more significant role in the pathogenesis of MASLD. Once MASLD progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and liver, which results in a harmful cycle of insulin resistance, liver fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with NAFLD. Adiponectin has several properties that protect the liver. These properties include improved liver fat metabolism, decreased de novo lipogenesis, decreased glucose production in the liver, anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in MASLD. Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes the redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the liver. === Dysbiosis === Disruptions in the intestinal microbiota seem to influence NAFLD risk in several ways. People with NASH can have elevated levels of blood ethanol and Pseudomonadota (which produce alcohol), with dysbiosis proposed as a mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence NAFLD risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased liver exposure to harmful substances (e.g., translocated bacteria, bacterial toxins, and inflammatory chemical signals). The increased transport of these harmful substances to the liver promotes liver inflammation, enhances nutrient and calorie absorption, and alters choline metabolism. Higher levels of intestinal bacteria that produce butyrate may be protective. Excessive macronutrient intake contributes to gut inflammation and perturbation of homeostasis, and micronutrients may also be involved. In addition to reducing weight and risk factors, lifestyle changes may prompt positive changes in the gut microbiota. In particular, diet diversity may play a role that was overlooked in animal studies, since they often compare a Western high-fat, low-diversity diet against a low-fat but higher-diversity chow. The health benefits after bariatric surgery may also involve changes in the gut microbiota by increasing gut permeability. == Diagnosis == NAFLD was defined by the presence of excess fat in the liver that cannot be explained by another factor, such as excessive alcohol use (>21 standard drinks/week for men and >14 for women in the USA; >30 g daily for men and >20 g for women in UK and EU, >140 g/week for men and >70 g/week for women in Asia-Pacific), liver injury caused by drugs or toxins or viruses, nutritional deficiency, or endocrine conditions. In practice, diagnosis was often made simply based on the clinical presentation and a lack of high-volume alcohol consumption reported by the patient, but this is an unreliable method of diagnosis. NAFLD comprises two histological categories: NAFL, and the more aggressive form NASH. The presence of at least 5% fatty liver is common to both NAFL and NASH, but the features of substantial lobular inflammation and hepatocyte injuries such as ballooning or Mallory hyaline only occur in NASH. The majority of NAFL cases show minimal or no inflammation. Pericentral and perisinusoidal fibrosis occur more often in adult-onset NASH, whereas portal fibrosis is more common in children with the disorder. NASH represents a more advanced stage of NAFL and is associated with poor outcomes such as cardiovascular events, cirrhosis, or hepatocellular carcinoma. ICD-11 does not use the term NAFL as it was deemed confusing with the family of disorders NAFLD. The preferred descriptions are instead: NAFLD without NASH or simple steatosis and "NASH". Also, the modifier with or without fibrosis or cirrhosis completes the diagnostic description. Following the renaming of NAFLD to MASLD, these definitions are being updated. === Blood tests === Liver function tests may be abnormal, but they often remain within the normal range even in advanced disease. Other blood tests that may be useful to confirm the diagnosis include erythrocyte sedimentation rate, serum glucose, and albumin. Because the liver is important for making proteins used in blood clotting, coagulation-related studies are often carried out, especially the prothrombin time. In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out certain types of viral hepatitis and autoimmune diseases. Low thyroid activity is more prevalent in people with NASH, which would be detected by determining the thyroid-stimulating hormone. Some biomarker-based blood tests have been developed and may be useful for diagnosis. Although blood tests cannot diagnose MASLD, circulating serum biomarkers of liver fibrosis can give moderate estimates in the diagnosis of liver fibrosis and cirrhosis. The ratio of the transaminase liver enzyme aspartate aminotransferase (AST) to platelets in the blood, known as the AST/platelet ratio index (APRI score), and Fibrotest are recommended as the preferred noninvasive tests for cirrhosis by the Asian-Pacific Association for Study of the Liver (APASL). Several other scores such as FIB-4 score and NAFLD fibrosis score can also reflect the burden of the fibrosis in the liver, and previous studies have confirmed that these scores can predict future development of mortality and liver cancer. === Imaging === A liver ultrasound scan or magnetic resonance imaging (MRI) can diagnose steatosis, but not fibrosis, and confirmation of early cirrhosis detection by ultrasound by other diagnostic methods is recommended. The European Association for the Study of the Liver (EASL) recommends screening for steatosis whenever NAFLD is suspected as this is a strong predictor of the disease evolution and predicts future type 2 diabetes, cardiovascular events, and hypertension. These non-invasive methods can be used for NAFLD screening but are not accepted as a substitute for liver biopsy in NAFLD nor NASH clinical trials, as only a liver biopsy can define liver pathology. Ultrasound presented average sensitivity and specificity for diagnosing the disease in children, while in the adult population, sensitivity and specificity were significantly higher. Proton density fat fraction magnetic resonance imaging has been increasingly used for the diagnosis of steatosis in pediatric patients. Ultrasound elastography is an effective tool for staging liver fibrosis and discriminating NASH in children. Computerized tomography and magnetic resonance imaging are more accurate in detecting cirrhosis than conventional ultrasound. Transient elastography is recommended for the initial assessment of liver fibrosis and cirrhosis and helps to predict complications and prognosis, but the interpretation of results is carefully weighed in the presence of limiting factors such as steatosis, high BMI, low amount of hepatic fibrosis, narrow spaces between the ribs, and portal hypertension. Transient elastography is not a substitute for liver biopsy. Magnetic resonance elastography (MRE) is an established method that can accurately assess hepatic fibrosis and is recommended by the APASL, AGA, ACR and AASLD. MRE possesses excellent accuracy to detect fibrosis in NAFLD regardless of BMI and inflammation, and is suggested as a more reliable alternative to diagnose NAFLD and its progression to NASH compared to ultrasound and blood tests. === Liver biopsy === A liver biopsy (tissue examination) is the only test widely accepted (gold standard) as definitively diagnosing and distinguishing NAFLD (including NAFL and NASH) from other forms of liver disease and can be used to assess the severity of the inflammation and resultant fibrosis. However, since most people affected by NAFLD are likely to be asymptomatic, liver biopsy presents too high a risk for routine diagnosis, so other methods are preferred, such as liver ultrasonography or liver MRI. For young people, guidelines recommend liver ultrasonography, but biopsy remains the best evidence. Liver biopsy is also the gold standard to detect hepatic fibrosis and assess its progression. Routine liver function blood tests are not sensitive enough to detect MASLD, and biopsy is the only procedure that can reliably differentiate NAFL from NASH. There are several liver biopsy techniques available to obtain liver tissue. Percutaneous liver biopsy remains the most common practice. Biopsies can also be performed via the transvenous route, either during surgery or by laparoscopy, especially for people with contraindications to a percutaneous approach. The liver biopsy can also be image-guided, in real-time or not, which is recommended for some clinical situations such as people with known intra-hepatic lesions, previous intra-abdominal surgery who may have adhesions, a small liver that is difficult to percuss, obese people and people with evident ascites. Vital signs must be monitored frequently afterward (at least every 15 minutes in the hour following the biopsy). According to AASLD guidelines, a liver biopsy may be considered in people with NAFLD who are at increased risk of having steatohepatitis with or without advanced fibrosis, but only when all other competing chronic liver diseases are excluded (such as alcoholic liver disease). The presence of metabolic syndrome, NAFLD Fibrosis Score (FIB-4), or liver stiffness (as measured by Vibration-controlled transient elastography or MRE) can identify the individuals who are at higher risk of steatohepatitis or advanced fibrosis. The AASLD and ICD-11 consider that clinically useful pathology reporting distinguishes "between NAFL (steatosis), NAFL with inflammation and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning)" with the presence or absence of fibrosis being described and optionally comment on severity. The EASL recommends the Fatty Liver Inhibition of Progression (FLIP) algorithm to grade the ballooning and classify MASLD-associated liver injury, and the use of the NAFLD Activity Score (NAS) to grade the severity of NASH rather than for its diagnosis. They also consider the steatosis, activity, and fibrosis (SAF) score to be an accurate and reproducible scoring system. The AASLD recommends the use of the NAS scoring system with or without the SAF score if deemed appropriate. The Asia-Pacific Working Group disadvises the use of NAS, as it is considered uninformative for NAFLD and inappropriate to diagnose NASH. For liver fibrosis assessment, percutaneous liver biopsy, with or without image guidance, is contraindicated in uncooperative people. Transjugular liver biopsy is indicated for any person with diffuse liver disease who needs a biopsy but has a contraindication to percutaneous biopsy or needs a hemodynamic evaluation for diagnostic purposes. A transvenous liver biopsy is recommended instead of a percutaneous approach in people with clinically evident ascites, although percutaneous biopsy is an acceptable alternative approach after the removal of ascites. == Management == MASLD warrants treatment regardless of whether the affected person is overweight or not. MASLD is a preventable cause of death. Guidelines are available from the American Association for the Study of Liver Diseases (AASLD), American Association of Clinical Endocrinologists (AACE) National Institute for Health and Care Excellence (NICE), the European Association for the Study of the Liver (EASL), and the Asia-Pacific Working Party on NAFLD. === Lifestyle === Weight loss is the most effective treatment for MASLD and MASH. A loss of 5% to 10% body weight is recommended and has shown regression of liver damage, with 10% to 40% weight loss completely reversing MASH without cirrhosis. A weight loss of greater than 10% was associated with resolution of MASH in 90% of people in a biopsy based study. A structured weight loss program helps people with MASLD lose more weight compared with advice alone. This type of program also leads to improvements in NAFLD measured using blood tests, ultrasound, imaging, or liver biopsies. Although fibrosis improves with lifestyle interventions and weight loss, there is limited evidence for cirrhosis improvement. A combination of improved diet and exercise, rather than either alone, appears to best help manage NAFLD and reduce insulin resistance. Motivational support, such as with cognitive behavioral therapy, is helpful, as most people with MASLD do not perceive their condition as a disease, and thus have a low motivation to change. Higher-intensity behavioral weight loss therapies (diet and exercise combined) may produce more weight loss than lower-intensity ones. A 2019 systematic review suggested a change of guidelines to recommend these therapies for MASLD management. Weight loss is associated with improvements in biomarkers, MASLD grade, and reduced chances of NASH, but its effect on long-term health was not known. 2021 meta-analyses of trials over periods of 1 to 28 months found limited evidence to indicate that lifestyle modifications and nutritional supplementation have an effect on mortality, liver cirrhosis, liver decompensation, liver transplantation, and hepatocellular carcinoma in people with non-alcohol-related fatty liver disease; authors said that it was unlikely that differences in clinical outcomes would become apparent in trials with less than 5 years to 10 years of follow‐up, and that sample sizes needed to be much larger than had been used. === Diet === Treatment of NAFLD typically involves counseling to improve nutrition and calorie restriction. People with NAFLD can benefit from a moderate to low-carbohydrate diet and a low-fat diet. The Mediterranean diet also showed promising results in a 6-week study with a reduction of NASH induced inflammation and fibrosis, independently from weight loss. Tentative evidence supports dietary interventions in individuals with fatty liver who are not overweight. The EASL recommends energy restriction of 500–1000 kcal per week less than the normal daily diet, a target of 7–10% weight loss for obese/overweight MASLD, a low- to moderate-fat, and moderate- to high-carbohydrate diet, or a low-carbohydrate ketogenic or high-protein diet such as the Mediterranean diet, and avoiding all beverages and food containing fructose. Alcohol is an aggravating factor, and the AASLD recommends that people with NAFLD or NASH avoid alcohol consumption. The EASL allows alcohol consumption below 30g/day for men and 20g/day for women. The role of coffee consumption for NAFLD treatment is unclear though some studies indicate that regular coffee consumption may have protective effects. Herbal compounds such as silymarin (a milk thistle seed extract), curcumin, a turmeric extract, and green tea appear to improve NAFLD biomarkers and reduce the grade of NAFLD. Studies suggest an association between microscopic organisms that inhabit the gut (microbiota) and MASLD. Reviews reported the use of probiotics and synbiotics (combinations of probiotics and prebiotics) were associated with improvement in liver-specific markers of hepatic inflammation, measurements of liver stiffness, and steatosis in persons with MASLD. Vitamin E does not improve established liver fibrosis in those with MASLD but seems to improve certain markers of liver function and reduces inflammation and fattiness of the liver in some people with MASLD. The Asia-Pacific Work Group advises that Vitamin E may improve liver condition and aminotransferase levels, but only in adults without diabetes or cirrhosis who have NASH. The NICE guidelines recommend Vitamin E as an option for children and adults with NAFLD with advanced liver fibrosis, regardless of whether the person has diabetes mellitus. === Physical activity === Weight loss may improve MASLD and is recommended particularly for obese or overweight people; similar physical activities and diets are advisable for overweight people with MASLD as for other obese and overweight people. Although physical activity is less important for weight loss than dietary adaptations (to reduce caloric intake), the NICE advises physical activity to reduce liver fat even if there is no overall bodyweight reduction. Weight loss, through exercise or diet, is the most effective way to reduce liver fat and help NASH and fibrosis remission. Exercise alone can prevent or reduce hepatic steatosis, but it remains unknown whether it can improve all other aspects of the liver; hence a combined approach with diet and exercise is advised. Aerobic exercise may be more effective than resistance training, although there are contradictory results. Vigorous training is preferable to moderate training, as only the high-intensity exercise reduced the chances of MASLD developing into NASH or advanced fibrosis. The EASL recommends between 150 and 200 min/week in 3 to 5 sessions of moderate-intensity aerobic physical activity or resistance training. Since both effectively reduce liver fat, a pragmatic approach to the choice of physical activity that accounts for the individual's preferences for what they can maintain in the long-term is preferred. Any engagement in physical activity or increase over previous levels is better than remaining sedentary. === Medication === While many treatments appear to improve biochemical markers such as alanine transaminase levels, most do not reverse histological abnormalities or improve outcomes. Treatment with medications is primarily aimed at improving liver disease and is generally limited to those with biopsy-proven NASH and fibrosis. Insulin sensitizers (metformin and thiazolidinediones, such as pioglitazone) are not specifically recommended for MASLD as they do not directly improve the liver condition. They can be indicated for diabetic individuals, after a careful assessment of risks, to reduce insulin resistance and risks of complications. Indeed, the side effects associated with thiazolidinedione medications, which include osteopenia, increased fracture risk, fluid retention, congestive heart failure, bladder cancer, and long-term weight gain, have limited their adoption. Due to these side effects, the AASLD recommends the use of pioglitazone only for individuals with biopsy-proven NASH, and the Asia-Pacific Work Group recommends them only for individuals with MASLD with known diabetic issues. However, the AASLD advises against the use of metformin as studies were inconclusive about the improvement of the liver's histological condition. Although there was an improvement in insulin resistance and serum aminotransferases, this did not translate into NASH improvements. The NICE provides similar guidelines to the AASLD regarding pioglitazone and recommends it be administered in secondary care to adults with advanced liver fibrosis irrespective of whether or not they have diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1s) are at least as effective as pioglitazone and Vitamin E and significantly reduce steatosis, ballooning necrosis, lobular inflammation, and fibrosis according to a 2023 systematic review. Dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonists appear to be effective treatments; tirzepatide was more effective than placebo for resolution of MASH without worsening of fibrosis in patients with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis when given once-weekly for 52 weeks, while survodutide decreased liver fat content and improved fibrosis compared to placebo, although with more frequent adverse effects of nausea, diarrhea, and vomiting SGLT-2 inhibitors have also found success in some clinical trials, and proved more beneficial than GLP-1 agonists in the only head-to-head-trial completed as of 2024. Statin medications appear to improve liver histology and markers of liver biochemistry in people with MASLD. Since people with NAFLD are at a higher risk of cardiovascular disease, statin treatment is indicated. People with NAFLD are not at higher risk for serious liver injury from statins, according to AASLD and EASL. However, even if statins are safe to use in people with NASH cirrhosis, the AASLD suggests avoiding them in people with decompensated cirrhosis. Guidelines recommend statins to treat dyslipidemia for people with MASLD. According to NICE guidelines, statins can continue unless liver enzyme levels double within three months of starting statins. Treatment with pentoxifylline is not recommended. Omega-3 fatty acids may reduce liver fat and improve blood lipid profile but do not seem to improve liver histology (fibrosis, cirrhosis, cancer). The NICE does not recommend omega-3 fatty acid supplementation since randomized trials were inconclusive. Previous systematic reviews found that omega-3 fatty acid supplementation in those with NAFLD/NASH using doses of one gram daily or more (median dose four grams/day with median treatment duration six months) has been associated with improvements in liver fat. According to AASLD guidelines, "omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia for patients with NAFLD". Resmetirom (Rezdiffra) was approved for medical use in the United States in March 2024 for the treatment of noncirrhotic nonalcoholic steatohepatitis. Aspirin, 81 mg for 6 months, significantly reduced hepatic fat quantity compared with placebo among 40 randomized participants with MASLD in a 6-month, phase 2, randomized, double-blind clinical trial conducted at a single hospital in Boston, Massachusetts. In July 2024, two recent papers explore the metabolic effects of GLP-1 receptor agonists can be enhanced by combining them with other incretin hormones or molecules affecting complementary pathways. Two phase 2 trials reported by Loomba et al. and Sanyal et al. examined these enhanced treatments. Tirzepatide, which combines a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide receptor agonist, has synergistic effects on appetite, food intake, and metabolic function. Similarly, survodutide, a dual agonist of GLP-1 and glucagon receptors, promotes fat oxidation and reduces lipid synthesis in liver cells through its action on glucagon receptors. === Surgery === Bariatric surgery is an effective method for obese and diabetic individuals with MASLD to induce weight loss and reduce or resolve NASH inflammation, including fibrosis, and improve longevity. For the AASLD, bariatric surgery can be considered only for NASH on a case-by-case basis by an experienced bariatric surgery program. Indeed, some individuals might develop new or worsened features of MASLD. About 92% of people with MASLD saw an improvement in steatosis and 70% a complete resolution after bariatric surgery. A preoperative diet such as a low-calorie diet or a very-low-calorie diet is usually recommended to reduce liver volume by 16–20%. Preoperative weight loss is the only factor associated with postoperative weight loss. Preoperative weight loss can reduce operative time and hospital stay, although there is insufficient evidence whether preoperative weight loss reduces long-term morbidity or complications. Weight loss and decreases in liver size may be independent of the amount of calorie restriction. The APWG on MASLD recommends bariatric surgery as a treatment option for those with class II obesity (BMI >32.5 kg/m2 for Asians, 35 kg/m2 for Caucasians). They consider its effects on improving liver-related complications as unproven yet, but it effectively increases longevity by improving cardiovascular factors. Surgery carries more risks for individuals with NASH cirrhosis, with a review estimating overall morbidity to be 21%. For people with MASLD who have undifferentiated cirrhosis, the APWG recommends an investigation to determine the cause of the cirrhosis as well as the person's liver function and whether they have portal hypertension. === Screening === Cardiovascular system screening is considered mandatory by the EASL, as MASLD outcomes often result in cardiovascular complications, which can manifest as subclinical atherosclerosis, the cause of the majority of MASLD-related deaths. People with MASLD are at high risk for cardiovascular morbidity and mortality, and "aggressive modification of cardiovascular disease risk factors is warranted in all patients" according to AASLD. The AASLD further recommends for people with a cirrhotic NASH to be systematically screened for gastric and esophageal varices and liver cancer. They do not recommend routine liver biopsies and screening for liver cancer for non-cirrhotic people with NASH, but such screening sometimes occurs on a case-by-case basis. Also, people with MASLD may be considered for screening for hepatocellular carcinoma (liver cancer) and gastroesophageal varices. The NICE advises regular screening of NAFLD for advanced liver fibrosis every three years to adults and every two years for children using the enhanced liver fibrosis (ELF) blood test. Follow-up is recommended for people with obesity and insulin resistance using the homeostasis model assessment of insulin resistance (HOMA-IR). People with NASH with fibrosis and hypertension merit closer monitoring as there is a higher risk of disease progression. === Transplantation === MASLD is the second most common indication for liver transplantation in the US and Europe as of 2017. For people with NASH and end-stage liver disease, liver failure, or liver cancer, liver transplantation is an accepted procedure according to the EASL. People with NASH cirrhosis NASH who are being considered for a liver transplant warrant systematic evaluation for cardiovascular diseases (whether the symptoms are apparent or not). The overall survival is comparable to transplantation following other diseases. People with NASH cirrhosis who undergo liver transplantation are more likely to die post-transplant because of cardiovascular disease or chronic kidney disease. These people with NASH are often older and are thus more prone to these complications. For these reasons and others, individuals with morbid obesity (BMI ≥ 40 kg/m2) and NASH with cirrhosis may be considered unfit for liver transplantation until they follow lifestyle modifications to reduce bodyweight. Diabetic people with poor glycemic control are at similar risks, and optimal glycemic control is essential before attempting transplantation. The Asia Pacific Working Group guidelines recommend healthcare providers discuss lifestyle modifications before and after transplantation to reduce potential surgery risks and to assist with MASLD management after the transplant. Simultaneous bariatric surgery and liver transplantation were performed in exceptional circumstances. After transplantation, liver biopsy is the best method to monitor the evolution of post-transplant fibrosis, with significant fibrosis or portal hypertension one year after transplantation predicting rapid progression and graft loss and indicating the need for urgent intervention. == Prognosis == The average progression rate from one stage of liver fibrosis to the next in those with MASH is estimated to be seven years. The course of progression varies with different clinical manifestations among individuals. Fibrosis in those with MASH progressed more rapidly than in those with MASLD. The risk of cirrhosis, liver cancer, liver specific death and overall death is higher in those with MASH as compared to MASLD. All cause mortality in those with MASH is 25.5 deaths per 1000 person years, and liver specific mortality is 11.7 deaths per 1000 person years. In one study that examined people over 15 years, 11% of those with MASH developed cirrhosis as compared to less than 1% of people with MASLD. Other estimates have shown that MASLD and MASH were found to worsen with cirrhosis in respectively 2–3% and 15–20% of the people over a 10–20 year period. Obesity predicts a worse long-term outcome than for lean individuals. In the Asia-Pacific region, about 25% of MASLD cases progress to MASH under three years, but only a low proportion (3.7%) develop advanced liver fibrosis. An international study showed that people with MASLD with advanced fibrosis had a 10-year survival rate of 81.5%. MASLD is a risk factor for fibrosis, hypertension, chronic kidney disease, atrial fibrillation, myocardial infarction, ischemic stroke, and death from cardiovascular causes based on very-low to low-quality evidence from observational studies. Although MASLD can cause cirrhosis, liver failure and liver cancer, most deaths among people with MASLD are attributable to cardiovascular disease. According to a meta-analysis of 34,000 people with MASLD over seven years, these individuals have a 65% increased risk of developing fatal or nonfatal cardiovascular events when compared to those without MASLD. MASLD and MASH increase the risk of liver cancer. Cirrhosis and liver cancer induced by MASLD or MASH were the second cause of liver transplantation in the US in 2017, with MASLD or MASH expected to overtake alcohol related liver disease as the most common indication for a liver transplantation in the future. People with MASH cirrhosis have an increased risk of liver cancer. The rate of liver cancer associated with MASH increased fourfold between 2002 and 2012 in the US, which is more than any other cause of liver cancer. MASLD constitutes the third most common risk factor for liver cancer. Cirrhosis is found in only about 50% of people with MASLD and with liver cancer, so liver cancer may occur without cirrhosis being present. MASLD is a precursor of metabolic syndrome, although a bidirectional influence is possible. The presence and stage of fibrosis are the strongest prognostic factors for liver-related events and mortality, in particular for MASLD. == Epidemiology == MASLD incidence is rapidly rising, along with obesity and diabetes, and has become the most common cause of liver disease in developed countries, for adults, teenagers, and children. The percentage of people with MASLD ranges from 9 to 36.9% in different parts of the world. Approximately 20% of the United States and 25% of the Asia-Pacific populations have non-alcoholic fatty liver. Similar prevalence can be found in Europe, although less data is available. MASLD is the most common in the Middle East (32%) and South America (30%), while Africa has the lowest rates (13%). Compared to the 2000s, NAFL and NASH respectively increased 2-fold and 2.5-fold in the 2010s in the USA. MASLD and NASH are more prevalent in Hispanics - which can be attributed to high rates of obesity and type 2 diabetes in Hispanic populations, intermediate in Whites, and lowest in Blacks. NAFLD was observed to be twice as prevalent in men as women. For severely obese individuals, the prevalence of MASLD rises over 90%, and for those with diabetes, over 60%, and up to 20% for normal-weight people. MASLD is present in 65% to 90% of people who had bariatric surgery, and up to 75% of them have MASH. Ultrasonography and proton NMR spectroscopy studies suggest about 25% of the population seems to be affected by MASLD or MASH. Although the disease is commonly associated with obesity, a significant proportion of those affected are normal weight or lean. Lean MASLD affects between 10 and 20% of Americans and Europeans, and approximately 25% of Asians, although some countries have a higher incidence (e.g., India has a very high proportion of lean MASLD and almost no obese MASLD). PNPLA3 may be relevant for the progression of MASLD in lean people. Thus, people with MASLD deserve consideration for treatment regardless of the presence or absence of obesity. In children ages 1 to 19, the prevalence was found to be approximately 8% in the general population up to 34% in studies with data from child obesity clinics. The majority of cryptogenic cirrhosis is believed to be due to MASH. NAFLD prevalence is expected to increase steadily, from 25% in 2018 to a projected 33.5% of people with MASLD globally in 2030, and from 20% to a projected 27% of those with MASLD will progress to MASH. == History == The first acknowledged case of obesity-related non-alcoholic fatty liver was observed in 1952 by Samuel Zelman. Zelman started investigating after observing a fatty liver in a hospital employee who drank more than twenty bottles of Coca-Cola a day. He then went on to design a trial for a year and a half on 20 obese people who were not alcoholic, finding that about half of them had substantially fatty livers. Fatty liver was, however, linked to diabetes since at least 1784 — an observation picked up again in the 1930s. Studies in experimental animals implicated choline inadequacy in the 1920s and excess sugar consumption in 1949. The name "non-alcoholic steatohepatitis" (NASH) was later defined in 1980 by Jurgen Ludwig and his colleagues from the Mayo Clinic to raise awareness of the existence of this pathology, as similar reports previously were dismissed as "patients' lies". This paper was mostly ignored at the time but eventually came to be seen as a landmark paper, and starting in the mid-1990s, the condition began to be intensively studied, with a series of international meetings being held on the topic since 1998. The broader NAFLD term started to be used around 2002. Diagnostic criteria began to be worked out, and in 2005 the Pathology Committee of the NIH NASH Clinical Research Network proposed the NAS scoring system. == Society and culture == === Political recommendations === EASL recommends Europe's public health authorities to "restrict advertising and marketing of sugar-sweetened beverages and industrially processed foods high in saturated fat, sugar, and salt", as well as "fiscal measures to discourage the consumption of sugar-sweetened beverages and legislation to ensure that the food industry improves labeling and the composition of processed foods", as well as "public awareness campaigns on liver disease, highlighting that it is not only linked to excessive consumption of alcohol". === Media === In France, the French syndicate of non-alcoholic beverages "Boissons Rafraîchissantes de France" (that included soft drink producers such as Coca-Cola France, Orangina, PepsiCo France) was denounced by the French journal fr:Canard Enchainé for misleading consumers using a communication on their website titled "Better understanding the NASH pathology", explaining that "NASH pathology is sometimes called the soda illness by language abuse or an unfortunate semantic shortcut, as it is not directly linked to the consumption of non-alcoholic beverages". This page and others on the same website, such as one titled "Say no to disinformation," were since then removed. == Children == Pediatric MASLD was first reported in 1983. It is the most common chronic liver disease among children and adolescents since at least 2007, affecting 10 to 20% of them in the US in 2016. MASLD is associated with metabolic syndrome, which is a cluster of risk factors that contribute to the development of cardiovascular disease and type 2 diabetes mellitus. Studies have demonstrated that abdominal obesity and insulin resistance, in particular, are significant contributors to the development of NAFLD. Coexisting liver diseases, such as hepatitis C and cardiovascular diseases such as atherosclerosis, are also associated with an increased risk of NAFLD. Some children were diagnosed as early as two years old, with a mean age of diagnosis between 11 and 13 years old. The mean age is usually above 10 years, as children can also report non-specific symptoms and are thus difficult to diagnose for MASLD. Boys are more likely to be diagnosed with MASLD than girls. Overweight, or even weight gain, in childhood and adolescence, is associated with an increased risk of MASLD later in life, with adult MASLD predicted in a 31-year follow-up study by risk factors during childhood including BMI, plasma insulin levels, male sex, genetic background (PNPLA3 and TM6SF2 variants) and low birth weight, an emerging risk factor for adulthood MASLD. In a study, simple steatosis was present in up to 45% in children with a clinical suspicion of MASLD. Children with simple steatosis have a worse prognosis than adults, with significantly more of them progressing from NAFLD to NASH compared to adults. Indeed, 17-25% of children with MASLD develop MASH in general, and up to 83% for children with severe obesity (versus 29% for adults), further suggesting that hepatic fibrosis seems to follow a more aggressive clinical course in children compared to adults. Early diagnosis of MASLD in children may help prevent the development of liver disease during adulthood. This is challenging as most children with MASLD are asymptomatic, with only 42-59% showing abdominal pain. Other symptoms might be present, such as right upper quadrant pain or acanthosis nigricans, the latter of which is often present in children with NASH. An enlarged liver occurs in 30–40% of children with NAFLD. The AASLD recommends a diagnostic liver biopsy in children when the diagnosis is unclear or before starting a potentially hepatotoxic medical therapy. The EASL suggests using fibrosis tests such as elastography, acoustic radiation force impulse imaging, and serum biomarkers to reduce the number of biopsies. In follow up, NICE guidelines recommend that healthcare providers offer children regular MASLD screening for advanced liver fibrosis every two years using the enhanced liver fibrosis (ELF) blood test. Several studies also suggest magnetic resonance elastography as an alternative to the less reliable ultrasonography. Intensive lifestyle modifications, including physical activity and dietary changes, are the first line of treatment according to AASLD and EASL as it improves the liver histology and aminotransferase levels. In terms of pharmacological treatment, the AASLD and EASL do not recommend metformin, but vitamin E may improve liver health for some children. The NICE advises the use of vitamin E for children with advanced liver fibrosis, whether they have diabetes or not. The only treatment shown to be effective in childhood MASLD is weight loss. Some evidence indicates that maternal undernutrition or overnutrition increases a child's susceptibility to NASH and hastens its progression. == Research == === Diagnosis and biomarkers === Since a MASLD diagnosis based on a liver biopsy is invasive and makes it difficult to estimate epidemiology, it is a high research priority to find accurate, inexpensive, and noninvasive methods of diagnosing and monitoring MASLD disease and its progression. The search for these biomarkers of MASLD, NAFL, and NASH involves lipidomics, medical imaging, proteomics, blood tests, and scoring systems. According to a review, proton density fat fraction estimation by magnetic resonance imaging (MRI-PDFF) may be considered the most accurate and even gold standard test to quantify hepatic steatosis. They recommend ultrasound-based transient elastography to accurately diagnose both fibrosis and cirrhosis in a routine clinical setting, with more objectivity than ultrasonography but with lower accuracy than magnetic resonance elastography; and plasma cytokeratin 18 (CK18) fragment levels to be a moderately accurate biomarker of steatohepatitis. However, transient elastography can fail for people with pre-hepatic portal hypertension. === Medication development === A variety of medications with different mechanisms of action have been tested in clinical trials. Clinical trials can be separated into four main targets believed to reduce the progression of the disease or reverse it: Improving metabolism (improving insulin sensitivity, inhibiting de novo lipogenesis, or increasing fatty acid oxidation). Metabolic modulators tested in NASH include glucagon-like peptide-1 receptor agonists (GLP-1 agonists), GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) or glucagon co-agonists and thyromimetics. Some of these drugs may treat NAFLD by significantly reducing body weight. Reducing inflammation, for example reducing oxidative stress and hepatocyte death. These drugs, such as chemokine antagonists, anti-apoptotics, vascular adhesion protein-1 inhibitors, and c-Jun N-terminal kinase inhibitors, have not shown benefit. "Gut-liver axis targets" that either change a person's microbiome, or act on bile acids Anti-fibrotic drugs, such as fibroblast growth factor analogues, which have largely not met their endpoints Other treatments such as farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, and ASK1 (apoptosis signal-regulating kinase 1) inhibitors may improve NAFLD by multiple mechanisms simultaneously. Drugs in phase III trials as of 2024 are the thyromimetic resmetirom, lanifibranor (a pan-PPAR agonist), and the GLP-1 agonist semaglutide. == Notes == == References == == External links == Nonalcoholic Fatty Liver Disease (NAFLD) & NASH National Institutes of Health (NIH)	Wikipedia/Metabolic_dysfunction–associated_steatotic_liver_disease
Whipple's disease is a rare systemic infectious disease caused by the bacterium Tropheryma whipplei. First described by George Hoyt Whipple in 1907 and commonly considered as a gastrointestinal disorder, Whipple's disease primarily causes malabsorption, but may affect any part of the human body, including the heart, brain, joints, skin, lungs and the eyes. Weight loss, diarrhea, joint pain, and arthritis are common presenting symptoms, but the presentation can be highly variable in certain individuals, and about 15% of patients do not have the standard signs and symptoms. Whipple's disease is significantly more common in men, with 87% of patients diagnosed being male. When recognized and treated, Whipple's disease can usually be cured with long-term antibiotic therapy, but if the disease is left undiagnosed or untreated, it can ultimately be fatal. == Signs and symptoms == The most common symptoms are diarrhea, abdominal pain, weight loss, and joint pains. The joint pains may be due to migratory nondeforming arthritis, which may occur many years before any digestive-tract symptoms develop; they tend to involve the large joints, but can occur in any pattern and tend not to damage the joint surface to the point that the joint becomes deformed. Fever and chills occur in a small proportion of people. In its more advanced form, malabsorption (insufficient absorption of nutrients from the diet) leads to wasting and the enlargement of lymph nodes in the abdomen. Neurological symptoms (discussed below) are more common in those with the severe form of the abdominal disease. Chronic malabsorptive diarrhea leads to the poor absorption of fat, causing steatorrhea (fatty, offensive-smelling stool), flatulence, and abdominal distension. Protein-losing enteropathy may also occur, causing depletion of albumin, a blood protein, which may lead to peripheral edema caused by the lowered oncotic pressures. Hyperpigmentation of the skin occurs in almost half; some also have skin nodules. Various eye problems, such as uveitis, may occur; this is typically associated with deteriorating vision and pain in the affected eye. Endocarditis (infection of the heart valve) has been reported in a small number of cases, sometimes in people with no other symptoms of Whipple's disease; this is typically noticed as breathlessness and leg swelling due to fluid accumulation as the heart is unable to pump fluid through the body. Of those affected by Whipple's disease, 10–40% have problems related to the involvement of the brain; the symptoms relate to the part of the brain that is affected. The most common problems are dementia, memory loss, confusion, and decreased level of consciousness. Eye-movement disturbances and myorhythmia (rapidly repetitive movements of the muscles) of the face, together referred to as oculomasticatory myorhythmia, are highly characteristic for Whipple's disease. Weakness and poor coordination of part of the body, headaches, seizures, and a number of more uncommon neurological features are present in some cases. == Pathogenesis == T. whipplei is one of the Actinomycetes, and is a distant relative of the Mycobacterium avium complex, explaining in part why Whipple's disease is similar to the diseases caused by MAC bacteria. The disease is common in farmers and those exposed to soil and animals, suggesting that the infection is acquired from these sources. Individuals who are most susceptible to the disease are those with decreased ability to perform intracellular degradation of ingested pathogens or particles, particularly within macrophages. Several studies indicate that defective T-lymphocyte (particularly TH1 population) function may be an important predisposing factor for the disease. In particular, circulating cells which are CD11b (also known as integrin alpha) expressive are reduced in susceptible individuals. CD11b has a vital role in activation of macrophages to destroy intracellularly ingested T. whipplei bacteria. == Diagnosis == Common clinical signs and symptoms of Whipple's disease include diarrhea, steatorrhea, abdominal pain, weight loss, migratory arthropathy, fever, and neurological symptoms. Weight loss and diarrhea are the most common symptoms that lead to identification of the process, but may be preceded by chronic, unexplained, relapsing episodes of nondestructive seronegative arthritis, often of large joints. Endoscopy of the duodenum and jejunum can reveal pale yellow shaggy mucosa with erythematous eroded patches in patients with classic intestinal Whipple's disease, and small bowel X-rays may show some thickened folds. Other pathological findings may include enlarged mesenteric lymph nodes, hypercellularity of lamina propria with "foamy macrophages", and a concurrent decreased number of lymphocytes and plasma cells, per high power field view of the biopsy. Diagnosis is made by biopsy, usually by duodenal endoscopy, which reveals PAS-positive macrophages in the lamina propria containing non acid-fast, Gram-positive bacilli. Immunohistochemical staining for antibodies against T. whipplei has been used to detect the organism in a variety of tissues, and a polymerase chain reaction-based assay is also available, which can be confirmatory if performed on blood, vitreous fluid, synovial fluid, heart valves, or cerebrospinal fluid. PCR of saliva, gastric or intestinal fluid, and stool specimens is highly sensitive, but not specific enough, indicating that healthy individuals can also harbor the causative bacterium without the manifestation of Whipple's disease, but that a negative PCR is most likely indicative of a healthy individual. == Treatment == Treatment is with penicillin, ampicillin, tetracycline, or co-trimoxazole for one to two years. Any treatment lasting less than a year has a relapse rate around 40%. Expert opinion as of 2007 is that Whipple's disease should be treated with doxycycline with hydroxychloroquine for 12 to 18 months. Hydroxychloroquine increases antibiotic and bactericides activity against the replication of the bacteria in acidic vacuoles of macrophages by increasing the macrophage intraphagosomal pH. Sulfonamides (sulfadiazine or sulfamethoxazole) may be added for treatment of neurological symptoms. == Epidemiology == The disease is regarded as extremely rare, with an incidence (new number of cases per year) of one case per million people. The patients are predominantly male, with various studies and sources typically reporting a ratio between 2:1 and 3:1 of male to female patients. In the United States and some other countries, it occurs predominantly in those of Caucasian ethnicity, suggesting a possible genetic predisposition in that population. T. whipplei appears to be an environmental organism that is commonly present in the gastrointestinal tract, but remains asymptomatic. Several lines of evidence suggest that some defect—inherited or acquired—in immunity is required for it to become pathogenic. The possible immunological defect may be specific for T. whipplei, since the disease is not associated with a substantially increased risk of other infections. The disease is usually diagnosed in middle age (median 49 years). Studies from Germany have shown that age at diagnosis has been rising since the 1960s. == History == Whipple described the disease in 1907 in a paper in the now-defunct Bulletin of Johns Hopkins Hospital. The patient was a 36-year-old medical missionary. Whipple referred to the disease as "intestinal lipodystrophy". It was long presumed to be an infectious disease, but the causative organism was only fully identified in 1992. In 2003, doctors from Johns Hopkins Hospital, together with the French microbiologist Didier Raoult applied novel diagnostic methods to stored tissue samples from Whipple's original patient, and demonstrated T. whipplei in these tissues. == See also == Tropheryma whipplei == Notes == == References == == External links == "Whipple's Disease". National Digestive Disease Information Clearinghouse NDDIC.	Wikipedia/Whipple's_disease
Milk is a white liquid food produced by the mammary glands of lactating mammals. It is the primary source of nutrition for young mammals (including breastfed human infants) before they are able to digest solid food. Milk contains many nutrients, including calcium and protein, as well as lactose and saturated fat; the enzyme lactase is needed to break down lactose. Immune factors and immune-modulating components in milk contribute to milk immunity. The first milk, which is called colostrum, contains antibodies and immune-modulating components that strengthen the immune system against many diseases. As an agricultural product, milk is collected from farm animals, mostly cattle, on a dairy. It is used by humans as a drink and as the base ingredient for dairy products. The US CDC recommends that children over the age of 12 months (the minimum age to stop giving breast milk or formula) should have two servings of milk products a day, and more than six billion people worldwide consume milk and milk products. The ability for adult humans to digest milk relies on lactase persistence, so lactose intolerant individuals have trouble digesting lactose. In 2011, dairy farms produced around 730 million tonnes (800 million short tons) of milk from 260 million dairy cows. India is the world's largest producer of milk and the leading exporter of skimmed milk powder. New Zealand, Germany, and the Netherlands are the largest exporters of milk products. Between 750 and 900 million people live in dairy-farming households. == Etymology and terminology == The term milk comes from "Old English meoluc (West Saxon), milc (Anglian), from Proto-Germanic *meluks "milk" (source also of Old Norse mjolk, Old Frisian melok, Old Saxon miluk, Dutch melk, Old High German miluh, German Milch, Gothic miluks)". Since 1961, the term milk has been defined under Codex Alimentarius standards as "the normal mammary secretion of milking animals obtained from one or more milkings without either addition to it or extraction from it, intended for consumption as liquid milk or for further processing." The term dairy refers to animal milk and animal milk production. == Types of consumption == There are two distinct categories of milk consumption: all infant mammals drink milk directly from their mothers' bodies, and it is their primary source of nutrition; and humans obtain milk from other mammals for consumption by humans of all ages, as one component of a varied diet. === Nutrition for infant mammals === In almost all mammals, milk is fed to infants through breastfeeding, either directly or by expressing the milk to be stored and consumed later. The early milk from mammals is called colostrum. Colostrum contains antibodies that provide protection to the newborn baby as well as nutrients and growth factors. The makeup of the colostrum and the period of secretion varies from species to species. For humans, the World Health Organization recommends exclusive breastfeeding for six months and breastfeeding in addition to other food for up to two years of age or more. In some cultures it is common to breastfeed children for three to five years, and the period may be longer. Fresh goats' milk is sometimes substituted for breast milk, which introduces the risk of the child developing electrolyte imbalances, metabolic acidosis, megaloblastic anemia, and a host of allergic reactions. === Food product for humans === In many cultures, especially in the West, humans continue to consume milk beyond infancy, using the milk of other mammals (especially cattle, goats and sheep) as a food product. Initially, the ability to digest milk was limited to children as adults did not produce lactase, an enzyme necessary for digesting the lactose in milk. People therefore converted milk to curd, cheese, and other products to reduce the levels of lactose. Thousands of years ago, a chance mutation spread in human populations in northwestern Europe that enabled the production of lactase in adulthood. This mutation allowed milk to be used as a new source of nutrition which could sustain populations when other food sources failed. Milk is processed into a variety of products such as cream, butter, yogurt, kefir, ice cream and cheese. Modern industrial processes use milk to produce casein, whey protein, lactose, condensed milk, powdered milk, and many other food-additives and industrial products. Whole milk, butter, and cream have high levels of saturated fat. The sugar lactose is found only in milk, and possibly in forsythia flowers and a few tropical shrubs. Lactase, the enzyme needed to digest lactose, reaches its highest levels in the human small intestine immediately after birth, and then begins a slow decline unless milk is consumed regularly. Those groups who continue to tolerate milk have often exercised great creativity in using the milk of domesticated ungulates, not only cattle, but also sheep, goats, yaks, water buffalo, horses, reindeer and camels. India is the largest producer and consumer of cattle milk and buffalo milk in the world. == History == Humans first learned to consume the milk of other mammals regularly following the domestication of animals during the Neolithic Revolution or the development of agriculture. This development occurred independently in several global locations from as early as 9000–7000 BC in Mesopotamia to 3500–3000 BC in the Americas. People first domesticated the most important dairy animals – cattle, sheep and goats – in Southwest Asia, although domestic cattle had been independently derived from wild aurochs populations several times since. Initially animals were kept for meat, and archaeologist Andrew Sherratt has suggested that dairying, along with the exploitation of domestic animals for hair and labor, began much later in a separate secondary products revolution in the fourth millennium BC. Sherratt's model is not supported by recent findings, based on the analysis of lipid residue in prehistoric pottery, that shows that dairying was practiced in the early phases of agriculture in Southwest Asia, by at least the seventh millennium BC. From Southwest Asia domestic dairy animals spread to Europe (beginning around 7000 BC but did not reach Britain and Scandinavia until after 4000 BC), and South Asia (7000–5500 BC). The first farmers in central Europe and Britain milked their animals. Pastoral and pastoral nomadic economies, which rely predominantly or exclusively on domestic animals and their products rather than crop farming, were developed as European farmers moved into the Pontic–Caspian steppe in the fourth millennium BC, and subsequently spread across much of the Eurasian steppe. Sheep and goats were introduced to Africa from Southwest Asia, but African cattle may have been independently domesticated around 7000–6000 BC. Camels, domesticated in central Arabia in the fourth millennium BC, have also been used as dairy animals in North Africa and the Arabian Peninsula. The earliest Egyptian records of burn treatments describe burn dressings using milk from mothers of male babies. In the rest of the world (i.e., East and Southeast Asia, the Americas and Australia), milk and dairy products were historically not a large part of the diet, either because they remained populated by hunter-gatherers who did not keep animals or the local agricultural economies did not include domesticated dairy species. Milk consumption became common in these regions comparatively recently, as a consequence of European colonialism and political domination over much of the world in the last 500 years. In the Middle Ages, milk was called the "virtuous white liquor" because alcoholic beverages were safer to consume than the water generally available. Incorrectly thought to be blood diverted from the womb to the breast, it was also known as "white blood", and treated like blood for religious dietary purposes and in humoral theory. James Rosier's record of the 1605 voyage made by George Weymouth to New England reported that the Wabanaki people Weymouth captured in Maine milked "Rain-Deere and Fallo-Deere." But Journalist Avery Yale Kamila and food historians said Rosier "misinterpreted the evidence." Historians report the Wabanaki did not domesticate deer. The tribes of the northern woodlands have historically been making nut milk. Cows were imported to New England in 1624. === Industrialization === The growth in urban population, coupled with the expansion of the railway network in the mid-19th century, brought about a revolution in milk production and supply. Individual railway firms began transporting milk from rural areas to London from the 1840s and 1850s. Possibly the first such instance was in 1846, when St Thomas's Hospital in Southwark contracted with milk suppliers outside London to ship milk by rail. The Great Western Railway was an early and enthusiastic adopter, and began to transport milk into London from Maidenhead in 1860, despite much criticism. By 1900, the company was transporting over 25 million imperial gallons (110 million litres; 30 million US gallons) annually. The milk trade grew slowly through the 1860s, but went through a period of extensive, structural change in the 1870s and 1880s. Urban demand began to grow, as consumer purchasing power increased and milk became regarded as a required daily commodity. Over the last three decades of the 19th century, demand for milk in most parts of the country doubled or, in some cases, tripled. Legislation in 1875 made the adulteration of milk illegal – This combined with a marketing campaign to change the image of milk. The proportion of rural imports by rail as a percentage of total milk consumption in London grew from under 5% in the 1860s to over 96% by the early 20th century. By that point, the supply system for milk was the most highly organized and integrated of any food product. Milk was analyzed for infection with tuberculosis. In 1907 180 samples were tested in Birmingham and 13.3% were found to be infected. The first glass bottle packaging for milk was used in the 1870s. The first company to do so may have been the New York Dairy Company in 1877. The Express Dairy Company in England began glass bottle production in 1880. In 1884, Hervey Thatcher, an American inventor from New York, invented a glass milk bottle, called "Thatcher's Common Sense Milk Jar," which was sealed with a waxed paper disk. In 1932, plastic-coated paper milk cartons were introduced commercially. In 1863, French chemist and biologist Louis Pasteur invented pasteurization, a method of killing harmful bacteria in beverages and food products. He developed this method while on summer vacation in Arbois, to remedy the frequent acidity of the local wines. He found out experimentally that it is sufficient to heat a young wine to only about 50–60 °C (122–140 °F) for a brief time to kill the microbes, and that the wine could be nevertheless properly aged without sacrificing the final quality. In honor of Pasteur, the process became known as "pasteurization". Pasteurization was originally used as a way of preventing wine and beer from souring. Commercial pasteurizing equipment was produced in Germany in the 1880s, and producers adopted the process in Copenhagen and Stockholm by 1885. == Sources == All mammal species have females who can produce milk for some time after giving birth. Cow milk dominates the amount of milk produced. In 2011, FAO estimates 85% of all milk worldwide was produced from cows. Human milk is not produced or distributed industrially or commercially; however, human milk banks collect donated human breastmilk and redistribute it to infants who may benefit from human milk for various reasons (premature neonates, babies with allergies, metabolic diseases, etc.) but who cannot breastfeed. Actual inability to produce enough milk is rare, with studies showing that mothers from malnourished regions still produce amounts of milk of similar quality to that of mothers in developed countries. There are many reasons a mother may not produce enough breast milk. The amount of milk produced depends on how often the mother is nursing and/or pumping: the more the mother nurses her baby or pumps, the more milk is produced. In the Western world, cow's milk is produced on an industrial scale and is, by far, the most commonly consumed form of milk. Commercial dairy farming using automated milking equipment produces the vast majority of milk in developed countries. Dairy cattle, such as the Holstein, have been bred selectively for increased milk production. About 90% of the dairy cows in the United States and 85% in Great Britain are Holsteins. Other dairy cows in the United States include Ayrshire, Brown Swiss, Guernsey, Jersey and Milking Shorthorn (Dairy Shorthorn). === Other animal-based sources === Aside from cattle, many kinds of livestock provide milk used by humans for dairy products. These animals include water buffalo, goat, sheep, camel, donkey, horse, reindeer and yak. The first four respectively produced about 11%, 2%, 1.4% and 0.2% of all milk worldwide in 2011. In Russia and Sweden, small moose dairies also exist. According to the US National Bison Association, American bison (also called American buffalo) are not milked commercially; however, various sources report cows resulting from cross-breeding bison and domestic cattle are good milk producers, and have been used both during the European settlement of North America and during the development of commercial Beefalo in the 1970s and 1980s. Swine are almost never milked, even though their milk is similar to cow's milk and perfectly suitable for human consumption. The main reasons for this are that milking a sow's numerous small teats is very cumbersome, and that sows cannot store their milk as cows can. A few pig farms do sell pig cheese as a novelty item; these cheeses are exceedingly expensive. == Production worldwide == In 2012, the largest producer of milk and milk products was India, followed by the United States of America, China, Pakistan and Brazil. All 28 European Union members together produced 153.8 million tonnes (169.5 million short tons) of milk in 2013, the largest by any politico-economic union. Increasing affluence in developing countries, as well as increased promotion of milk and milk products, has led to a rise in milk consumption in developing countries in recent years. In turn, the opportunities presented by these growing markets have attracted investments by multinational dairy firms. Nevertheless, in many countries production remains on a small scale and presents significant opportunities for diversification of income sources by small farms. Local milk collection centers, where milk is collected and chilled prior to being transferred to urban dairies, are a good example of where farmers have been able to work on a cooperative basis, particularly in countries such as India. === Production yields === FAO reports Israel dairy farms are the most productive in the world, with a yield of 12,546 kilograms (27,659 lb) milk per cow per year. This survey over 2001 and 2007 was conducted by ICAR (International Committee for Animal Recording) across 17 developed countries. The survey found that the average herd size in these developed countries increased from 74 to 99 cows per herd between 2001 and 2007. A dairy farm had an average of 19 cows per herd in Norway, and 337 in New Zealand. Annual milk production in the same period increased from 7,726 to 8,550 kg (17,033 to 18,850 lb) per cow in these developed countries. The lowest average production was in New Zealand at 3,974 kg (8,761 lb) per cow. The milk yield per cow depended on production systems, nutrition of the cows, and only to a minor extent different genetic potential of the animals. What the cow ate made the most impact on the production obtained. New Zealand cows with the lowest yield per year grazed all year, in contrast to Israel with the highest yield where the cows ate in barns with an energy-rich mixed diet. The milk yield per cow in the United States was 9,954 kg (21,945 lb) per year in 2010. In contrast, the milk yields per cow in India and China – the second and third largest producers – were respectively 1,154 kg (2,544 lb) and 2,282 kg (5,031 lb) per year. The IPCC Sixth Assessment Report mentions the possibility that the already recorded stagnation of dairy production in both China and West Africa can be attributed to persistent increases in heat stress caused by climate change.: 747 This is a plausible hypothesis, because even mild heat stress can reduce daily yields: research in Sweden found that average daily temperatures of 20–25 °C (68–77 °F) reduce daily milk yield per cow by 0.2 kg, with the loss reaching 0.54 kg for 25–30 °C (77–86 °F). Research in a humid tropical climate describes a more linear relationship, with every unit of heat stress reducing yield by 2.13%. In the intensive farming systems, daily milk yield per cow declines by 1.8 kg during severe heat stress. In organic farming systems, the effect of heat stress on milk yields is limited, but milk quality suffers substantially, with lower fat and protein content. In China, daily milk production per cow is already lower than the average by between 0.7 and 4 kg in July (the hottest month of the year), and by 2070, it may decline by up to 50% (or 7.2 kg) due to climate change. Heatwaves can also reduce milk yield, with particularly acute impacts if the heatwave lasts for four or more days, as at that point the cow's thermoregulation capacity is usually exhausted, and its core body temperature starts to increase. === Price === It was reported in 2007 that with increased worldwide prosperity and the competition of bio-fuel production for feed stocks, both the demand for and the price of milk had substantially increased worldwide. Particularly notable was the rapid increase of consumption of milk in China and the rise of the price of milk in the United States above the government subsidized price. In 2010 the Department of Agriculture predicted farmers would receive an average of $1.35 per US gallon ($0.36/L; $1.62/imp gal) of cow's milk, which is down 30 cents per US gallon (7.9 ¢/L; 36 ¢/imp gal) from 2007 and below the break-even point for many cattle farmers. == Composition == Milk is an emulsion or colloid of butterfat globules within a water-based fluid that contains dissolved carbohydrates and protein aggregates with minerals. Because it is produced as a food source for the young, all of its contents provide benefits for growth. The principal requirements are energy (lipids, lactose, and protein), biosynthesis of non-essential amino acids supplied by proteins (essential amino acids and amino groups), essential fatty acids, vitamins and inorganic elements, and water. === pH === The pH of cow's milk, ranging from 6.7 to 6.9, is similar to other bovines and non-bovine mammals. === Lipids === Full fat milk contains about 33 grams of fat per liter, including about 19 grams of saturated fat, 1.2 grams of omega 6 fatty acids, and 0.75 grams of omega 3 fatty acids per liter. The amount of fat varies for products where (some of) the fat has been removed, such as in skimmed milk. Initially milk fat is secreted in the form of a fat globule surrounded by a membrane. Each fat globule is composed almost entirely of triacylglycerols and is surrounded by a membrane consisting of complex lipids such as phospholipids, along with proteins. These act as emulsifiers which keep the individual globules from coalescing and protect the contents of these globules from various enzymes in the fluid portion of the milk. Although 97–98% of lipids are triacylglycerols, small amounts of di- and monoacylglycerols, free cholesterol and cholesterol esters, free fatty acids, and phospholipids are also present. Unlike protein and carbohydrates, fat composition in milk varies widely due to genetic, lactational, and nutritional factor difference between different species. Fat globules vary in size from less than 0.2 to about 15 micrometers in diameter between different species. Diameter may also vary between animals within a species and at different times within a milking of a single animal. In unhomogenized cow's milk, the fat globules have an average diameter of two to four micrometers and with homogenization, average around 0.4 micrometers. The fat-soluble vitamins A, D, E, and K along with essential fatty acids such as linoleic and linolenic acid are found within the milk fat portion of the milk. === Proteins === Normal bovine milk contains 30–35 grams of protein per liter, of which about 80% is arranged in casein micelles. Total proteins in milk represent 3.2% of its composition (nutrition table). ==== Caseins ==== The largest structures in the fluid portion of the milk are "casein micelles": aggregates of several thousand protein molecules with superficial resemblance to a surfactant micelle, bonded with the help of nanometer-scale particles of calcium phosphate. Each casein micelle is roughly spherical and about a tenth of a micrometer across. There are four different types of casein proteins: αs1-, αs2-, β-, and κ-caseins. Most of the casein proteins are bound into the micelles. There are several competing theories regarding the precise structure of the micelles, but they share one important feature: the outermost layer consists of strands of one type of protein, k-casein, reaching out from the body of the micelle into the surrounding fluid. These kappa-casein molecules all have a negative electrical charge and therefore repel each other, keeping the micelles separated under normal conditions and in a stable colloidal suspension in the water-based surrounding fluid. Milk contains dozens of other types of proteins beside caseins and including enzymes. These other proteins are more water-soluble than caseins and do not form larger structures. Because the proteins remain suspended in whey, remaining when caseins coagulate into curds, they are collectively known as whey proteins. Lactoglobulin is the most common whey protein by a large margin. The ratio of caseins to whey proteins varies greatly between species; for example, it is 82:18 in cows and around 32:68 in humans. === Salts, minerals, and vitamins === Bovine milk contains a variety of cations and anions traditionally referred to as "minerals" or "milk salts". Calcium, phosphate, magnesium, sodium, potassium, citrate, and chloride are all included and they typically occur at concentrations of 5–40 mM. The milk salts strongly interact with casein, most notably calcium phosphate. It is present in excess and often, much greater excess of solubility of solid calcium phosphate. In addition to calcium, milk is a source of many vitamins: Vitamins A, B1, B2, B5 B6, B7, B12, and D. ==== Calcium phosphate structure ==== For many years the most widely accepted theory of the structure of a micelle was that it was composed of spherical casein aggregates, called submicelles, that were held together by calcium phosphate linkages. However, there are two recent models of the casein micelle that refute the distinct micellular structures within the micelle. The first theory, attributed to de Kruif and Holt, proposes that nanoclusters of calcium phosphate and the phosphopeptide fraction of beta-casein are the centerpiece to micellar structure. Specifically in this view unstructured proteins organize around the calcium phosphate, giving rise to their structure, and thus no specific structure is formed. Under the second theory, proposed by Horne, the growth of calcium phosphate nanoclusters begins the process of micelle formation, but is limited by binding phosphopeptide loop regions of the caseins. Once bound, protein-protein interactions are formed and polymerization occurs, in which K-casein is used as an end cap to form micelles with trapped calcium phosphate nanoclusters. Some sources indicate that the trapped calcium phosphate is in the form of Ca9(PO4)6; whereas others say it is similar to the structure of the mineral brushite, CaHPO4·2H2O. === Sugars and carbohydrates === Milk contains several different carbohydrates, including lactose, glucose, galactose, and other oligosaccharides. The lactose gives milk its sweet taste and contributes approximately 40% of the calories in whole cow's milk's. Lactose is a disaccharide composite of two simple sugars, glucose and galactose. Bovine milk averages 4.8% anhydrous lactose, which amounts to about 50% of the total solids of skimmed milk. Levels of lactose are dependent upon the type of milk as other carbohydrates can be present at higher concentrations than lactose in milks. === Miscellaneous contents === Other components found in raw cow's milk are living white blood cells, mammary gland cells, various bacteria, vitamin C, and a large number of active enzymes. === Appearance === Both the fat globules and the smaller casein micelles, which are just large enough to deflect light, contribute to the opaque white color of milk. The fat globules contain some yellow-orange carotene, enough in some breeds (such as Guernsey and Jersey cattle) to impart a golden or "creamy" hue to a glass of milk. The riboflavin in the whey portion of milk has a greenish color, which sometimes can be discerned in skimmed milk or whey products. Fat-free skimmed milk has only the casein micelles to scatter light, and they tend to scatter shorter-wavelength blue light more than they do red, giving skimmed milk a bluish tint. == Processing == In most Western countries, centralized dairy facilities process milk and products obtained from milk, such as cream, butter, and cheese. In the US, these dairies usually are local companies, while in the Southern Hemisphere facilities may be run by large multi-national corporations such as Fonterra. === Pasteurization === Pasteurization is used to kill harmful pathogenic bacteria such as M. paratuberculosis and E. coli 0157:H7 by heating the milk for a short time and then immediately cooling it. Types of pasteurized milk include full cream, reduced fat, skim milk, calcium enriched, flavored, and UHT. The standard high temperature short time (HTST) process of 72 °C (162 °F) for 15 seconds completely kills pathogenic bacteria in milk, rendering it safe to drink for up to three weeks if continually refrigerated. Dairies print best before dates on each container, after which stores remove any unsold milk from their shelves. A side effect of the heating of pasteurization is that some vitamin and mineral content is lost. Soluble calcium and phosphorus decrease by 5%, thiamin and vitamin B12 by 10%, and vitamin C by 20% or greater (even to complete loss). Because losses are small in comparison to the large amount of the two B-vitamins present, milk continues to provide significant amounts of thiamin and vitamin B12. The loss of vitamin C is not nutritionally significant in a well-balanced diet, as milk is not an important dietary source of vitamin C. ==== Filtration ==== Microfiltration is a process that partially replaces pasteurization and produces milk with fewer microorganisms and longer shelf life without a change in the taste of the milk. In this process, cream is separated from the skimmed milk and is pasteurized in the usual way, but the skimmed milk is forced through ceramic microfilters that trap 99.9% of microorganisms in the milk (as compared to 99.999% killing of microorganisms in standard HTST pasteurization). The skimmed milk then is recombined with the pasteurized cream to reconstitute the original milk composition. Ultrafiltration uses finer filters than microfiltration, which allow lactose and water to pass through while retaining fats, calcium and protein. As with microfiltration, the fat may be removed before filtration and added back in afterwards. Ultrafiltered milk is used in cheesemaking, since it has reduced volume for a given protein content, and is sold directly to consumers as a higher protein, lower sugar content, and creamier alternative to regular milk. === Creaming and homogenization === Upon standing for 12 to 24 hours, fresh milk has a tendency to separate into a high-fat cream layer on top of a larger, low-fat milk layer. The cream often is sold as a separate product with its own uses. Today the separation of the cream from the milk usually is accomplished rapidly in centrifugal cream separators. The fat globules rise to the top of a container of milk because fat is less dense than water. The smaller the globules, the more other molecular-level forces prevent this from happening. The cream rises in cow's milk much more quickly than a simple model would predict: rather than isolated globules, the fat in the milk tends to form into clusters containing about a million globules, held together by a number of minor whey proteins. These clusters rise faster than individual globules can. The fat globules in milk from goats, sheep, and water buffalo do not form clusters as readily and are smaller to begin with, resulting in a slower separation of cream from these milks. Milk often is homogenized, a treatment that prevents a cream layer from separating out of the milk. The milk is pumped at high pressures through very narrow tubes, breaking up the fat globules through turbulence and cavitation. A greater number of smaller particles possess more total surface area than a smaller number of larger ones, and the original fat globule membranes cannot completely cover them. Casein micelles are attracted to the newly exposed fat surfaces. Nearly one-third of the micelles in the milk end up participating in this new membrane structure. The casein weighs down the globules and interferes with the clustering that accelerated separation. The exposed fat globules are vulnerable to certain enzymes present in milk, which could break down the fats and produce rancid flavors. To prevent this, the enzymes are inactivated by pasteurizing the milk immediately before or during homogenization. Homogenized milk tastes blander but feels creamier in the mouth than unhomogenized. It is whiter and more resistant to developing off flavors. Creamline (or cream-top) milk is unhomogenized. It may or may not have been pasteurized. Milk that has undergone high-pressure homogenization, sometimes labeled as "ultra-homogenized", has a longer shelf life than milk that has undergone ordinary homogenization at lower pressures. === UHT === Ultra-heat treatment (UHT) is a type of milk processing where all bacteria are destroyed with high heat to extend its shelf life for up to six months, as long as the package is not opened. Milk is firstly homogenized and then is heated to 138 °C (280 °F) for 2–4 seconds. The milk is immediately cooled down and packed into a sterile container. As a result of this treatment, all the pathogenic bacteria within the milk are destroyed, unlike when the milk is just pasteurized. The treated milk will keep for up to 6 months if unopened. UHT milk does not need to be refrigerated until the package is opened, which makes it easier to ship and store. However, in this process there is a loss of vitamin B1 and vitamin C, and there is also a slight change in the taste of the milk. == Nutrition and health == The composition of milk differs widely among species. Factors such as the type of protein; the proportion of protein, fat, and sugar; the levels of various vitamins and minerals; and the size of the butterfat globules, and the strength of the curd are among those that may vary. For example: Human milk contains, on average, 1.1% protein, 4.2% fat, 7.0% lactose (a sugar), and supplies 72 kcal of energy per 100 grams. Cow's milk contains, on average, 3.4% protein, 3.6% fat, and 4.6% lactose, 0.7% minerals and supplies 66 kcal of energy per 100 grams. See also Nutritional value further on in this article and more complete lists at online sources that list values and differences in categories. Donkey and horse milk have the lowest fat content, while the milk of seals and whales may contain more than 50% fat. === Cow's milk: variation by breed === These compositions vary by breed, animal, and point in the lactation period. The protein range for these four breeds is 3.3% to 3.9%, while the lactose range is 4.7% to 4.9%. Milk fat percentages may be manipulated by dairy farmers' stock diet formulation strategies. The infection known as mastitis, especially in dairy cattle, can cause fat levels to decline. === Nutritional value === Processed cow's milk was formulated to contain differing amounts of fat during the 1950s. One cup (250 mL) of 2%-fat cow's milk contains 285 mg of calcium, which represents 22% to 29% of the daily recommended intake (DRI) of calcium for an adult. Depending on its age, milk contains 8 grams of protein, and a number of other nutrients (either naturally or through fortification). Whole milk has a glycemic index of 39±3. A food is considered to have a low GI if it is 55 or less. For protein quality, whole milk has a Digestible Indispensable Amino Acid Score (DIAAS) of 1.43, with the limiting amino acid for those groups being methionine and cysteine. A DIAAS of 1 or more is considered to be an excellent/high protein quality source. === Disease === There is mixed evidence that drinking milk increases the risk of cancer in general, and good evidence that milk drinking may have a protective effect specifically against bowel cancer. === Allergy === One of the most common food allergies in infants is to cow's milk. This is an immunologically mediated adverse reaction, rarely fatal, to one or more cow's milk proteins. Milk allergy affects between 2% and 3% of babies and young children. To reduce risk, recommendations are that babies should be exclusively breastfed for at least four months, preferably six months, before introducing cow's milk. The majority of children outgrow milk allergy, but for about 0.4% the condition persists into adulthood. === Lactose intolerance === Lactose intolerance is a condition in which people have symptoms due to deficiency or absence of the enzyme lactase in the small intestine, causing poor absorption of milk lactose. People affected vary in the amount of lactose they can tolerate before symptoms develop, which may include abdominal pain, bloating, diarrhea, gas, and nausea. Severity depends on the amount of milk consumed. Those affected are usually able to drink at least one cup of milk without developing significant symptoms, with greater amounts tolerated if drunk with a meal or throughout the day. == Evolution of lactation == The mammary gland is thought to have derived from apocrine skin glands. It has been suggested that the original function of lactation (milk production) was keeping eggs moist. Much of the argument is based on monotremes (egg-laying mammals). The original adaptive significance of milk secretions may have been nutrition and immunological protection. Tritylodontid cynodonts seem to have displayed lactation, based on their dental replacement patterns. == Bovine growth hormone supplementation == Since November 1993, recombinant bovine somatotropin (rbST), also called rBGH, has been sold to dairy farmers in the US with Food and Drug Administration (FDA) approval. Cows produce bovine growth hormone naturally, but some producers administer an additional recombinant version of BGH which is produced through genetically engineered E. coli to increase milk production. Bovine growth hormone also stimulates liver production of insulin-like growth factor 1 (IGF1). === Human health === The US Food and Drug Administration, the National Institutes of Health and the World Health Organization have reported that both of these compounds are safe for human consumption at the amounts present. Milk from cows given rBST may be sold in the United States, and the FDA stated that no significant difference has been shown between milk derived from rBST-treated and that from non-rBST-treated cows. Milk that advertises that it comes from cows not treated with rBST is required to state this finding on its label. === Animal welfare === Cows receiving rBGH supplements may more frequently contract an udder infection known as mastitis. Problems with mastitis have led to Canada, Australia, New Zealand, and Japan banning milk from rBST-treated cows. Mastitis, among other diseases, may be responsible for the fact that levels of white blood cells in milk vary naturally. rBGH is also banned in the European Union for reasons of animal welfare. == Varieties and brands == Milk products are sold in a number of varieties based on types/degrees of: additives (e.g. vitamins, flavorings) age (e.g. cheddar, old cheddar) coagulation (e.g. cottage cheese) farming method (e.g. organic, grass-fed, haymilk) fat content (e.g. half and half, 3% fat milk, 2% milk, 1% milk, skim milk) fermentation (e.g. buttermilk) flavoring (e.g. chocolate and strawberry) homogenization (e.g. cream top) packaging (e.g. bottle, carton, bag) pasteurization (e.g. raw milk, pasteurized milk) reduction or elimination of lactose species (e.g. cow, goat, sheep) sweetening (e.g., chocolate and strawberry milk) water content (e.g. dry milk powder, condensed milk, ultrafiltered milk) Milk preserved by the UHT process does not need to be refrigerated before opening and has a much longer shelf life (six months) than milk in ordinary packaging. It is typically sold unrefrigerated in the UK, US, Europe, Latin America, and Australia. === Fat content === The fat content of whole milk varies, and is adjusted to make different varieties by separating skim milk from cream, and then using either to mix different ratios, potentially even from the whole milk base. Thereby the different fat content categories are created, like 1%, 2%, and "half and half". === Reduction or elimination of lactose === Lactose-free milk can be produced by passing milk over lactase enzyme bound to an inert carrier. Once the molecule is cleaved, there are no lactose ill effects. Forms are available with reduced amounts of lactose (typically 30% of normal), and alternatively with nearly 0%. The only noticeable difference from regular milk is a slightly sweeter taste due to the cleavage of lactose into glucose and galactose. Lactose-reduced milk can also be produced via ultra filtration, which removes smaller molecules such as lactose and water while leaving calcium and proteins behind. Milk produced via these methods has a lower sugar content than regular milk. To aid digestion in those with lactose intolerance, another alternative is dairy foods, milk and yogurt, with added bacterial cultures such as Lactobacillus acidophilus ("acidophilus milk") and bifidobacteria. Another milk with Lactococcus lactis bacteria cultures ("cultured buttermilk") often is used in cooking to replace the traditional use of naturally soured milk, which has become rare due to the ubiquity of pasteurization, which also kills the naturally occurring Lactococcus bacteria. === Additives and flavoring === Commercially sold milk commonly has vitamin D added to it to make up for lack of exposure to UVB radiation. Reduced-fat milks often have added vitamin A palmitate to compensate for the loss of the vitamin during fat removal; in the United States this results in reduced fat milks having a higher vitamin A content than whole milk. Milk often has flavoring added to it for better taste or as a means of improving sales. Chocolate milk has been sold for many years and has been followed more recently by strawberry milk and others. Some nutritionists have criticized flavored milk for adding sugar, usually in the form of high-fructose corn syrup, to the diets of children who are already commonly obese in the US. === Distribution === Due to the short shelf life of normal milk, it used to be delivered to households daily in many countries; however, improved refrigeration at home, changing food shopping patterns because of supermarkets, and the higher cost of home delivery mean that daily deliveries by a milkman are no longer available in most countries. ==== Australia and New Zealand ==== In Australia and New Zealand, prior to metrication, milk was generally distributed in 1 pint (568 mL) glass bottles. In Australia and Ireland there was a government funded "free milk for school children" program, and milk was distributed at morning recess in 1/3 pint bottles. With the conversion to metric measures, the milk industry was concerned that the replacement of the pint bottles with 500 mL bottles would result in a 13.6% drop in milk consumption; hence, all pint bottles were recalled and replaced by 600 mL bottles. With time, due to the steadily increasing cost of collecting, transporting, storing and cleaning glass bottles, they were replaced by cardboard cartons. A number of designs were used, including a tetrahedron which could be close-packed without waste space, and could not be knocked over accidentally (slogan: "No more crying over spilt milk"). However, the industry eventually settled on a design similar to that used in the United States. Milk is now available in a variety of sizes in paperboard milk cartons (250 mL, 375 mL, 600 mL, 1 liter and 1.5 liters) and plastic bottles (1, 2 and 3 liters). A significant addition to the marketplace has been "long-life" milk (UHT), generally available in 1 and 2 liter rectangular cardboard cartons. In urban and suburban areas where there is sufficient demand, home delivery is still available, though in suburban areas this is often three times per week rather than daily. Another significant and popular addition to the marketplace has been flavored milks; for example, as mentioned above, Farmers Union Iced Coffee outsells Coca-Cola in South Australia. ==== India ==== In rural India, milk is home delivered, daily, by local milkmen carrying bulk quantities in a metal container, usually on a bicycle. In other parts of metropolitan India, milk is usually bought or delivered in plastic bags or cartons via shops or supermarkets. The current milk chain flow in India is from milk producer to milk collection agent. Then it is transported to a milk chilling center and bulk transported to the processing plant, then to the sales agent and finally to the consumer. A 2011 survey by the Food Safety and Standards Authority of India found that nearly 70% of samples had not conformed to the standards set for milk. The study found that due to lack of hygiene and sanitation in milk handling and packaging, detergents (used during cleaning operations) were not washed properly and found their way into the milk. About 8% of samples in the survey were found to have detergents, which are hazardous to health. Although India is the world's largest milk producer and a major exporter, the country's ever-increasing demand for dairy products could eventually make it a net importer. ==== Pakistan ==== In Pakistan, milk is supplied in jugs. Milk has been a staple food, especially among the pastoral tribes in this country. ==== United Kingdom ==== Since the late 1990s, milk-buying patterns have changed drastically in the UK. The classic milkman, who travels his local milk round (route) using a milk float (often battery powered) during the early hours and delivers milk in 1-pint glass bottles with aluminum foil tops directly to households, has almost disappeared. Two of the main reasons for the decline of UK home deliveries by milkmen are household refrigerators (which lessen the need for daily milk deliveries) and private car usage (which has increased supermarket shopping). Another factor is that it is cheaper to purchase milk from a supermarket than from home delivery. In 1996, more than 2.5 billion liters of milk were still being delivered by milkmen, but by 2006 only 637 million liters (13% of milk consumed) was delivered by some 9,500 milkmen. By 2010, the estimated number of milkmen had dropped to 6,000. Assuming that delivery per milkman is the same as it was in 2006, this means milkmen deliveries now only account for 6–7% of all milk consumed by UK households (6.7 billion liters in 2008/2009). Almost 95% of all milk in the UK is thus sold in shops today, most of it in plastic bottles of various sizes, but some also in milk cartons. Milk is hardly ever sold in glass bottles in UK shops. ==== United States ==== In the United States, glass milk bottles have been replaced mostly with milk cartons and plastic jugs. Gallons of milk are almost always sold in jugs, while half gallons and quarts may be found in both paper cartons and plastic jugs, and smaller sizes are almost always in cartons. The "half pint" (237 mL, 5⁄12 imp pt) milk carton is the traditional unit as a component of school lunches, though some companies have replaced that unit size with a plastic bottle, which is also available at retail in 6- and 12-pack size. === Packaging === Glass milk bottles are now rare. Most people purchase milk in bags, plastic bottles, or plastic-coated paper cartons. Ultraviolet (UV) light from fluorescent lighting can alter the flavor of milk, so many companies that once distributed milk in transparent or highly translucent containers are now using thicker materials that block the UV light. Milk comes in a variety of containers with local variants: Argentina Commonly sold in 1-liter bags and cardboard boxes. The bag is then placed in a plastic jug and the corner cut off before the milk is poured. Australia and New Zealand Distributed in a variety of sizes, most commonly in aseptic cartons for up to 1.5 liters, and plastic screw-top bottles beyond that with the following volumes; 1.1 L, 2 L, and 3 L. 1-liter milk bags are starting to appear in supermarkets, but have not yet proved popular. Most UHT-milk is packed in 1 or 2 liter paper containers with a sealed plastic spout. Brazil Used to be sold in cooled 1-liter bags, just like in South Africa. Today the most common form is 1-liter aseptic cartons containing UHT skimmed, semi-skimmed or whole milk, although the plastic bags are still in use for pasteurized milk. Higher grades of pasteurized milk can be found in cartons or plastic bottles. Sizes other than 1-liter are rare. Canada 1.33 liter plastic bags (sold as 4 liters in 3 bags) are widely available in some areas (especially the Maritimes, Ontario and Quebec), although the 4 liter plastic jug has supplanted them in western Canada. Other common packaging sizes are 2 liter, 1 liter, 500 mL, and 250 mL cartons, as well as 4 liter, 1 liter, 250 mL aseptic cartons and 500 mL plastic jugs. Chile Distributed most commonly in aseptic cartons for up to 1 liter, but smaller, snack-sized cartons are also popular. The most common flavors, besides the natural presentation, are chocolate, strawberry and vanilla. China Sweetened milk is a drink popular with students of all ages and is often sold in small plastic bags complete with straw. Adults not wishing to drink at a banquet often drink milk served from cartons or milk tea. Colombia Sells milk in 1-liter plastic bags. Croatia, Bosnia and Herzegovina, Serbia, Montenegro UHT milk (trajno mlijeko/trajno mleko/трајно млеко) is sold in 500 mL and 1 L (sometimes also 200 mL) aseptic cartons. Non-UHT pasteurized milk (svježe mlijeko/sveže mleko/свеже млеко) is most commonly sold in 1 L and 1.5 L PET bottles, though in Serbia one can still find milk in plastic bags. Estonia Commonly sold in 1 L bags or 0.33 L, 0.5 L, 1 L or 1.5 L cartons. Parts of Europe Sizes of 500 mL, 1 liter (the most common), 1.5 liters, 2 liters and 3 liters are commonplace. Finland Commonly sold in 1 L or 1.5 L cartons, in some places also in 2 dl and 5 dl cartons. Germany Commonly sold in 1-liter cartons. Sale in 1-liter plastic bags (common in the 1980s) is now rare. Hong Kong Milk is sold in glass bottles (220 mL), cartons (236 mL and 1 L), plastic jugs (2 liters) and aseptic cartons (250 mL). India Commonly sold in 500 mL plastic bags and in bottles in some parts like in the West. It is still customary to serve the milk boiled, despite pasteurization. Milk is often buffalo milk. Flavored milk is sold in most convenience stores in waxed cardboard containers. Convenience stores also sell many varieties of milk (such as flavored and ultra-pasteurized) in various sizes, usually in aseptic cartons. Indonesia Usually sold in 1-liter cartons, but smaller, snack-sized cartons are available. Italy Commonly sold in 1-liter cartons or bottles and less commonly in 0.5 or 0.25-liter cartons. Whole milk, semi-skimmed milk, skimmed, lactose-free, and flavored (usually in small packages) milk is available. Milk is sold fresh or UHT. Goat's milk is also available in small amounts. UHT semi-skimmed milk is the most sold, but cafés use almost exclusively fresh whole milk. Japan Commonly sold in 1-liter waxed paperboard cartons. In most city centers there is also home delivery of milk in glass jugs. As seen in China, sweetened and flavored milk drinks are commonly seen in vending machines. Kenya Milk in Kenya is mostly sold in plastic-coated aseptic paper cartons supplied in 300 mL, 500 mL or 1 liter volumes. In rural areas, milk is stored in plastic bottles or gourds. The standard unit of measuring milk quantity in Kenya is a liter. Pakistan Milk is supplied in 500 mL plastic bags and carried in jugs from rural to cities for selling Philippines Milk is supplied in 1000 mL plastic bottles and delivered from factories to cities for selling. Poland UHT milk is mostly sold in aseptic cartons (500 mL, 1 L, 2 L), and non-UHT in 1 L plastic bags or plastic bottles. Milk, UHT is commonly boiled, despite being pasteurized. South Africa Commonly sold in 1-liter bags. The bag is then placed in a plastic jug and the corner cut off before the milk is poured. South Korea Sold in cartons (180 mL, 200 mL, 500 mL 900 mL, 1 L, 1.8 L, 2.3 L), plastic jugs (1 L and 1.8 L), aseptic cartons (180 mL and 200 mL) and plastic bags (1 L). Sweden Commonly sold in 0.3 L, 1 L or 1.5 L cartons and sometimes as plastic or glass milk bottles. Turkey Commonly sold in 500 mL or 1 L cartons or special plastic bottles. UHT milk is more popular. Milkmen also serve in smaller towns and villages. United Kingdom Most stores stock imperial sizes: 1 pint (568 mL), 2 pints (1.136 L), 4 pints (2.273 L), 6 pints (3.408 L) or a combination including both metric and imperial sizes. Glass milk bottles delivered to the doorstep by the milkman are typically pint-sized and are returned empty by the householder for repeated reuse. Milk is sold at supermarkets in either aseptic cartons or HDPE bottles. Supermarkets have also now begun to introduce milk in bags, to be poured from a proprietary jug and nozzle. United States Commonly sold in gallon (3.78 L), half-gallon (1.89 L) and quart (0.94 L) containers of natural-colored HDPE resin, or, for sizes less than one gallon, cartons of waxed paperboard. Bottles made of opaque PET are also becoming commonplace for smaller, particularly metric, sizes such as one liter. The US single-serving size is usually the half-pint (about 240 mL). Less frequently, dairies deliver milk directly to consumers, from coolers filled with glass bottles which are typically half-gallon sized and returned for reuse. Some convenience store chains in the United States (such as Kwik Trip in the Midwest) sell milk in half-gallon bags, while another rectangular cube gallon container design used for easy stacking in shipping and displaying is used by warehouse clubs such as Costco and Sam's Club, along with some Walmart stores. Uruguay Pasteurized milk is commonly sold in 1-liter bags and ultra-pasteurized milk is sold in cardboard boxes called Tetra Briks. Non-pasteurized milk is forbidden. Until the 1960s no treatment was applied; milk was sold in bottles. As of 2017, plastic jugs used for pouring the bags, or "sachets", are in common use. Practically everywhere, condensed milk and evaporated milk are distributed in metal cans, 250 and 125 mL paper containers and 100 and 200 mL squeeze tubes, and powdered milk (skim and whole) is distributed in boxes or bags. === Spoilage and fermented milk products === When raw milk is left standing for a while, it turns "sour". This is the result of fermentation, where lactic acid bacteria ferment the lactose in the milk into lactic acid. Prolonged fermentation may render the milk unpleasant to consume. This fermentation process is exploited by the introduction of bacterial cultures (e.g. Lactobacilli sp., Streptococcus sp., Leuconostoc sp., etc.) to produce a variety of fermented milk products. The reduced pH from lactic acid accumulation denatures proteins and causes the milk to undergo a variety of different transformations in appearance and texture, ranging from an aggregate to smooth consistency. Some of these products include sour cream, yogurt, cheese, buttermilk, viili, kefir, and kumis. See Dairy product for more information. Pasteurization of cow's milk initially destroys any potential pathogens and increases the shelf life, but eventually results in spoilage that makes it unsuitable for consumption. This causes it to assume an unpleasant odor, and the milk is deemed non-consumable due to unpleasant taste and an increased risk of food poisoning. In raw milk, the presence of lactic acid-producing bacteria, under suitable conditions, ferments the lactose present to lactic acid. The increasing acidity in turn prevents the growth of other organisms, or slows their growth significantly. During pasteurization, however, these lactic acid bacteria are mostly destroyed. In order to prevent spoilage, milk can be kept refrigerated and stored between 1 and 4 °C (34 and 39 °F) in bulk tanks. Most milk is pasteurized by heating briefly and then refrigerated to allow transport from factory farms to local markets. The spoilage of milk can be forestalled by using ultra-high temperature (UHT) treatment. Milk so treated can be stored unrefrigerated for several months until opened but has a characteristic "cooked" taste. Condensed milk, made by removing most of the water, can be stored in cans for many years, unrefrigerated, as can evaporated milk. === Powdered milk === The most durable form of milk is powdered milk, which is produced from milk by removing almost all water. The moisture content is usually less than 5% in both drum- and spray-dried powdered milk. Freezing of milk can cause fat globule aggregation upon thawing, resulting in milky layers and butterfat lumps. These can be dispersed again by warming and stirring the milk. It can change the taste by destruction of milk-fat globule membranes, releasing oxidized flavors. == Use in other food products == Milk is used to make yogurt, cheese, ice milk, pudding, hot chocolate and french toast, among many other products. Milk is often added to dry breakfast cereal, porridge and granola. Milk is mixed with ice cream and flavored syrups in a blender to make milkshakes. Milk is often served in coffee and tea. Frothy steamed milk is used to prepare espresso-based drinks such as cafe latte. == In language and culture == In Greek mythology, the Milky Way was formed after the trickster god Hermes suckled the infant Heracles at the breast of Hera, the queen of the gods, while she was asleep. When Hera awoke, she tore Heracles away from her breast and splattered her breast milk across the heavens. In another version of the story, Athena, the patron goddess of heroes, tricked Hera into suckling Heracles voluntarily, but he bit her nipple so hard that she flung him away, spraying milk everywhere. In many African and Asian countries, butter is traditionally made from fermented milk rather than cream. It can take several hours of churning to produce workable butter grains from fermented milk. Holy books have also mentioned milk. The Bible contains references to the "Land of Milk and Honey" as a metaphor for the bounty of the Promised Land. In the Qur'an, there is a request to wonder on milk as follows: "And surely in the livestock there is a lesson for you, We give you to drink of that which is in their bellies from the midst of digested food and blood, pure milk palatable for the drinkers" (16-The Honeybee, 66). The Ramadan fast is traditionally broken with a glass of milk and dates. In Jewish religious law, Chalav Yisrael is the term regulating consumption of milk. Abhisheka is conducted by Hindu and Jain priests, by pouring libations on the idol of a deity being worshipped, amidst the chanting of mantras. Usually offerings such as milk, yogurt, ghee, honey may be poured among other offerings depending on the type of abhishekam being performed. A milksop is an "effeminate spiritless man," an expression which is attested to in the late 14th century. Milk toast is a dish consisting of milk and toast. Its soft blandness served as inspiration for the name of the timid and ineffectual comic strip character Caspar Milquetoast, drawn by H. T. Webster from 1924 to 1952. Thus, the term "milquetoast" entered the language as the label for a timid, shrinking, apologetic person. Milk toast also appeared in Disney's Follow Me Boys as an undesirable breakfast for the aging main character Lem Siddons. To "milk" someone, in the vernacular of many English-speaking countries, is to take advantage of the person, by analogy to the way a farmer "milks" a cow and takes its milk. The word "milk" has had many slang meanings over time. In the 19th century, milk was used to describe a cheap and very poisonous alcoholic drink made from methylated spirits (methanol) mixed with water. The word was also used to mean defraud, to be idle, to intercept telegrams addressed to someone else, and a weakling or "milksop." In the mid-1930s, the word was used in Australia to refer to siphoning gas from a car. == Non-culinary uses == Besides serving as a beverage or source of food, milk has been described as used by farmers and gardeners as an organic fungicide and fertilizer, however, its effectiveness is debated. Diluted milk solutions have been demonstrated to provide an effective method of preventing powdery mildew on grape vines, while showing it is unlikely to harm the plant. Milk paint is a nontoxic water-based paint. It can be made from milk and lime, generally with pigments added for color. In other recipes, borax is mixed with milk's casein protein in order to activate the casein and as a preservative. Milk has been used for centuries as a hair and skin treatment. Hairstylist Richard Marin states that some women rinse their hair with milk to add a shiny appearance to their hair. Cosmetic chemist Ginger King states that milk can "help exfoliate and remove debris [from skin] and make hair softer. Hairstylist Danny Jelaca states that milk's keratin proteins may "add weight to the hair". Some commercial hair products contain milk. A milk bath is a bath taken in milk rather than just water. Often additives such as oatmeal, honey, and scents such as rose, daisies and essential oils are mixed in. Milk baths use lactic acid, an alpha hydroxy acid, to dissolve the proteins which hold together dead skin cells. == Interspecies milk consumption == The consumption of milk between species is not unique to humans. Seagulls, sheathbills, skuas, western gulls and feral cats have been reported to directly pilfer milk from the elephant seals' teats. == See also == == References == == Further reading == Angier, Natalie, "Not Milk?" (review of Anne Mendelson, Spoiled: The Myth of Milk as Superfood, Columbia University Press, 2023, 396 pp.), The New York Review of Books, vol. LXX, no. 16 (19 October 2023), pp. 36, 38–39. "[Americans'] consumption of cow's milk [...] peak[ed in] 1945, when [they] drank an average of forty-five gallons apiece. By 2001 the nation's per capita milk intake had been cut in half, to twenty-three gallons, and in 2021 the figure was down to just sixteen gallons of milk per person, or 5.6 ounces a day... Leading the... drop-off are members of Generation Z: people born after 1996... Among the eco-conscious, antipathy toward dairy milk is great enough that some high-end coffee shops feel no obligation to offer it at all." (p. 36.) Dillon, John J. Seven decades of milk,: A history of New York's dairy industry (1941) Innis, Harold A. (1937). The Dairy Industry in Canada. Kardashian, Kirk. Milk Money: Cash, Cows, and the Death of the American Dairy Farm (2012) Kurlansky, Mark. Milk: A 10,000-Year History (2019); also published as Milk!: A 10,000-Year Food Fracas (2019) McGee, Harold (2004). On Food and Cooking (2nd ed.). New York: Scribner. ISBN 978-0-684-80001-1. Prasad R (2017). "Historical Aspects of Milk Consumption in South, Southeast, and East Asia" (PDF). Asian Agricultural History. 21 (4): 287–307. Scherbaum V, Srour ML (2018). "Milk products in the dietary management of childhood undernutrition – a historical review" (PDF). Nutrition Research Reviews. 31 (1): 71–84. doi:10.1017/s0954422417000208. PMID 29113618. S2CID 910669. Archived from the original (PDF) on February 12, 2020. Smith-Howard, Kendra. Pure and Modern Milk: An Environmental History Since 1900. (Oxford University Press; 2013). Valenze, Deborah. Milk: A Local and Global History (Yale University Press, 2011) 368 pp. Wiley, Andrea. Re-imagining Milk: Cultural and Biological Perspectives (Routledge, 2010) (Series for Creative Teaching and Learning in Anthropology)	Wikipedia/Milk_protein
Periodontitis as a manifestation of systemic diseases is one of the seven categories of periodontitis as defined by the American Academy of Periodontology 1999 classification system and is one of the three classifications of periodontal diseases and conditions within the 2017 classification. At least 16 systemic diseases have been linked to periodontitis. These systemic diseases are associated with periodontal disease because they generally contribute to either a decreased host resistance to infections or dysfunction in the connective tissue of the gums, increasing patient susceptibility to inflammation-induced destruction. These secondary periodontal inflammations should not be confused with other conditions in which an epidemiological association with periodontitis was revealed, but no causative connection was proved yet. Such conditions are coronary heart diseases, cerebrovascular diseases and erectile dysfunction. == Conditions associated with periodontitis == Diabetes mellitus Recent evidence suggests that, similar to diabetes mellitus, individuals with impaired fasting glucose have higher degree of periodontal inflammation. Associated with hematologic disorders: Acquired neutropenia Leukemia For those patients with periodontitis as a manifestation of hematologic disorders, coordination with the patient's physician is instrumental in planning periodontal treatment. Therapy should be avoided during periods of exacerbation of the malignancy or during active phases of chemotherapy, and antimicrobial therapy might be considered when urgent treatment must be performed when granulocyte counts are low. Associated with genetic disorders Familial and cyclic neutropenia Down syndrome Leukocyte adhesion deficiency disorder Papillon–Lefèvre syndrome Chédiak–Higashi syndrome Langerhans cell disease (histiocytosis syndromes) Glycogen storage disease Chronic granulomatous disease Infantile genetic agranulocytosis Cohen syndrome Ehlers–Danlos syndrome (Types IV and VIII) Hypophosphatasia Crohn's disease (inflammatory bowel disease) Marfan syndrome Klinefelter syndrome == References ==	Wikipedia/Periodontitis_as_a_manifestation_of_systemic_disease
Functional dyspepsia (FD) is a common gastrointestinal disorder defined by symptoms arising from the gastroduodenal region in the absence of an underlying organic disease that could easily explain the symptoms. Characteristic symptoms include epigastric burning, epigastric pain, postprandial fullness, and early satiety. FD was formerly known as non-ulcer dyspepsia, as opposed to "organic dyspepsia" with underlying conditions of gastritis, peptic ulcer disease, or cancer. The exact cause of functional dyspepsia is unknown however there have been many hypotheses regarding the mechanisms. Theories behind the pathophysiology of functional dyspepsia include gastroduodenal motility, gastroduodenal sensitivity, intestinal microbiota, immune dysfunction, gut-brain axis dysfunction, abnormalities of gastric electrical rhythm, and autonomic nervous system/central nervous system dysregulation. Risk factors for developing functional dyspepsia include female sex, smoking, non-steroidal anti-inflammatory medication use, and H pylori infection. Gastrointestinal infections can trigger the onset of functional dyspepsia. Functional dyspepsia is diagnosed based on clinical criteria and symptoms. Depending on the symptoms present people suspected of having FD may need blood work, imaging, or endoscopies to confirm the diagnosis of functional dyspepsia. Functional dyspepsia is further classified into two subtypes, postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Functional dyspepsia can be managed with medications such as prokinetic agents, fundus-relaxing drugs, centrally acting neuromodulators, and proton pump inhibitors. Up to 15-20% of patients with functional dyspepsia experience persistent symptoms. Functional dyspepsia is more common in women than men. In Western nations, the prevalence is believed to be 10-40% and 5-30% in Asian nations. == Signs and symptoms == Symptoms of functional dyspepsia include epigastric burning, epigastric pain, postprandial fullness (often described as bloating by those who have FD), and early satiety. Food consumption frequently makes symptoms worse. Although functional dyspepsia is typically chronic, the symptoms are generally sporadic, even during periods of severe symptoms. Those with FD typically refer to early satiety as a vague abundance of gas after eating or discomfort, but in reality, what they truly mean is that they find it difficult to finish a normal-sized meal because they are uncomfortable or feel full. While nausea and heartburn are still possible co-occurring symptoms, they are no longer regarded as major dyspeptic symptoms and may originate from different processes. When certain symptoms occur, such as vomiting, a coexisting or alternative condition, like gastroparesis, needs to be evaluated. == Causes == Functional dyspepsia has a wide range of complex etiologies. Gastric motor function abnormalities have long been linked to functional dyspepsia. However, a study revealed that there was no relationship between symptoms and stomach physiological abnormalities. The symptoms are significantly influenced by meal consumption, and genetic factors may also play a part. === Risk factors === Several epidemiological studies have demonstrated a moderate correlation between dyspepsia in the general population and female sex, smoking, non-steroidal anti-inflammatory medication use, and H pylori infection. In one long-term investigation, a high body mass index was an independent predictor of the emergence of functional dyspepsia. Since the brain and gut communicate through the hypothalamic-pituitary-adrenal axis and the enteric nerve system, psychological comorbidity plays a significant influence in the development of functional dyspepsia. Anxious participants had an eight-fold increased risk of developing functional dyspepsia compared to those without anxiety in a population-based survey conducted in Sweden. According to two Australian longitudinal investigations, there are reciprocal effects between the stomach and the brain. Specifically, people who had functional dyspepsia at baseline were more likely than those who did not experience anxiety or depression during follow-up. === Triggers === Acute gastroenteritis can lead to the development of post-infection functional dyspepsia. According to a meta-analysis of 19 papers, exposed people had nearly three times the chance of developing functional dyspepsia over the course of more than six months following an infection compared to non-exposed people. == Mechanism == Because functional dyspepsia symptoms are complicated and vary so much, the underlying pathophysiology of the disorder is still unknown. The causes of dyspeptic symptoms have been attributed to a number of pathophysiologic processes. These include gastroduodenal motility, gastroduodenal sensitivity, intestinal microbiota, immune dysfunction, gut-brain axis dysfunction, abnormalities of gastric electrical rhythm, and autonomic nervous system/central nervous system dysregulation. === Gastroduodenal motility === Patients with functional dyspepsia frequently have sensorimotor abnormalities of the gastroduodenum, including altered motility and pathological reactions to mechanical and chemical stimuli. One of the main pathophysiologic mechanisms thought to underlie the symptoms of functional dyspepsia is delayed stomach emptying. Several studies have looked into the connection between the pattern and intensity of symptoms and delayed stomach emptying. The proportion of dyspeptic individuals with delayed stomach emptying varies from 20% to 50%, depending on the study. In response to gastric balloon distension during fasting and following meal intake, patients with functional dyspepsia demonstrate impaired proximal stomach accommodation. Due to the poor accommodation, there is a disproportional volume distribution, with the fundus volume being less and the antral volume being bigger than usual. Furthermore, individuals suffering from functional dyspepsia exhibit compromised fundus accommodation in reaction to duodenal distension. === Gastroduodenal sensitivity === In functional dyspepsia, the stomach's sensitivity to chemical and mechanical stimuli is changed. After fasting and meal consumption, patients with functional dyspepsia exhibit visceral hypersensitivity following gastric fundus distension. Following stomach distension, even patients with normal accommodation experience discomfort. Additionally, some individuals exhibit hypersensitivity to distension of the duodenum, jejunum, or rectal cavity, indicating a more widespread sensitization of the central and autonomic nervous systems. === Intestinal microbiota === The small intestinal microbiota has been identified as a possible contributing factor. In one study, an elevated duodenal mucosal bacterial load was inversely connected with quality of life and correlated with meal-related symptoms during a nutritional challenge test, despite the fact that relative bacterial abundance in the small intestine is difficult to interpret. The bile acid pool may vary as a result of microbiome modifications brought on by small intestine inflammation. On the other hand, a decrease in primary bile acid levels may have an impact on the small intestine's microbial diversity, which may promote the proliferation of proinflammatory bacteria and low-grade inflammation, both of which may result in the breakdown of the epithelial barrier. A shift in the ratio of main to secondary bile acids and decreased amounts of total bile acids in certain patients with functional dyspepsia during fasting further suggest the involvement of gastrointestinal microbes. === Immune dysfunction === Some other functional gastrointestinal disorders have been linked to low-grade mucosal inflammation and elevated quantities of inflammatory cells, such as intraepithelial lymphocytes and mast cells. The quantity of cell-surface markers needed for more proliferation or differentiation of specialized cells, however, does not increase in functional dyspepsia; rather, it indicates the active state of these cells. Reduced expression of two markers—FAS, which is involved in lymphocyte homoeostasis and cell apoptosis, and HLA-DRA, which is involved in B-cell proliferation—has been linked to functional dyspepsia and is thought to reflect changes in duodenal lymphocyte populations. Moreover, duodenal eosinophilia has been linked to symptoms of postprandial distress syndrome, as opposed to an increase in mast cells. === Gut-brain axis dysfunction === There is a subpopulation of people with functional dyspepsia who have involvement in the gut-brain axis. Through the hypothalamic-pituitary-adrenal axis, changes in epithelial barrier function brought on by immune system and gastrointestinal microbiota disruptions can control gut-brain connections. The mechanisms involving corticotropin-releasing hormone and stress play a significant part in gastrointestinal permeability. This impact has been demonstrated in controlled trials including healthy volunteers under stress as well as in animal models of functional dyspepsia. Anatomical and functional connectivity impairments were observed in brain regions important for processing visceral afferent information in patients with functional dyspepsia, according to MRI results. === Abnormalities of gastric electrical rhythm === Additionally, there is proof that up to two thirds of patients with functional dyspepsia have anomalies in the underlying stomach myoelectrical activity, as determined by cutaneous electrogastrography. It is yet unknown how this discovery relates to stomach emptying and symptom patterns. There was no association discovered between the pattern of dyspeptic symptoms and the existence of electrogastrography results. There has been good evidence of a relationship between aberrant gastric electrical rhythm and delayed stomach emptying. === Autonomic nervous system/central nervous system dysregulation === It has been proposed that certain patients with functional dyspepsia may have anomalies in their autonomic nervous system. Particularly, it has been suggested that efferent vagal dysfunction may be the cause of antral hypomotility and poor adaption to a meal. Additionally, there is proof that psychological variables and both stomach functionality and symptoms of functional dyspepsia are related to psychopathology. Low vagal activity has been suggested as the mediating mechanism in these relationships. == Diagnosis == Functional dyspepsia is diagnosed using clinical symptoms and Rome IV criteria, which were recently revised. The clinical examination and patient history should look for alarm symptoms. Alarm symptoms include dysphagia, especially if progressive, or odynophagia, overt gastrointestinal bleeding, such as melena or hematemesis, persistent vomiting, unintentional weight loss, family history of gastric or esophageal cancer, palpable abdominal or epigastric mass or abdominal adenopathy, and signs of iron-deficiency anemia. The diagnostic criteria for functional dyspepsia is as follows: At least one of the following: Troublesome postprandial fullness. Troublesome early satiation. Troublesome epigastric pain. Troublesome epigastric burning. The criteria must be met over the past three months, with the onset of symptoms occurring at least six months before diagnosis and there must be an absence of structural disease evidence that could account for the symptoms, including upper endoscopy. Taking a thorough history that includes all relevant symptoms is the first step in the process. Patients are then categorized into the relevant subtype and any alarm symptoms or indicators that might point to a different diagnosis are reviewed. The following step is a thorough physical examination, which is crucial for a number of reasons. Patients are first reassured by the examination that their problems are being addressed seriously. Second, even in a patient with typical symptoms, the examination may yield results that point to a different diagnosis. Unfortunately, there is currently no reliable biomarker to aid in the diagnosis, and history and clinical examination cannot reliably differentiate functional dyspepsia from organic dyspepsia causes. There is no validated diagnostic algorithm, and current guidelines and the Rome committee oppose routine laboratory testing in all patients. Requesting a complete blood count is probably a good idea because anemia diagnosis could alter the final diagnosis. Liver function tests are needed if there is concern regarding a potential hepatobiliary cause of severe episodic epigastric discomfort. It is not advised to regularly monitor thyroid testing or celiac serology, nor is it advised to frequently screen for pancreatitis using serum lipase or amylase levels. While a negative endoscopy is strictly necessary to validate a functional dyspepsia diagnosis, the majority of dyspepsia patients (80%) have been reported to have no organic abnormalities at endoscopy, with under 10 percent having a peptic ulcer and fewer than 0,5% having gastro-esophageal cancer. The most recent guidelines for managing dyspepsia prohibit endoscopic use in patients under 60 years of age because its low yield, even in cases where alarm symptoms are present. Noninvasive urea breath tests or stool antigen testing for H pylori should be performed on these patients. People who have chronic symptoms should be considered candidates for endoscopy. Gastric biopsies should also be taken, and if H pylori is found, treatment for the infection should begin. Because of the low yield, routinely requesting an abdominal ultrasound or CT scan in the absence of alarm symptoms or signs is not advised. Up to 25% of individuals with functional dyspepsia display delayed stomach emptying, making gastric emptying investigations of little benefit despite the significant symptom overlap and diagnostic confusion between gastroparesis and functional dyspepsia. Differential diagnoses for functional dyspepsia include gastro-oesophageal reflux disease, medication side effects, chronic mesenteric ischemia, symptomatic gallstone disease, sphincter of Oddi dysfunction, biliary dyskinesia, or gallbladder cancer, Crohn's disease, peptic ulcer disease (and infection with Helicobacter pylori), infiltrative diseases such as eosinophilic gastroenteritis, sarcoidosis, and amyloidosis, gastro-oesophageal malignancy, gastrointestinal complications of parasites such as giardia lamblia, strongyloides, and anisakiasis, gastroparesis, chronic pancreatitis or pancreatic cancer, and hepatocellular carcinoma. === Classification === The Rome IV criteria further classifies functional dyspepsia into two subtypes, postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Postprandial distress syndrome is marked by dyspeptic symptoms brought on by meals, such as postprandial fullness and early satiety and accounts for 69% of patients with functional dyspepsia. Epigastric pain syndrome is characterized by burning or pain in the stomach that may not always happen after eating and accounts for 7% of patients. 25% of patients have overlapping PDS and EPS. == Treatment == Treatment for functional dyspepsia involves addressing the predominant symptom or symptoms with a realistic discussion of the limitations of available therapies to manage expectations, as well as providing reassurance that there is no structural cause for the symptoms and an explanation of the pathophysiology and natural history of the disorder. For individuals with functional dyspepsia who are infected, H. pylori eradication treatment is recommended in all guidelines because it can potentially alleviate symptoms and reduce the risk of developing stomach cancer and peptic ulcers. Although they haven't been thoroughly investigated, dietary and lifestyle changes are typically advised. It makes sense to advise patients to eat smaller, more frequent meals and to steer clear of foods that worsen their symptoms. Eating less fattening meals may be advised because the duodenum's lipid content increases the stomach's mechanosensitivity. Although there is no proof connecting coffee and spicy meals high in capsaicin to symptoms, they are generally avoided. Prokinetic medications are effective in treating functional dyspepsia by stimulating the contractions of the stomach's smooth muscle and have been suggested as initial treatments for PDS. Prokinetics include agonists of the 5-HT receptor 4 (5-HT4), antagonists of the D(2) dopamine receptor, and agonists of the motilin receptor, such erythromycin. There aren't many high-quality trials and there's frequently little evidence in the literature supporting their symptomatic benefit. 5-HT1A agonists, muscarinic auto-receptor antagonists, and acetylcholinesterase inhibitors, such as acotiamide, can all target impaired stomach accommodation. Research has demonstrated that the 5-HT1A agonists buspirone, tandospirone, and acotiamide are beneficial for PDS symptoms. Numerous, frequently tiny,??? investigations have assessed centrally acting neuromodulators in the context of functional dyspepsia. Its reasoning stems from the common occurrence of psychiatric comorbidity and the theory that visceral hypersensitivity may react to centrally active neuromodulators and play a role in the development of symptoms. These medications are most likely the most helpful for EPS. However, similar to 5-HT1A agonists that act on stomach accommodation, they may also have therapeutic effects in PDS through their effects on gastrointestinal motility. When administered at a modest dosage in the evening, the antidepressant mirtazapine has demonstrated effectiveness in treating early satiety and nausea in individuals with functional dyspepsia who have lost weight and do not exhibit clinically significant co-occurring depression or anxiety. The most widely utilized first-line therapy for functional dyspepsia is inhibition of acid secretion. The results indicate that gastro-esophageal reflux disease is the principal indication, as response rates are highest (up to 45%) in patients with associated heartburn. Compared to people with PDS, those with EPS are more likely to respond. == Outlook == The natural history of most people with functional dyspepsia is chronic and variable, consisting of periods during which the patient has no symptoms at all interspersed with phases of symptom return. According to data from population-based studies, during an extended period of follow-up, 15–20% of patients with functional dyspepsia may experience persistent symptoms, and 50–35% may experience a resolution of symptoms; the remaining 30–35% of patients may experience fluctuating symptoms that meet the criteria for another functional gastrointestinal disorder. Functional dyspepsia is a chronic condition, although there is no proof that it is linked to a lower chance of survival. == Epidemiology == Regardless of the various functional dyspepsia criteria, the population prevalence of the disorder varies greatly around the world, with high overall rates (10–40%) in Western nations and low overall rates (5–30%) in Asian nations. Women are more likely than males to experience functional dyspepsia. == See also == Gastroparesis Functional gastrointestinal disorder == References == == Further reading == Mahadeva, Sanjiv (2006). "Epidemiology of functional dyspepsia: A global perspective". World Journal of Gastroenterology. 12 (17). Baishideng Publishing Group Inc.: 2661. doi:10.3748/wjg.v12.i17.2661. ISSN 1007-9327. PMC 4130971. PMID 16718749. El-Serag, H. B.; Talley, N. J. (2004). "The prevalence and clinical course of functional dyspepsia". Alimentary Pharmacology & Therapeutics. 19 (6): 643–654. doi:10.1111/j.1365-2036.2004.01897.x. ISSN 0269-2813. PMID 15023166. == External links == Cleveland Clinic Mayo Clinic	Wikipedia/Functional_dyspepsia
Hartnup disease (also known as "pellagra-like dermatosis" and "Hartnup disorder") is an autosomal recessive metabolic disorder affecting the absorption of nonpolar amino acids (particularly tryptophan that can be, in turn, converted into serotonin, melatonin, and niacin). Niacin is a precursor to nicotinamide (both are forms of vitamin B3), a necessary component of NAD+.: 541 The causative gene, SLC6A19, is located on chromosome 5. It is named after the British family, Hartnup, who had this disease. == Signs and symptoms == Hartnup disease manifests during infancy with variable clinical presentation: failure to thrive, photosensitivity, intermittent ataxia, nystagmus, and tremor. Nicotinamide is necessary for neutral amino acid transporter production in the proximal renal tubules found in the kidney, and intestinal mucosal cells found in the small intestine. Therefore, a symptom stemming from this disorder results in increased amounts of amino acids in the urine. Pellagra, a similar condition, is also caused by low nicotinamide; this disorder results in dermatitis, diarrhea, and dementia. Hartnup disease is a disorder of amino acid transport in the intestine and kidneys; otherwise, the intestine and kidneys function normally, and the effects of the disease occur mainly in the brain and skin. Symptoms may begin in infancy or early childhood, but sometimes they begin as late as early adulthood. Symptoms may be triggered by sunlight, fever, drugs, or emotional or physical stress. A period of poor nutrition nearly always precedes an attack. The attacks usually become progressively less frequent with age. Most symptoms occur sporadically and are caused by a deficiency of niacinamide. A rash develops on parts of the body exposed to the sun. Mental retardation, short stature, headaches, unsteady gait, and collapsing or fainting are common. Psychiatric problems (such as anxiety, rapid mood changes, delusions, and hallucinations) may also result. == Causes == Hartnup disease is inherited as an autosomal recessive trait. Heterozygotes are normal. Consanguinity is common. The failure of amino-acid transport was reported in 1960 from the increased presence of indoles (bacterial metabolites of tryptophan) and tryptophan in the urine of patients as part of a generalized aminoaciduria of the disease. The excessive loss of tryptophan from malabsorption was the cause of the pellagra like symptoms. From studies on ingestion of tryptophan it seemed that there was a generalized problem with amino-acid transport. In 2004, a causative gene, SLC6A19, was located on band 5p15.33. SLC6A19 is a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominantly in the kidneys and intestine. == Diagnosis == The defective gene controls the absorption of certain amino acids from the intestine and the reabsorption of those amino acids in the kidneys. Consequently, a person with Hartnup disease cannot absorb amino acids properly from the intestine and cannot reabsorb them properly from tubules in the kidneys. Excessive amounts of amino acids, such as tryptophan, are excreted in the urine. The body is thus left with inadequate amounts of amino acids, which are the building blocks of proteins. With too little tryptophan in the blood, the body is unable to make a sufficient amount of the B-complex vitamin niacinamide, particularly under stress when more vitamins are needed. In Hartnup disease, urinary excretion of proline, hydroxyproline, and arginine remains unchanged, differentiating it from other causes of generalized aminoaciduria, such as Fanconi syndrome. With urine chromatography, increased levels of neutral amino acids (e.g., glutamine, valine, phenylalanine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, serine, histidine, tyrosine, tryptophan) and indican are found in the urine. Increased urinary indican can be tested by Obermeyer test. == Treatment == A high-protein diet can overcome the deficient transport of neutral amino acids in most patients. Poor nutrition leads to more frequent and more severe attacks of the disease, which is otherwise asymptomatic. All patients who are symptomatic are advised to use physical and chemical protection from sunlight: avoid excessive exposure to sunlight, wear protective clothing, and use chemical sunscreens with a SPF of 15 or greater. Patients also should avoid other aggravating factors, such as photosensitizing drugs, as much as possible. In patients with niacin deficiency and symptomatic disease, daily supplementation with nicotinic acid or nicotinamide reduces both the number and severity of attacks. Neurologic and psychiatric treatment is needed in patients with severe central nervous system involvement. == See also == Citrullinemia Cystinosis Cystinuria == References == == External links ==	Wikipedia/Hartnup_disease
Management of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Since Crohn's disease is an immune system condition, it cannot be cured by medication or surgery. Treatment initially involves the use of medications to eliminate infections (generally antibiotics) and reduce inflammation (generally aminosalicylate anti-inflammatory drugs and corticosteroids). Surgery may be required for complications such as obstructions, fistulae, abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease. It involves removing the diseased part of the intestine and rejoining the healthy ends, but the disease tends to recur after surgery. Once remission is induced, the goal of treatment becomes maintenance of remission: avoiding the return of active disease, or "flares". Because of side effects, the prolonged use of corticosteroids is avoided. Although some people are able to maintain remission spontaneously, many require immunosuppressive drugs. == Aminosalicylates == 5-ASA compounds, such as mesalazine and sulfasalazine, have shown to be of very little efficacy in the treatment of Crohn's disease, either for induction or for maintenance of remission. Current guidelines do not advise the use of 5-ASA compounds in Crohn's disease. == Corticosteroids == Corticosteroids are a class of anti-inflammatory drugs used to treat moderate to severe flares of Crohn's disease. However, they are used sparingly because they can cause serious side effects, including Cushing's syndrome, mania, insomnia, hypertension, high blood glucose, osteoporosis, and avascular necrosis of long bones. Corticosteroids should not be confused with the anabolic steroids used to enhance athletic performance. The most commonly prescribed oral steroid is prednisone, which is typically dosed at 0.5 mg/kg for induction of remission in Crohn's disease. Intravenous steroids, administered in a hospital setting, are used when oral steroids do not work or cannot be taken. Because corticosteroids reduce the body's ability to fight infection, care must be taken to ensure that there is no active infection, particularly an intra-abdominal abscess, before the initiation of steroids. Another oral corticosteroid, budesonide (trade name Entocort), has limited absorption and a high level of first-pass metabolism, meaning that lower quantities of the drug enter the bloodstream. It has been shown to be useful in the treatment of mild to moderate Crohn's disease, and in maintaining remission. It is also effective when used in combination with antibiotics to treat active Crohn's disease. Budesonide is released in the ileum and right colon, and therefore has a topical effect against disease in that area. Steroid enemas can also be used to treat symptoms in the lower colon and rectum. Hydrocortisone and budesonide liquid and foam enemas are marketed for this purpose. == Mercaptopurine immunosuppressing drugs == Azathioprine and 6-mercaptopurine (6-MP) are the most commonly used immunosuppressants for maintenance therapy of Crohn's disease. They are purine anti-metabolites, meaning that they interfere with the synthesis of purines required for inflammatory cells. They have a duration of action of months (slow-acting). Both drugs are dosed at 1.5 to 2.5 mg/kg, with literature supporting the use of higher doses. A Cochrane systematic review that included 13 randomized controlled trials, concluded that azathioprine and 6-mercaptopurine are not effective for inducing remission when a person has Crohn's disease. Azathioprine and 6-MP may be useful for the following indications: Maintenance therapy with azathioprine or 6-mercaptopurine may lead people with active Crohn's to take less steroid medication. This may lower side effects related to steroid treatments. Fistulizing disease Maintenance of remission after surgery for Crohn's disease A combination of azathioprine and infliximab treatment may be more effective than a single dose of infliximab to induce steroid-free remission for people with active Crohn's disease. Azathioprine treatment may lead to rare but life-threatening side effects. The rare side effects include leukopenia or pancreatitis. There may also be an increased risk of lymphoma that is associated with azathioprine or 6-mercaptopurine treatment. Azathioprine is listed by the United States FDA as a human carcinogen. However, it confers considerably less morbidity and mortality than corticosteroids. == Biologic therapies == === Infliximab === Infliximab (trade name Remicade, among others) is a mouse-human chimeric antibody that targets tumor necrosis factor alpha (TNFα), a cytokine in the inflammatory response. It is a monoclonal antibody that inhibits the pro-inflammatory cytokine TNFα. It is administered intravenously and dosed per weight starting at 5 mg/kg and increasing according to character of disease. Infliximab has found utility as follows: Induction and maintenance of remission for people with Crohn's disease Maintenance for fistulizing Crohn's disease Side effects of infliximab, like other immunosuppressants of the TNF class, can be serious and potentially fatal, and infliximab carries an FDA black-box warning on the label. Listed side effects include hypersensitivity and allergic reactions, risk of re-activation of tuberculosis, serum sickness, and risk of multiple sclerosis. Serious side effect also include lymphoma and severe infections. === Adalimumab === Adalimumab, like infliximab, is an antibody that targets tumor necrosis factor. It has been shown to reduce the signs and symptoms of, and is approved for treatment of, moderate to severe Crohn's disease in adults who have not responded well to conventional treatments and who have lost response to or are unable to tolerate infliximab. Adalimumab also has a number of serious, potentially fatal, safety concerns characteristic of the anti-TNFα drugs. It, too, has a black-box warning on its FDA label. Listed potential side effects include serious and sometimes fatal blood disorders; serious infections including tuberculosis and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma and solid tissue cancers; rare reports of serious liver injury; and rare reports of demyelinating central nervous system disorders; and rare reports of cardiac failure. === Natalizumab === Natalizumab is an anti-integrin monoclonal antibody that has shown utility as induction and maintenance treatment for moderate to severe Crohn's disease. Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha, such as infliximab. In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease. A total of 3 large randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission and maintaining symptom-free status in patients with Crohn's disease. Natalizumab has also been linked to PML (though only when used in combination with interferon beta-1a). The label also recommends monitoring of liver enzymes due to concerns over possible damage or failure. Also associated with a rare but serious risk of multifocal leukoencephalopathy (brain infection leading to death or severe disability). Therefore, a specific program exists in which prescribers must be enrolled, CD-TOUCH (Crohn's Disease-Tysabri Outreach Unified Commitment to Health) Prescribing Program. === Ustekinumab === Ustekinumab (CNTO 1275) is a monoclonal antibody that suppresses cytokines IL-12 and IL-23. Originally designed to treat psoriasis, ustekinumab was approved by the FDA for the treatment of Crohn's disease in 2016. Evidence from four quality randomized control trials suggest that ustekinumab is effective for induction of clinical remission and clinical improvement in patients with moderate to severe Crohn's disease. Based on these studies, ustekinumab appears to be safe, but the implications of longer-term drug administration needs to be studied. === Vedolizumab === Vedolizumab is a gut-selective, Alpha-4 Beta-7 anti-integrin, monoclonal antibody that was approved by the U.S. Food and Drug Administration (FDA) to treat Crohn's disease in 2014. It is indicated for management of moderate-to-severe, active Crohn's disease patients and it works by inhibiting the trafficking of pro-inflammatory immune cells to the site of inflammation. Evidence from three randomized control trials, including an international, multi-center, randomized, parallel-group, double-blind clinical trial, GEMINI 2 (NCT00783692), demonstrated that Vedolizumab is effective for induction and maintenance of remission in patients with active Crohn's disease. == Surgery == Surgery is normally reserved for complications of Crohn's disease or when disease that resists treatment with drugs is confined to one location that can be removed. Surgery is often used to manage complications of Crohn's disease, including fistulae, small bowel obstruction, colon cancer, small intestine cancer and fibrostenotic strictures, when strictureplasty (expansion of the stricture) is sometimes performed. Otherwise, and for other complications, resection and anastomosis – the removal of the affected section of intestine and the rejoining of the healthy sections – is the surgery usually performed for Crohn's disease (e.g., ileocolonic resection). None of these surgeries cure or eliminate Crohn's disease, as the disease eventually comes back in healthy segments of the intestine, although when Crohn's disease recurs after surgery, it usually comes back at the site of the surgery. Small intestine transplants are becoming less experimental, but are still mainly performed in response to short bowel syndrome due to a high rate of transplant rejection. == Diet and lifestyle == Many diets have been proposed for the management of Crohn's disease, and many do improve symptoms, but none have been proven to cure the disease. The specific carbohydrate diet usually requires adjustments by patients; if a patient finds that certain foods increase or decrease symptoms, they may adjust their diet accordingly. A food diary is recommended to see what positive or negative effects particular foods have. A low residue diet may be used to reduce the volume of stools excreted daily. People with lactose intolerance due to small bowel disease may benefit from avoiding lactose-containing foods. Patients who cannot eat may be given total parenteral nutrition (TPN), a source of vitamins and nutrients. Fish oil may be effective in reducing the chance of relapse in less severe cases. Because the terminal ileum is the most common site of involvement and is the site for vitamin B12 absorption, people with Crohn's disease are at risk for B12 deficiency and may need supplementation. In cases with extensive small intestine involvement, the fat-soluble vitamins A, D, E and K may be deficient. Folate deficiency is a risk for patients treated with methotrexate who do not simultaneously receive folate supplementation. Stress can influence the course of Crohn's disease. Smoking has also been associated with the disease, and smokers with Crohn's are encouraged to explore smoking cessation programs. Smoking can not only make Crohn's disease worse in people who do it, but also increase the risk of recurrence after surgery. If a Crohn's disease patient who undergoes surgery does not quit smoking, the disease is likely to recur more aggressively. == Microbiome Modification == The use of oral probiotic supplements to modify the composition and behaviour of the gastrointestinal microbiome has been researched recently to understand whether it may help to improve remission rate in people with Crohn's disease. However only 2 controlled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation. == Helminthic therapy == In an experimental idea called helminthic therapy, moderate hookworm infections have been demonstrated to have beneficial effects on hosts who have diseases linked to overactive immune systems. This may be explained by the hygiene hypothesis. Hookworm therapy is currently in the trial stage at the University of Nottingham. Due to the unconventional nature of this therapy, it is not widely used. == Alternative medicine == More than half of people with Crohn's disease have tried complementary or alternative therapy. These include diets, probiotics, fish oil and other herbal and nutritional supplements. The benefit, if any, and risks of these therapies is uncertain. === Acupuncture === Acupuncture is used to treat inflammatory bowel disease in China, and is being used more frequently in Western society. Evidence has been put forth suggesting that acupuncture can have benefits beyond the placebo effect, improving quality of life, general well-being and a small decrease in blood-bound inflammatory markers. This study however had a very small test set and did not reach the threshold for benefit. === Herbal === Boswellia is an ayurvedic (Indian traditional medicine) herb, used as a natural alternative to drugs. One study has found that the effectiveness of H-15 extract is not inferior to mesalazine: "Considering both safety and efficacy of Boswellia serrata extract H15, it appears to be superior over mesalazine in terms of a benefit-risk-evaluation." Yunnan Baiyao == Other medications == Methotrexate is a folate anti-metabolite drug that is also used for chemotherapy. It is useful in maintenance of remission for those no longer taking corticosteroids. The antibiotics Metronidazole and ciprofloxacin may be used to treat Crohn's disease with colonic or perianal involvement, although this usage has not been approved by the Food and Drug Administration. They are also used to treat complications, including abscesses and other infections. Thalidomide has shown efficacy in reversing endoscopic evidence of disease. Cannabis may be used to treat Crohn's disease because of its anti-inflammatory properties. Cannabis and cannabis-derived drugs may also help to heal the gut lining, and may reduce the need for surgery and other medications. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, can cause flares of inflammatory bowel disease in approximately 25% of patients. These flares tend to occur within one week after starting regular use of the NSAID. In contrast, acetaminophen (paracetamol) and aspirin appear to be safe. Celecoxib (Celebrex), a cox-2 inhibitor, also appears to be safe, at least in short-term studies of patients in remission and on medication for their Crohn's disease. == Research == Many clinical trials have been recently completed or are ongoing for new therapies for Crohn's disease. They include the following: Certolizumab is a PEGylated Fab fragment of a humanized anti-TNFα monoclonal antibody that was found to have efficacy over placebo in one large trial. Traficet-EN/CCX282/GSK'786/vercirnon is a CCR9 chemokine receptor antagonist intended to modulate immune response. It failed in Phase III clinical trials, showing no improvement over a placebo. ABT-874 is a human anti-IL-12 monoclonal antibody being developed by Abbott Laboratories in conjunction with Cambridge Antibody Technology for the treatment of multiple autoimmune diseases, including Crohn's disease. Phase II trials showed promising results, Sargramostim, or granulocyte-monocyte colony stimulating factor (GM-CSF), has been shown to substantially improve health-related quality of life in pilot studies, measured by an increase in score on a 32-item IBD questionnaire. A recent Phase II trial showed that Sargramostim significantly decreased CD severity (48%, compared with 26% in the placebo group) and improved quality of life (40%, versus 19% for placebo). Trichuris suis is a pig whipworm that been shown in one study to improve Crohn's disease symptoms. Autologous stem cell transplants have also been evaluated. Rifabutin, clarithromycin and clofazimine are antibiotics designed to attack mycobacterium avium subsp. paratuberculosis, which may be a cause of Crohn's disease. This treatment, called Myoconda, is being tested by Giaconda. A pilot study found that Low-dose naltrexone, a very inexpensive drug, helped patients with active Crohn's disease. In the study, 89% of patients exhibited a response to therapy, and 67% achieved remission within four weeks. == See also == Biological therapy for inflammatory bowel disease Cholestyramine (Bile acid sequestrant) Essential fatty acid interactions == References ==	Wikipedia/Management_of_Crohn's_disease
Glycogen storage disease type I (GSD I) is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. There are also possibly rarer subtypes, the translocases for inorganic phosphate (GSD Ic) or glucose (GSD Id); however, a recent study suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable, and are therefore GSD Ib. GSD Ia is caused by a deficiency in the enzyme glucose-6-phosphatase; GSD Ib, a deficiency in the transport protein glucose-6-phosphate translocase. Because glycogenolysis is the principal metabolic mechanism by which the liver supplies glucose to the body during fasting, both deficiencies cause severe hypoglycemia and, over time, excess glycogen storage in the liver and (in some cases) in the kidneys. Because of the glycogen buildup, GSD I patients typically present with enlarged livers from non-alcoholic fatty liver disease. Other functions of the liver and kidneys are initially intact in GSD I, but are susceptible to other problems. Without proper treatment, GSD I causes chronic low blood sugar, which can lead to excessive lactic acid, and abnormally high lipids in the blood, and other problems. Frequent feedings of cornstarch or other carbohydrates are the principal treatment for all forms of GSD I. GSD Ib also features chronic neutropenia due to a dysfunction in the production of neutrophils in the bone marrow. This immunodeficiency, if untreated, makes GSD Ib patients susceptible to infection. The principal treatment for this feature of GSD Ib is filgrastim; however, patients often still require treatment for frequent infections, and a chronically enlarged spleen is a common side effect. GSD Ib patients often present with inflammatory bowel disease. It is the most common of the glycogen storage diseases. GSD I has an incidence of approximately 1 in 100,000 births in the American population, and approximately 1 in 20,000 births among Ashkenazi Jews. The disease was named after German doctor Edgar von Gierke, who first described it in 1929. == Signs and symptoms == Early research into GSD I identified numerous clinical manifestations falsely thought to be primary features of the genetic disorder. However, continuing research has revealed that these clinical features are the consequences of only one (in GSD Ia) or two (in GSD Ib) fundamental abnormalities: impairment in the liver's ability to convert stored glycogen into glucose through glycogenolysis in GSD Ib, impairment of the neutrophil's ability to take up glucose, resulting in neutrophil dysfunction and neutropenia These fundamental abnormalities give rise to a small number of primary clinical manifestations, which are the features considered in the diagnosis of GSD I: Low blood sugar (hypoglycemia), due to impairment of glycogen breakdown (glycogenolysis) causing insufficient fasting blood glucose hepatomegaly of non-alcoholic fatty liver disease, due to impairment of glycogenolysis causing glycogen accumulation in the liver in GSD Ib, increased infection risk, due to neutropenia and neutrophil dysfunction Affected people commonly present with secondary clinical manifestations, linked to one or more of the primary clinical manifestations: High levels of uric acid in the blood and attendant risk of gout or kidney damage, caused by low serum insulin levels in prolonged hypoglycemia High levels of lactic acid in the blood, in extreme cases leading to lactic acidosis, caused by prolonged hypoglycemia hepatic adenomas developing in adulthood and attendant risk of anemia, suspected to be caused by blood glucose dysregulation in the presence of non-alcoholic fatty liver disease in GSD Ib, inflammatory bowel disease and attendant risk of anemia, caused by neutrophil dysfunction and exacerbated by the increased carbohydrate intake required to prevent hypoglycemia In addition, there are several clinical manifestations that often result from the treatment of the primary clinical manifestations: pancreatic hypertrophy, due to increased carbohydrate intake causing frequent engagement of the insulin response in GSD Ib, splenomegaly, due to the long-term use of filgrastim to treat neutropenia causing sequestration of blood factors in the spleen in GSD Ib, an abnormally low number of platelets in the blood may occur, due to long-term use of filgrastim causing sequestration of platelets in the spleen in GSD Ib, anemia, due to long-term use of filgrastim causing sequestration of hemoglobin in the spleen, potentially exacerbated by uncontrolled inflammatory bowel disease === Hypoglycemia === Low blood sugar (hypoglycemia) is the primary clinical symptom common to both GSD Ia and GSD Ib and most often prompts initial diagnosis of the disease. During fetal development in utero, maternal glucose transferred across the placenta prevents hypoglycemia. However, after birth, the inability to maintain blood glucose from stored glycogen in the liver causes measurable hypoglycemia in no more than 1–2 hours after feedings. Without proper dietary treatment after birth, prolonged hypoglycemia often leads to sudden lactic acidosis that can induce primary respiratory distress in the newborn period, as well as ketoacidosis. Neurological manifestations of hypoglycemia are less severe in GSD I than in other instances. Rather than acute hypoglycemia, GSD I patients experience persistent mild hypoglycemia. The diminished likelihood of neurological manifestations is due to the habituation of the brain to mild hypoglycemia. Given the reduced blood glucose level, the brain adapts to using alternative fuels like lactate. These gradual metabolic adaptations during infancy make severe symptoms like unconsciousness or seizure uncommon before diagnosis. In the early weeks of life, undiagnosed infants with GSD I tolerate persistent hypoglycemia and compensated lactic acidosis between feedings without symptoms. Without consistent carbohydrate feeding, infant blood glucose levels typically measure between 25 and 50 mg/dL (1.4 to 2.8 mmol/L). After weeks to months without treatment with consistent oral carbohydrates, infants will progress to show clear symptoms of hypoglycemia and lactic acidosis. Infants may present with paleness, clamminess, irritability, respiratory distress, and an inability to sleep through the night even in the second year of life. Developmental delay is not an intrinsic effect of GSD I, but is common if the diagnosis is not made in early infancy. == Genetics == GSD I is inherited in an autosomal recessive manner. People with one copy of the faulty gene are carriers of the disease and have no symptoms. As with other autosomal recessive diseases, each child born to two carriers of the disease has a 25% chance of inheriting both copies of the faulty gene and manifesting the disease. Unaffected parents of a child with GSD I can be assumed to be carriers. Prenatal diagnosis has been made by fetal liver biopsy at 18–22 weeks of gestation, but no fetal treatment has been proposed. Prenatal diagnosis is possible with fetal DNA obtained by chorionic villus sampling when a fetus is known to be at risk. The most common forms of GSD I are designated GSD Ia and GSD Ib, the former accounting for over 80% of diagnosed cases and the latter for less than 20%. A few rarer forms have been described. GSD Ia results from mutations of G6PC, the gene for glucose-6-phosphatase, located on chromosome 17q21. GSD Ib results from mutations of the gene for SLC37A4 or "G6PT1", the glucose-6-phosphate transporter. GSD Ic results from mutations of SLC17A3 or SLC37A4. Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit is associated with a calcium binding protein, and three transport proteins (T1, T2, T3) that facilitate movement of glucose-6-phosphate (G6P), phosphate, and glucose (respectively) into and out of the enzyme. == Pathophysiology == === Normal carbohydrate balance and maintenance of blood glucose levels === Glycogen in the liver and (to a lesser degree) kidneys serve as a form of stored, rapidly accessible glucose so that the blood glucose level can be maintained between meals. For about 3 hours after a carbohydrate-containing meal, high insulin levels direct liver cells to take glucose from the blood, to convert it to glucose-6-phosphate (G6P) with the enzyme glucokinase and add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into the production of triglycerides and exported for storage in adipose tissue as fat. When digestion of a meal is complete, insulin levels fall, and enzyme systems in the liver cells begin to remove glucose molecules from strands of glycogen in the form of G6P. This process is termed glycogenolysis. The G6P remains within the liver cell unless the phosphate is cleaved by glucose-6-phosphatase. This dephosphorylation reaction produces free glucose and free PO4 anions. The free glucose molecules can be transported out of the liver cells into the blood to maintain an adequate supply of glucose to the brain and other organs. Glycogenolysis can supply the glucose needs of an adult body for 12–18 hours. When fasting continues for more than a few hours, falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue. The products of these processes are amino acids (mainly alanine), free fatty acids, and lactic acid. Free fatty acids from triglycerides are converted to ketones, and to acetyl-CoA. Amino acids and lactic acid are used to synthesize new G6P in liver cells by the process of gluconeogenesis. The last step of normal gluconeogenesis, like the last step of glycogenolysis, is the dephosphorylation of G6P by glucose-6-phosphatase to free glucose and PO4. Thus glucose-6-phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. The effect is amplified because the resulting high levels of glucose-6-phosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis. === Pathophysiology === The principal metabolic effects of deficiency of glucose-6-phosphatase are hypoglycemia, lactic acidosis, hypertriglyceridemia, and hyperuricemia. The hypoglycemia of GSD I is termed "fasting", or "post-absorptive", usually about 4 hours after the complete digestion of a meal. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in GSD I, and typically the problem that leads to the diagnosis. Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol. Lactic acidosis arises from impairment of gluconeogenesis. Lactic acid is generated both in the liver and muscle and is oxidized by NAD+ to pyruvic acid and then converted via the gluconeogenic pathway to G6P. Accumulation of G6P inhibits the conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored. Hypertriglyceridemia resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis, amplified by chronically low insulin levels. During fasting, the normal conversion of triglycerides to free fatty acids, ketones, and ultimately acetyl-CoA is impaired. Triglyceride levels in GSD I can reach several times normal and serve as a clinical index of "metabolic control". Hyperuricemia results from a combination of increased generation and decreased excretion of uric acid, which is generated when increased amounts of G6P are metabolized via the pentose phosphate pathway. It is also a byproduct of purine degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue. === Elevated lactate and lactic acidosis === High levels of lactic acid in the blood are observed in all people with GSD I, due to impaired gluconeogenesis. Baseline elevations generally range from 4 to 10 mol/mL, which will not cause any clinical impact. However, during and after an episode of low blood sugar, lactate levels will abruptly rise to exceed 15 mol/mL, the threshold for lactic acidosis. Symptoms of lactic acidosis include vomiting and hyperpnea, both of which can exacerbate hypoglycemia in the setting of GSD I. In cases of acute lactic acidosis, patients need emergency care to stabilize blood oxygen and restore blood glucose. Proper identification of lactic acidosis in undiagnosed children presents a challenge since the first symptoms are typically vomiting and dehydration, both of which mimic childhood infections like gastroenteritis or pneumonia. Moreover, both of these common infections can precipitate more severe hypoglycemia in undiagnosed children, making diagnosis of the underlying cause difficult. As elevated lactate persists, uric acid, ketoacids, and free fatty acids further increase the anion gap. In adults and children, the high concentrations of lactate cause significant discomfort in the muscles. This discomfort is an amplified form of the burning sensation a runner may feel in the quadriceps after sprinting, which is caused by a brief buildup of lactic acid. Proper control of hypoglycemia in GSD I eliminates the possibility of lactic acidosis. === Elevated urate and complications === High levels of uric acid often present as a consequence of elevated lactic acid in GSD I patients. When lactate levels are elevated, blood-borne lactic acid competes for the same kidney tubular transport mechanism as urate, limiting the rate which urate can be cleared by the kidneys into the urine. If present, increased purine catabolism is an additional contributing factor. Uric acid levels of 6 to 12 mg/dl (530 to 1060 umol/L) are common among GSD I patients if the disease is not properly treated. In some affected people, the use of the medication allopurinol is necessary to lower blood urate levels. Consequences of hyperuricemia among GSD I patients include the development of kidney stones and the accumulation of uric acid crystals in joints, leading to kidney disease and gout, respectively. === Hyperlipidemia and plasma effects === Elevated triglycerides in GSD I result from low serum insulin in patients with frequent prolonged hypoglycemia. It may also be caused by intracellular accumulation of glucose-6-phosphate with secondary shunting to pyruvate, which is converted into Acetyl-CoA, which is transported to the cytosol where the synthesis of fatty acids and cholesterol occurs. Triglycerides above the 3.4 mmol/L (300 mg/dL) range may produce visible lipemia, and even a mild pseudohyponatremia due to a reduced aqueous fraction of the blood plasma. In GSD I, cholesterol is typically only mildly elevated compared to other lipids. === Hepatomegaly === Impairment in the liver's ability to perform gluconeogenesis leads to clinically apparent hepatomegaly. Without this process, the body is unable to liberate glycogen from the liver and convert it into blood glucose, leading to an accumulation of stored glycogen in the liver. Hepatomegaly from the accumulation of stored glycogen in the liver is considered a form of non-alcoholic fatty liver disease. GSD I patients present with a degree of hepatomegaly throughout life, but severity often relates to the consumption of excess dietary carbohydrate. Reductions in the mass of the liver are possible since most patients retain residual hepatic function that allows for the liberation of stored glycogen at a limited rate. GSD I patients often present with hepatomegaly from the time of birth. In fetal development, maternal glucose transferred to the fetus prevents hypoglycemia, but the storage of glucose as glycogen in the liver leads to hepatomegaly. There is no evidence that this hepatomegaly presents any risk to proper fetal development. Hepatomegaly in GSD type I generally occurs without sympathetic enlargement of the spleen. GSD Ib patients may present with splenomegaly, but this is connected to the use of filgrastim to treat neutropenia in this subtype, not comorbid hepatomegaly. Hepatomegaly will persist to some degree throughout life, often causing the abdomen to protrude, and in severe cases may be palpable at or below the navel. In GSD-related non-alcoholic fatty liver disease, hepatic function is usually spared, with liver enzymes and bilirubin remaining within the normal range. However, liver function may be affected by other hepatic complications in adulthood, including the development of hepatic adenomas. === Hepatic adenomas === The specific etiology of hepatic adenomas in GSD I remains unknown, despite ongoing research. The typical GSD I patient presenting with at least one adenoma is an adult, though lesions have been observed in patients as young as fourteen. Adenomas, composed of heterogeneous neoplasms, may occur individually or in multiples. Estimates on the rate of conversion of a hepatocellular adenoma into hepatocellular carcinoma in GSD I range from 0% to 11%, with the latter figure representing more recent research. One reason for the increasing estimate is the growing population of GSD I patients surviving into adulthood when most adenomas develop. Treatment standards dictate regular observation of the liver by MRI or CT scan to monitor for structural abnormalities. Hepatic adenomas may be misidentified as focal nodular hyperplasia in diagnostic imaging, though this condition is rare. However, hepatic adenomas in GSD I uniquely involve diffuse Mallory hyaline deposition, which is otherwise commonly observed in focal nodular hyperplasia. Unlike common hepatic adenomas related to oral contraception, hemorrhaging in GSD I patients is rare. While the reason for the high prevalence of adenomas in GSD I is unclear, research since the 1970s has implicated serum glucagon as a potential driver. In studies, patients who have been put on a dietary regimen to keep blood sugar in a normal range spanning 72 to 108 mg/dL (4.0 to 6.0 mmol/L) have shown a decreased likelihood of developing adenomas. Moreover, patients with well-controlled blood glucose have consistently seen a reduction in the size and number of hepatic adenomas, suggesting that adenomas may be caused by imbalances of hepatotropic agents like serum insulin and especially serum glucagon in the liver. === Osteopenia === Patients with GSD I will often develop osteopenia. The specific etiology of low bone mineral density in GSD is unknown, though it is strongly associated with poor metabolic control. Osteopenia may be directly caused by hypoglycemia or the resulting endocrine and metabolic sequelae. Improvements in metabolic control have consistently been shown to prevent or reverse clinically relevant osteopenia in GSD I patients. In cases where osteopenia progresses with age, bone mineral density in the ribs is typically more severe than in the vertebrae. In some cases bone mineral density T-score will drop below -2.5, indicating osteoporosis. There is some evidence that osteopenia may be connected with associated kidney abnormalities in GSD I, particularly glomerular hyperfiltration. The condition also seems responsive to calcium supplementation. In many cases bone mineral density can increase and return to the normal range given proper metabolic control and calcium supplementation alone, reversing osteopenia. === Kidney effects === The kidneys are usually 10 to 20% enlarged with stored glycogen. In adults with GSD I, chronic glomerular damage similar to diabetic nephropathy may lead to kidney failure. GSD I may present with various kidney complications. Renal tubular abnormalities related to hyperlactatemia are seen early in life, likely because prolonged lactic acidosis is more likely to occur in childhood. This will often present as Fanconi syndrome with multiple derangements of renal tubular reabsorption, including tubular acidosis with bicarbonate and phosphate wasting. These tubular abnormalities in GSD I are typically detected and monitored by urinary calcium. Long term these derangements can exacerbate uric acid nephropathy, otherwise driven by hyperlactatemia. In adolescence and beyond, glomerular disease may independently develop, initially presenting as glomerular hyperfiltration indicated by elevated urinary eGFR. === Splenomegaly === Enlargement of the spleen (splenomegaly) is common in GSD I and has two primary causes. In GSD Ia, splenomegaly may be caused by a relation between the liver and the spleen which causes either to grow or shrink to match the relative size of the other, to a lessened degree. In GSD Ib, it is a side effect of the use of filgrastim to treat neutropenia. === Bowel effects === Intestinal involvement can cause mild malabsorption with greasy stools (steatorrhea) but usually requires no treatment. === Infection risk === Neutropenia is a distinguishing feature of GSD Ib, absent in GSD Ia. The microbiological cause of neutropenia in GSD Ib is not well understood. Broadly, the problem arises from compromised cellular metabolism in the neutrophil, resulting in accelerated neutrophil apoptosis. The neutropenia in GSD is characterized by both a decrease in absolute neutrophil count and diminished neutrophil function. Neutrophils use a specific G6P metabolic pathway which relies on the presence of G6Pase-β or G6PT to maintain energy homeostasis within the cell. The absence of G6PT in GSD Ib limits this pathway, leading to endoplasmic reticulum stress, oxidative stress within the neutrophil, triggering premature apoptosis. Granulocyte colony-stimulating factor (G-CSF), available as filgrastim, can reduce the risk of infection. In some cases, G-CSF formulated as pegfilgrastim, sold under the trade name Neulasta, may be used as a slow-acting alternative, requiring less frequent dosing. === Thrombocytopenia and blood clotting problems === Impaired platelet aggregation is an uncommon consequence of chronic hypoglycemia, seen in GSD I patients. Research has demonstrated decreased platelet function, characterized by decreased prothrombin consumption, abnormal aggregation reactions, prolonged bleeding time, and low platelet adhesiveness. Severity of platelet dysfunction typically correlates with clinical condition, with the most severe cases correlating with lactic acidosis and severely lipidemia. It may cause clinically significant bleeding, especially epistaxis. Additionally, GSD I patients may present with thrombocytopenia as a consequence of splenomegaly. In the setting of splenomegaly, various hematologic factors may be sequestered in the tissues of the spleen as blood is filtered through the organ. This can diminish levels of platelets available in the bloodstream, leading to thrombocytopenia. === Developmental effects === Developmental delay is a potential secondary effect of chronic or recurrent hypoglycemia, but is at least theoretically preventable. Normal neuronal and muscle cells do not express glucose-6-phosphatase and are thus not impacted by GSD I directly. However, without proper treatment of hypoglycemia, growth failure commonly results from chronically low insulin levels, persistent acidosis, chronic elevation of catabolic hormones, and calorie insufficiency (or malabsorption). The most dramatic developmental delays are often the cause of severe (not just persistent) episodes of hypoglycemia. == Diagnosis == Several different problems may lead to the diagnosis, usually by two years of age: seizures or other manifestations of severe fasting hypoglycemia hepatomegaly with abdominal protuberance hyperventilation and apparent respiratory distress due to metabolic acidosis episodes of vomiting due to metabolic acidosis, often precipitated by minor illness and accompanied by hypoglycemia Once the diagnosis is suspected, the multiplicity of clinical and laboratory features usually makes a strong circumstantial case. If hepatomegaly, fasting hypoglycemia, and poor growth are accompanied by lactic acidosis, hyperuricemia, hypertriglyceridemia, and enlarged kidneys by ultrasound, GSD I is the most likely diagnosis. The differential diagnosis list includes glycogenoses types III and VI, fructose 1,6-bisphosphatase deficiency, and a few other conditions (page 5), but none are likely to produce all of the features of GSD I. The next step is usually a carefully monitored fast. Hypoglycemia often occurs within six hours. A critical blood specimen obtained at the time of hypoglycemia typically reveals a mild metabolic acidosis, high free fatty acids and beta-hydroxybutyrate, very low insulin levels, and high levels of glucagon, cortisol, and growth hormone. Administration of intramuscular or intravenous glucagon (0.25 to 1 mg, depending on age) or epinephrine produces little rise in blood sugar. The diagnosis is definitively confirmed by liver biopsy with electron microscopy and assay of glucose-6-phosphatase activity in the tissue and/or specific gene testing, available in recent years. == Treatment == The primary treatment goal is the prevention of hypoglycemia and secondary metabolic derangements by frequent feedings of foods high in glucose or starch (which is readily digested to glucose). To compensate for the inability of the liver to provide sugar, the total amount of dietary carbohydrates should approximate the 24-hour glucose production rate. The diet should contain approximately 65–70% carbohydrate, 10–15% protein, and 20–25% fat. At least a third of the carbohydrates should be supplied through the night so that a young child goes no more than 3–4 hours without carbohydrate intake. Once a diagnosis is made, the priority in GSD I treatment is to maintain adequate blood glucose. Patients aim to maintain blood glucose above the 72 mg/dL (4.0 mmol/L) cutoff for hypoglycemia. GSD Ib patients have an additional treatment priority relating to neutropenia. Proper management of blood glucose in GSD I is critical in avoiding the more severe effects of high levels of lactic acid and uric acid in the blood, and the development of hepatic adenomas. In the last 30 years, two methods have been used to achieve this goal in young children: (1) continuous nocturnal gastric infusion of glucose or starch; and (2) night-time feedings of uncooked cornstarch. An elemental formula, glucose polymer, and/or cornstarch can be infused continuously through the night at a rate supplying 0.5–0.6 g/kg/h of glucose for an infant, or 0.3–0.4 for an older child. This method requires a nasogastric or gastrostomy tube and pump. Sudden death from hypoglycemia has occurred due to malfunction or disconnection, and periodic cornstarch feedings are now preferred to continuous infusion. Cornstarch is an inexpensive way to provide gradually digested glucose. One tablespoon contains nearly 9 grams of carbohydrates (36 calories). Although it is safer, less expensive, and requires no equipment, this method does require that parents arise every 3–4 hours to administer the cornstarch. A typical requirement for a young child is 1.6 g/kg every 4 hours. Long-term management should eliminate hypoglycemic symptoms and maintain normal growth. Treatment should achieve normal glucose, lactic acid, and electrolyte levels, and only mild elevations of uric acid and triglycerides. === Avoidance of other sugars === Intake of carbohydrates which must be converted to G6P to be utilized (e.g., galactose and fructose) should be minimized. Although elemental formulas are available for infants, many foods contain fructose or galactose in the form of sucrose or lactose. Adherence becomes a contentious treatment issue after infancy. === Other therapeutic measures === Persistent elevation of uric acid above 6.5 mg/dl warrants treatment with allopurinol to prevent uric acid deposition in kidneys and joints. Because of the potential for impaired platelet function, coagulation ability should be checked and the metabolic state normalized before surgery. Bleeding time may be normalized with 1–2 days of glucose loading and improved with ddavp. During surgery, IV fluids should contain 10% dextrose and no lactate. A patient with GSD, type 1b was treated with a liver transplant at UCSF Medical Center in 1993 that resulted in the resolution of hypoglycemic episodes and the need for the patient to stay away from natural sources of sugar. Other patients have undergone this procedure as well with positive results. Although a liver transplant resulted in the resolution of hypoglycemia it did not however resolve the chronic neutropenia and the risk of infection among patients. === Treatment of acute metabolic acidosis episodes === The most significant acute problem in childhood is a vulnerability to episodes of metabolic acidosis precipitated by minor illnesses. If a vomiting illness persists longer than 2–4 hours, the child should be seen and assessed for dehydration, acidosis, and hypoglycemia. If these are developing, intravenous fluids should be provided at a rate above maintenance. For mild acidosis, an effective fluid is 10% dextrose in ½ normal saline with 20 mEq/L KCl, but if acidosis is severe, 75–100 mEq/L NaHCO3 and 20 mEq/L of K acetate can be substituted for the NaCl and KCl. === Metabolic control === Metabolic control often diminishes during and after puberty, as a result of a patient outgrowing their dietary treatment plan. == Prognosis == Without adequate metabolic treatment, patients with GSD I have died in infancy or childhood of overwhelming hypoglycemia and acidosis. Those who survived were stunted in physical growth and delayed in puberty because of chronically low insulin levels. Intellectual disability resulting from recurrent, severe hypoglycemia is considered preventable with appropriate treatment. Liver complications have been serious in some patients. Adenomas of the liver can develop in the second decade or later, with a small chance of later malignant transformation to hepatoma or hepatic carcinomas (detectable by alpha-fetoprotein screening). Several children with advanced hepatic complications have improved after liver transplantation. Additional problems reported in adolescents and adults with GSD I have included hyperuricemic gout, pancreatitis, and chronic kidney failure. Despite hyperlipidemia, atherosclerotic complications are uncommon. With diagnosis before serious harm occurs, prompt reversal of acidotic episodes, and appropriate long-term treatment, most children will be healthy. With exceptions and qualifications, adult health and life span may also be fairly good, although the lack of effective treatment before the mid-1980s means information on long-term efficacy is limited. == Epidemiology == In the United States, GSD I has an incidence of approximately 1 in 50,000 to 100,000 births. None of the glycogenoses are currently detected by standard or extended newborn screening. The disease is more common in people of Ashkenazi Jewish, Mexican, Chinese, and Japanese descent. == References == == Further reading == GeneReview/NIH/UW entry on Glycogen Storage Disease Type I == External links == Media related to Glycogen storage disease type I at Wikimedia Commons	Wikipedia/Von_Gierke's_disease
Oral manifestations of systematic disease are signs and symptoms of disease occurring elsewhere in the body detected in the oral cavity and oral secretions. High blood sugar can be detected by sampling saliva. Saliva sampling may be a non-invasive way to detect changes in the gut microbiome and changes in systemic disease. Another example is tertiary syphilis, where changes to teeth can occur. Syphilis infection can be associated with longitudinal furrows of the tongue. Mineral and vitamin deficiencies can cause the tongue to appear beefy red and feel sore. Those deficiencies are iron, folate, and vitamin B12. A hairy tongue may be an indication of Epstein Barr virus infection and is usually seen in those infected with human immunodeficiency virus. Other systemic diseases that can cause the tongue to form aphthous ulcers are: Crohn's disease and ulcerative colitis, Behcet's Syndrome, pemphigus vulgaris, herpes simplex, histoplasmosis, and reactive arthritis. == Cardiovascular and haematological system == A heart attack is a blood vessel in the heart being constricted either by a blood clot or atherosclerosis formation. A heart attack can cause pain the chest; sometimes this pain can radiate up to the jaw. (Malik et al., 2013) Calcium channel blockers are medications prescribed for the treatment of a number of heart conditions and primarily to treat high blood pressure. They can cause gingival hypertrophy (overgrowth), particularly dihydropyridine and nifidipine. Poor dental hygiene and inflamed gums are a risk factor. The overgrowth is not permanent, it is suggested that if the medication is stopped then the overgrowth can reduce[ however, this is a decision that would have to be made in conjunction with the patient's dentist and cardiologist as the risk of stopping some medications outweigh any advantage gained (Livada and Shiloah, 2013) Nicorandil is a medication that is prescribed for the treatment of angina. It can cause major aphthous-like ulcer formation (BNF, 2020). Iron, folate and vitamin B12 deficiencies – The most commonest cause of iron deficiencies is low ferritin; this can cause the tongue to appear beefy red and appear sore. It can also present in the mouth as angular chelitis, which is an infection caused by either staphylococcus or candidiasis, and can make the corners of the mouth appear red and crispy. Sickle cell disease is a hereditary genetic condition that results in deformed red blood cells to be formed. Sickle patients can experience sickle crisis, these are painful events in which if in the jaw can mimic dental pain and facial swelling can also occur during a crisis. The dental pulp can be affected by sickling and there may be a delayed eruption and hypoplasia of the dentition. Sickle patients are also at an increased risk of developing infection. Thalasseamias is a group of inherited genetic disorders that affect the haemoglobin synthesis; it can result in either a reduced or absent globin chain production. If beta thalassaemia major is left untreated or under transfused, there is expansion of ineffective bone marrow, this leads to bony deformities resulting in dental malocclusion. Beta thalassaemia major patients may also be on bisphosphonates and are therefore at risk of developing osteonecrosis of the jaw. Thrombocytopenia is a deficiency of platelets in the blood. It can present as red blood blisters in the mouth. == Respiratory system == Patients with respiratory conditions like asthma and chronic obstructive pulmonary disease can be prescribed steroidal inhalers to help strengthen their lungs. They must ensure after use that they rinse their mouths, otherwise there is an increase of dental caries, xerostomia, candidiasis, ulceration and gingivitis/periodontitis (Godara et al., 2011). == Renal system == There are a number of oral complications following renal transplantation. Ciclosporin is an immunosuppressant medication that is used to help prevent patients from rejecting the transplanted kidney (BNF, 2020). Due to the immunosuppression (suppressed immune system), these patients are more likely to have gingival hyperplasia, aphthous ulceration, herpes simplex virus, oral leucoplakia; which may transform into squamous cell carcinoma, candidiasis infection or Kaposi's sarcoma (BNF, 2020). == Digestive system == There are many specific diseases of the gastrointestinal tract which have an impact on oral health. Systemic disease can affect the upper GI tract such as dysphagia, dysmotility, gastro-oesophageal reflux and peptic ulcer disease; or lower in the tract such as coeliac disease, Crohn's disease, ulcerative colitis and familial adenomatous polyposis. Dysphagia is defined as a difficulty in swallowing. Structurally it worsens when eating solids and neurologically it is worse with fluids. Structural problems may include malignancy, stricture and pharyngeal pouching which can lead to halitosis, regurgitation of undigested food and high feeling of dysphagia. Neurological problems may be related to the patient having multiple sclerosis, motor neuron disease, or having had a stroke. Dysphagia may present as a barrier to care in the dental setting as the patient may require high volume suction in order to maintain patient comfort and reduce the risk of aspiration of dental material/ fluids. Gastroesophageal reflux can present as retrosternal pain, acid brash and a hoarse voice. Risk factors for gastroesophageal reflux disease are obesity, diet, smoking and hiatal hernia. Complications of which being oesophagitis, Barrett's oesophagus, Strictures and ulcers. Common management of gastroesophageal reflux disease include lifestyle measures, proton pump inhibitors and rarely surgery. There is a clear relationship between gastroesophageal reflux disease and dental erosion and therefore can be detrimental to hard tissues i.e. teeth and also soft tissues of the mouth. Crohn's disease is a patchy disease which can affect any area of the GI tract from the oral cavity to the anus. The manifestations depend on the affected area. The oral manifestations present as orofacial granulomatosis, an inflammatory condition affecting the oral mucosa. It is non-caveating granulomas and has a "cobblestone" appearance. Orofacial granulomatosis can be isolated or a manifestation of Crohn's disease and can be treated with local or systemic corticosteroids. An aggravating factor is cinnamon, therefore a cinnamon-free diet is recommended. Eating disorders are a psychological problem which has an impact on the gastrointestinal tract. Two common eating disorders are anorexia nervosa and bulimia nervosa. Anorexia nervosa is a refusal to maintain a "normal" body weight with a fear of weight gain and distorted perception of body image. Bulimia nervosa is binge-eating followed by attempts to restrict weight gain and can include purging. Eating disorder oral manifestation is severe palatal erosion due to vomiting. There is occlusal erosion of the maxillary teeth causing the incised edges of the incisors to be thin and knife-edged. Occlusal surfaces have a flat to cupped-out appearance. Extra-orally eating disorders may present with swollen parotid glands. Other oral manifestations of GI disease is angular stomatitis, commonly seen in iron-deficient anaemia and mouth ulcers in Crohn's disease. == Endocrine system == Diabetes Mellitus has two main types: Type 1, autoimmune destruction of beta-cells leading to reduced insulin production and Type 2, the body becomes increasingly resistant to the effects of insulin leading to the bodies inability to regulate plasma glucose levels resulting in a fall in insulin production. Diabetes has numerous implications on oral health. Patient with diabetes have increase extent and severity of periodontal disease, increased prevalence of dental caries due to xerostomia, can experience burning mouth syndrome and candidal infections as well as experiencing altered taste sensation, altered tooth eruption and hypertrophy of the parotid glands. Other oral health problems include chronic hyperglycaemia, infection, delayed wound healing and lichen planus/lichenoid reactions. The oral manifestations of Acromegaly predominate as spacing of the lower incisor teeth and widening of the mandible. Other complications include visual field defects, headaches, Diabetes, Sleep apnoea, Hypertension, Arthralgia and Arthritis and Carpal Tunnel Syndrome. Arthralgia and Carpal Tunnel Syndrome both have an impact on a patients' ability to maintain good oral hygiene practice and therefore may predispose them to Dental caries and Periodontal Disease. It is imperative these patients are given Enhanced Prevention in order to reduce the risk of Dental Caries and Periodontal Disease. Another endocrine disorder that may present orally is Addison's disease. Signs include skin hyperpigmentation, alabaster-coloured pale skin, low blood pressure, postural hypotension. Skin pigmentation have increased deposition in the palmer skin creases, nails and gingiva. Management of Addison's is with steroids. During dental treatment the patient may require an increased dose of steroids based on treatment need. == Skeletal system == Osteopgenesis imperfecta, also known as brittle bone disease, is caused by a gene mutation affecting the collagen genes, patients generally present with a large number of fractures from minor injuries. Teeth, if affected, are of the appearance of dentinogenesis imperfecta. Osteoporosis is a very common disease associated with a decreased bone mineral density, it mainly affects post menopausal women whose oestrogen levels have dropped. It is managed with the used of bisphosphonates. Prior to placement on bisphosphonates, a dental check must be done to extract any hopeless teeth as extractions in patients who have prolonged used of bisphosphonates are at risk of MRONJ. (SDCEP,2017) == Immune system == Human immunodeficiency virus infects and destroys cells of the immune system, principally the CD4+ T-helper lymphocytes. As well as lymphocytes, CD4 receptors are also present on the surface of macrophages and monocytes, cells in the brain, skin, and probably many other sites. The normal CD4 count is 500-1500 per mm3, and patients with human immunodeficiency virus infection often have a CD4 count less than 500. Patients who are infected with human immunodeficiency virus positive have an increased risk of developing infections and tumours. The lower the CD4 count, the greater the likelihood and the severity of illness. A CD4 count less than 200 is a diagnosis of Acquired Immunodeficiency Syndrome (AIDS). Oral manifestations of human immunodeficiency virus include candidiasis, oral hairy leukoplakia, oral ulcers, oral warts, oral lymphoma and Kaposi's sarcoma. Other presentations include gingivitis and oral malignancies. Treatment and management of AIDS is based on highly active anti-retroviral therapy, which significantly lowers the prevalence of oral lesions, particularly oral candidiasis and oral hairy leukoplakia. == Nervous system == == Muscular system == == References ==	Wikipedia/Oral_manifestations_of_systemic_disease
The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of inflammation. To perform the test, anticoagulated blood is traditionally placed in an upright tube, known as a Westergren tube, and the distance which the red blood cells fall is measured and reported in millimetres at the end of one hour. Since the introduction of automated analyzers into the clinical laboratory, the ESR test has been automatically performed. The ESR is influenced by the aggregation of red blood cells: blood plasma proteins, mainly fibrinogen, promote the formation of red cell clusters called rouleaux or larger structures (interconnected rouleaux, irregular clusters). As according to Stokes' law the sedimentation velocity varies like the square of the object's diameter, larger aggregates settle faster. While aggregation already takes place at normal physiological fibrinogen levels, these tend to increase when an inflammatory process is present, leading to increased ESR. The ESR is increased in inflammation, pregnancy, anemia, autoimmune disorders (such as rheumatoid arthritis and lupus), infections, some kidney diseases and some cancers (such as lymphoma and multiple myeloma). The ESR is decreased in polycythemia, hyperviscosity, sickle cell anemia, leukemia, chronic fatigue syndrome, low plasma protein (due to liver or kidney disease) and congestive heart failure. Although increases in immunoglobulins usually increase the ESR, very high levels can reduce it again due to hyperviscosity of the plasma. This is especially likely with IgM-class paraproteins, and to a lesser extent, IgA-class. The basal ESR is slightly higher in females. == Stages == Erythrocyte sedimentation rate (ESR) is the measure of ability of erythrocytes (red blood cell) to fall through the blood plasma and accumulate together at the base of container in one hour. There are three stages in erythrocyte sedimentation: Rouleaux formation Sedimentation or settling stage Packing stage - 10 minutes (sedimentation slows and cells start to pack at the bottom of the tube) In normal conditions, the red blood cells are negatively charged and therefore repel each other rather than stacking. ESR is also reduced by high blood viscosity, which slows the rate of fall. == Causes of elevation == The rate of erythrocyte sedimentation is affected by both inflammatory and non-inflammatory conditions. === Inflammation === In inflammatory conditions, fibrinogen, other clotting proteins, and alpha globulin are positively charged, thus increasing the ESR. ESR begins to rise at 24 to 48 hours after the onset of acute self-limited inflammation, decreases slowly as inflammation resolves, and can take weeks to months to return to normal levels. For ESR values more than 100 mm/hour, there is a 90% probability that an underlying cause would be found upon investigation. === Non-inflammatory conditions === In non-inflammatory conditions, plasma albumin concentration, size, shape, and number of red blood cells, and the concentration of immunoglobulin can affect the ESR. Non-inflammatory conditions that can cause raised ESR include anemia, kidney failure, obesity, ageing, and female sex. ESR is also higher in women during menstruation and pregnancy. The value of ESR does not change whether dialysis is performed or not. Therefore, ESR is not a reliable measure of inflammation in those with kidney injuries as the ESR value is already elevated. == Causes of reduction == An increased number of red blood cells (polycythemia) causes reduced ESR as blood viscosity increases. Hemoglobinopathy such as sickle-cell disease can have low ESR due to an improper shape of red blood cells that impairs stacking. == Medical uses == === Diagnosis === ESR can sometimes be useful in diagnosing diseases, such as multiple myeloma, temporal arteritis, polymyalgia rheumatica, various autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and chronic kidney diseases. In many of these cases, the ESR may exceed 100 mm/hour. It is commonly used for a differential diagnosis for Kawasaki's disease (from Takayasu's arteritis; which would have a markedly elevated ESR) and it may be increased in some chronic infective conditions like tuberculosis and infective endocarditis. It is also elevated in subacute thyroiditis also known as DeQuervain's. In markedly increased ESR of over 100 mm/h, infection is the most common cause (33% of cases in an American study), followed by cancer (17%), kidney disease (17%) and noninfectious inflammatory disorders (14%). Yet, in pneumonia the ESR stays under 100. The usefulness of the ESR in current practice has been questioned by some, as it is a relatively imprecise and non-specific test compared to other available diagnostic tests. Current literature suggests that an ESR should be "obtained on all patients over the age of 50" who have an intense headache. === Disease severity === It is a component of the PCDAI (pediatric Crohn's disease activity index), an index for assessment of the severity of inflammatory bowel disease in children. === Monitoring response to therapy === The clinical usefulness of ESR is limited to monitoring the response to therapy in certain inflammatory diseases such as temporal arteritis, polymyalgia rheumatica and rheumatoid arthritis. It can also be used as a crude measure of response in Hodgkin's lymphoma. Additionally, ESR levels are used to define one of the several possible adverse prognostic factors in the staging of Hodgkin's lymphoma. == Normal values == Note: mm/h. = millimeters per hour. Westergren's original normal values (men 3 mm/h and women 7 mm/h) made no allowance for a person's age. Later studies from 1967 confirmed that ESR values tend to rise with age and to be generally higher in women. Values of the ESR also appear to be slightly higher in normal populations of African-Americans than Caucasians of both genders. Values also appear to be higher in anemic individuals than non-anemic individuals. === Adults === The widely used rule calculating normal maximum ESR values in adults (98% confidence limit) is given by a formula devised in 1983 from a study of ≈1000 individuals over the age of 20: The normal values of ESR in men is age (in years) divided by 2; for women, the normal value is age (in years) plus 10, divided by 2. E S R ( m m / h ) ≤ A g e ( i n y e a r s ) + 10 ( i f f e m a l e ) 2 {\displaystyle {\rm {ESR}}\ (mm/h)\leq {\frac {{\rm {Age}}\ ({\it {in\ years}})+10\ ({\it {if\ female}})}{2}}} Other studies confirm a dependence of ESR on age and gender, as seen in the following: ESR reference ranges from a large 1996 study of 3,910 healthy adults (NB. these use 95% confidence intervals rather than the 98% intervals used in the study used to derive the formula above, and because of the skewness of the data, these values appear to be less than expected from the above formula): === Children === Normal values of ESR have been quoted as 1 to 2 mm/h at birth, rising to 4 mm/h 8 days after delivery, and then to 17 mm/h by day 14. Typical normal ranges quoted are: Newborn: 0 to 2 mm/h Neonatal to puberty: 3 to 13 mm/h, but other laboratories place an upper limit of 20. == Relation to C-reactive protein == C-reactive protein (CRP) is an acute phase protein. Therefore, it is a better marker for acute phase reaction than ESR. While ESR and CRP generally together correlate with the degree of inflammation, this is not always the case and results may be discordant in 12.5% of the cases. Cases with raised CRP but normal ESR may demonstrate a combination of infection and some other tissue damage such as myocardial infarction, and venous thromboembolism. Such inflammation may not be enough to raise the level of ESR. Those with high ESR usually do not have demonstrable inflammation. However, in cases of low grade bacterial infections of bone and joints such as coagulase negative staphylococcus (CoNS), and systemic lupus erythematosus (SLE), ESR can be a good marker for the inflammatory process. This may be due to the production of Interferon type I that inhibits the CRP production in liver cells during SLE. CRP is a better marker for other autoimmune diseases such as polymyalgia rheumatica, giant cell arteritis, post-operative sepsis, and neonatal sepsis. ESR may be reduced in those who are taking statins and non-steroidal anti-inflammatory drugs (NSAIDs). == History == The test was invented in 1897 by the Polish pathologist Edmund Biernacki. In some parts of the world the test continues to be referred to as Biernacki's Reaction (Polish: odczyn Biernackiego, OB). In 1918, Dr Robert Fåhræus noted that ESR differed only during pregnancy. Therefore, he suggested that ESR could be used as an indicator of pregnancy. In 1921, Dr Alf Vilhelm Albertsson Westergren used ESR to measure the disease outcome of tuberculosis. He defined the measurement standards of ESR which is still being used today. Robert Fåhræus and Alf Vilhelm Albertsson Westergren are eponymously remembered for the 'Fahraeus-Westergren test' (abbreviated as FW test; in the UK, usually termed Westergren test), which uses sodium citrate-anti-coagulated specimens. == Research == According to a study released in 2015, a stop gain mutation in HBB gene (p. Gln40stop) was shown to be associated with ESR values in Sardinian population. The red blood cell count, whose values are inversely related to ESR, is affected in carriers of this SNP. This mutation is almost exclusive of the inhabitants of Sardinia and is a common cause of beta thalassemia. According to a 2010 study, there is a reverse correlation between ESR and general intelligence (IQ) in Swedish males aged 18–20. == References == == External links == Mediscuss on ESR Brigden ML (October 1999). "Clinical utility of the erythrocyte sedimentation rate". American Family Physician. 60 (5): 1443–50. PMID 10524488. ESR at Lab Tests Online	Wikipedia/Erythrocyte_sedimentation_rate
The peritoneum is the serous membrane forming the lining of the abdominal cavity or coelom in amniotes and some invertebrates, such as annelids. It covers most of the intra-abdominal (or coelomic) organs, and is composed of a layer of mesothelium supported by a thin layer of connective tissue. This peritoneal lining of the cavity supports many of the abdominal organs and serves as a conduit for their blood vessels, lymphatic vessels, and nerves. The abdominal cavity (the space bounded by the vertebrae, abdominal muscles, diaphragm, and pelvic floor) is different from the intraperitoneal space (located within the abdominal cavity but wrapped in peritoneum). The structures within the intraperitoneal space are called "intraperitoneal" (e.g., the stomach and intestines), the structures in the abdominal cavity that are located behind the intraperitoneal space are called "retroperitoneal" (e.g., the kidneys), and those structures below the intraperitoneal space are called "subperitoneal" or "infraperitoneal" (e.g., the bladder). == Structure == === Layers === The peritoneum is one continuous sheet, forming two layers and a potential space between them: the peritoneal cavity. The outer layer, the parietal peritoneum, is attached to the abdominal wall and the pelvic walls. The tunica vaginalis, the serous membrane covering the male testis, is derived from the vaginal process, an outpouching of the parietal peritoneum. The inner layer, the visceral peritoneum, is wrapped around the visceral organs, located inside the intraperitoneal space for protection. It is thinner than the parietal peritoneum. The mesentery is a double layer of visceral peritoneum that attaches to the gastrointestinal tract. There are often blood vessels, nerves, and other structures between these layers. The space between these two layers is technically outside of the peritoneal sac, and thus not in the peritoneal cavity. The potential space between these two layers is the peritoneal cavity, filled with a small amount (about 50 mL) of slippery serous fluid that allows the two layers to slide freely over each other. The right paracolic gutter is continuous with the right and left subhepatic spaces. The epiploic foramen allows communication between the greater sac and the lesser sac. The peritoneal space in males is closed, while the peritoneal space in females is continuous with the extraperitoneal pelvis through openings of the fallopian tubes, the uterus, and the vagina. === Subdivisions === Peritoneal folds are omentums, mesenteries and ligaments; they connect organs to each other or to the abdominal wall. There are two main regions of the peritoneal cavity, connected by the omental foramen. The greater sac, represented in red in the diagrams above. The lesser sac, represented in blue. The lesser sac is divided into two "omenta": The lesser omentum (or hepatogastric) is attached to the lesser curvature of the stomach and the liver. The greater omentum (or gastrocolic) hangs from the greater curvature of the stomach and loops down in front of the intestines before curving back upwards to attach to the transverse colon. In effect it is draped in front of the intestines like an apron and may serve as an insulating or protective layer. The mesentery is the part of the peritoneum through which most abdominal organs are attached to the abdominal wall and supplied with blood and lymph vessels and nerves. ==== Omenta ==== ==== Mesenteries ==== ==== Other ligaments and folds ==== In addition, in the pelvic cavity there are several structures that are usually named not for the peritoneum, but for the areas defined by the peritoneal folds: === Classification of abdominal structures === The structures in the abdomen are classified as intraperitoneal, mesoperitoneal, retroperitoneal or infraperitoneal depending on whether they are covered with visceral peritoneum and whether they are attached by mesenteries (mensentery, mesocolon). Structures that are intraperitoneal are generally mobile, while those that are retroperitoneal are relatively fixed in their location. Some structures, such as the kidneys, are "primarily retroperitoneal", while others such as the majority of the duodenum, are "secondarily retroperitoneal", meaning that structure developed intraperitoneally but lost its mesentery and thus became retroperitoneal. === Development === The peritoneum develops ultimately from the mesoderm of the trilaminar embryo. As the mesoderm differentiates, one region known as the lateral plate mesoderm splits to form two layers separated by an intraembryonic coelom. These two layers develop later into the visceral and parietal layers found in all serous cavities, including the peritoneum. As an embryo develops, the various abdominal organs grow into the abdominal cavity from structures in the abdominal wall. In this process they become enveloped in a layer of peritoneum. The growing organs "take their blood vessels with them" from the abdominal wall, and these blood vessels become covered by peritoneum, forming a mesentery. Peritoneal folds develop from the ventral and dorsal mesentery of the embryo. == Clinical significance == === Imaging assessment === CT scan is a fast (15 seconds) and efficient way in visualising the peritoneal spaces. Although ultrasound is good at visualizing peritoneal collections and ascites, without ionising radiation, it does not provide a good overall assessment of all the peritoneal cavities. MRI scan is also increasingly used to visualise peritoneal diseases, but requires long scan time (30 to 45 minutes) and prone to motion artifacts due to respiration and peristalsis and chemical shift artifacts at the bowel-mesentery interface. Those with peritoneal carcinomatosis, acute pancreatitis, and intraabdominal sepsis may not tolerate prolonged MRI scan. === Peritoneal dialysis === In one form of dialysis, called peritoneal dialysis, a glucose solution is sent through a tube into the peritoneal cavity. The fluid is left there for a prescribed amount of time to absorb waste products, and then removed through the tube. The reason for this effect is the high number of arteries and veins in the peritoneal cavity. Through the mechanism of diffusion, waste products are removed from the blood. === Peritonitis === Peritonitis is the inflammation of the peritoneum. It is more commonly associated to infection from a punctured organ of the abdominal cavity. It can also be provoked by the presence of fluids that produce chemical irritation, such as gastric acid or pancreatic juice. Peritonitis causes fever, tenderness, and pain in the abdominal area, which can be localized or diffuse. The treatment involves rehydration, administration of antibiotics, and surgical correction of the underlying cause. Mortality is higher in the elderly and if present for a prolonged time. === Primary peritoneal carcinoma === Primary peritoneal cancer is a cancer of the cells lining the peritoneum. == Etymology == "Peritoneum" is derived from Greek: περιτόναιον, romanized: peritonaion, lit. 'peritoneum, abdominal membrane' via Latin. In Greek, περί, peri means "around", while τείνω, teino means "to stretch"; thus, "peritoneum" means "stretched over". == Additional images == == See also == Duodenorenal ligament Omental bursa (Lesser sac) Greater sac Omental foramen (Epiploic foramen, Foramen of Winslow) Lesser omentum Greater omentum == References == == External links ==	Wikipedia/Peritoneal_disease
Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms. Inflammatory bowel disease (IBD), a collection of systemic diseases involving inflammation of the gastrointestinal tract, includes two (or three) diseases of unknown causation: ulcerative colitis, which affects only the large bowel; Crohn's disease, which can affect the entire gastrointestinal tract; and indeterminate colitis, which consists of large bowel inflammation that shows elements of both Crohn's disease and ulcerative colitis. Although the causes of these diseases are unknown, genetic, environmental, immune, and other mechanisms have been proposed. Of these, the immune system plays a large role in the development of symptoms. Given this, a variety of biological therapies (such as TNF inhibitors and interleukin antagonists) have been developed for the treatment of these diseases. Although the use of antibodies to treat diseases can be dated back to the 1800s, biologic therapy as we know it today is a relatively new concept for the treatment of inflammatory bowel disease. The previous treatment options had many shortcomings, and the introduction of biological therapy changed the way physicians treat Crohn's disease and ulcerative colitis. Even so, biologic therapy still has its faults such as high cost and risk of side effects. A lot of research is being done in fields like biosimilars and oral delivery to address these concerns. == History == The use of antibodies to treat diseases can be traced all the way back to the late 1800s with the advent of diphtheria antitoxin for the treatment of diphtheria. It wasn't until the 1900s that the newly emerging class of naturally derived medications such as sera, vaccines, and antitoxins began to be referred to as biologics. The definition for biologics and biological therapy has changed a lot since. The development of recombinant DNA technology in the 1970s shaped the modern understanding of what constitutes as biological therapy, which often does not include traditional biological substances like vaccines. Today, biological therapy most commonly refers to the use of proteins, such as monoclonal antibodies, to regulate the immune system in the treatment of disease. In 1975, Georges J. F. Köhler and César Milstein generated the first monoclonal antibodies using their own hybridoma technology. They started the field of monoclonal antibody development and won the Nobel Prize for Medicine in 1984 for their work. Soon after, muromonab-CD3 became the first fully licensed monoclonal antibody in 1986 for its use in treating kidney transplant rejection. Since then, over 70 monoclonal antibodies have been approved by the FDA. The advancements in biological therapy greatly changed how IBD is treated. Patients with Crohn's disease and ulcerative colitis show an increase in proinflammatory cytokines such as IL-1, IL-6, IL-8, IL-23, and TNF. In 1988, a monoclonal antibody called infliximab was discovered at New York University's School of Medicine. Infliximab works by binding to TNF, stopping its inflammatory effects. It was initially used for the treatment of Crohn's disease and it became the first FDA approved TNF inhibitor in 1998. Infliximab as well as other TNF inhibitors like adalimumab, certolizumab, and golimumab are currently the most common biologics used in the treatment of both Crohn's disease and ulcerative colitis. The other main categories of biologics that treat IBD are integrin receptor antagonists such as vedolizumab and natalizumab and interleukin antagonists like ustekinumab. == Rationale for biological therapy == Prior to the development of biological therapy as a modality to treat IBD, other medications that modulate the immune system—including 5-aminosalicylates, steroids, azathioprine, and other immunosuppressants—were primarily used in treatment. Corticosteroids are effective in inducing clinical remission in patients with active IBD, but they can't be used long term due to the risk of steroid-dependence and harsh side effects. The other medications like 5-aminosalicylates and azathioprine are often used to reduce steroid use while maintaining remission, but their actual effect on the state of the disease and the need for surgery remains unknown. Patients with Crohn's disease that developed complications, including fistulae (= abnormal connections to the bowel) were treated with surgery. Patients with ulcerative colitis who do not respond to medications are still treated with colectomy (= removal of the colon). However, basic science research showed that many cytokines were elevated in both Crohn's disease and ulcerative colitis. Crohn's disease cytokines are of the type 1 (Th1) cytokines, which include TNF-α, interleukin-2, and interferon γ. Ulcerative colitis was less conclusively linked to the production of Th2 cytokines. TNF inhibiting biological therapies were initially used in IBD patients who weren't responding to conventional therapy. They proved to be very effective in some patients, shifting treatment goals from simply improving symptoms to actually changing the course of the disease by reversing mucosal inflammation and preventing long-term complications and surgery. Although there are strong initial responses in some patients, biologic therapies also have their downsides, and there is still a debate as to what the most effective treatment strategy is. == TNF inhibitors == TNF inhibitors are commonly the first drug prescribed when a patient begins biologic therapy. They have the most extensive history of clinical evidence because they have been available the longest, are the most accessible, and are often the least expensive. Initially, it was thought that TNF inhibitors inactivate the proinflammatory cytokine by direct neutralization, but TNF signaling is a very complex process. Many recent studies suggest that TNF inhibitors may act with a more complex mechanism than simple blockade. They are all administered systemically either subcutaneously or intravenously. === Infliximab === The monoclonal antibody infliximab is a mouse-human chimeric antibody to TNF-α. The FDA approved it in 1998, making it the first approved TNF inhibitor. Infliximab has shown significant success in treating both Crohn's disease and ulcerative colitis, but it is also approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. === Adalimumab === Adalimumab was approved by the FDA in 2002, becoming the first fully human monoclonal antibody to be approved. It was initially used in the treatment of rheumatoid arthritis, but it is now also used in patients with moderate-to-severe Crohn's disease and ulcerative colitis who don't respond well to conventional treatment. Adalimumab showed effectiveness in patients with Crohn's disease, but less than that of infliximab. It was the best selling drug in 2017 with sales upwards of $18 billion. === Certolizumab pegol === Certolizumab pegol is a recombinant antigen-binding fragment antibody that is attached to a 40kDa polyethylene glycol. The addition of polyethylene glycol, or PEGylation, increases bioavailability, drug stability, and plasma half-life. It was found to have efficacy over placebo medications for 10 weeks in the treatment of moderate to severe Crohn's disease in one large trial. It is not used in the treatment of ulcerative colitis, but it is used in the treatment of rheumatoid arthritis, active psoriatic arthropathy, and ankylosing spondylitis. === Golimumab === Golimumab is a fully human IgG1 monoclonal antibody that was first approved by the FDA in 2009 to treat rheumatoid arthritis. Since, it has been approved to also treat psoriatic arthritis, ankylosing spondylitis, and moderately to severely active ulcerative colitis. == Integrin receptor antagonists == Integrin receptor antagonists are different than TNF inhibitors because they block transmembrane receptors called integrins instead of cytokines like TNF. Integrins mediate adhesion, signaling, and migration in many different types of cells. During active periods of disease, cell adhesion molecules on the vascular endothelium increase in response to various proinflammatory cytokines. The alpha 4 integrin on inflammatory cells interacts with these adhesion molecules to allow for migration. Integrin receptor antagonists block the interaction and prevent the migration of inflammatory cells to disease sites. === Natalizumab === Natalizumab is a humanized IgG4 monoclonal antibody that inhibits the alpha 4 integrin. It was the first integrin receptor antagonist, receiving FDA approval in 2004 for the treatment of Crohn's disease. It was approved for the treatment of multiple sclerosis as well, but there have been concerns due to reports of progressive multifocal leukoencephalopathy. === Vedolizumab === Vedolizumab is very similar to natalizumab in that it is a humanized IgG monoclonal antibody, but vedolizumab is an IgG1 that specifically blocks the alpha 4 beta 7 integrin that is located primarily on cells in the gastrointestinal tract. It is promoted as being gut specific due to the localization of alpha 4 beta 7 integrin in the gastrointestinal tract and was the first biologic to be made specifically for inflammatory bowel disease. == Interleukin antagonists == Interleukins are a cytokine that play a major role in the immune system. IL-12 and IL-23 help with the activation and differentiation of natural killer cells and CD4+ T lymphocyte, both of which contribute to inflammation. Interleukin antagonists, the most recent class of biologics available for use in IBD, inhibit the action of IL-12 and IL-23 by binding to the p40 protein subunit that is found on both of these cytokines. === Ustekinumab === Ustekinumab was approved by the FDA in 2009 for the treatment of plaque psoriasis, making it the first and so far the only approved interleukin antagonist. It is also used for the treatment of Crohn's disease and psoriatic arthritis. Studies suggest that the blocking of IL-23, rather than IL-12, has the greatest effect on the therapeutic benefits of ustekinumab. == Biosimilars == When the patent period of a drug ends, a generic version is usually made. With conventional small-molecule drugs, it is possible to create a generic that is exactly the same as the original because small-molecule drugs can be characterized down to a single atom. However, the structure of biologics is far more complex and can't be fully characterized with current analytical techniques. Also, the cell-based manufacturing process of biologics results in undefinable post-translational modifications. Thus, it is impossible to prove whether two biologics are exactly the same in every aspect. There are no generic versions of biologics. Instead there are biosimilars. Biosimilars are defined by the FDA as, "a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product." Currently, the only two biologic treatments for IBD that have approved biosimilars are adalimumab and infliximab. == Side effects and concerns == Biologics are known to sometimes cause harsh side effects. Currently, Biologics are only delivered systemically. They can't be delivered orally because the harsh environment of the gastrointestinal tract would breakdown the drug before it could reach the diseased tissue. Because systemic administration results in blockading the same pathway in both healthy and diseased tissue, pharmacology is exaggerated leading to many side effects such as lymphoma, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, injection site reactions, and additional systemic side effects. Patients often wait until after other treatment options have failed to begin biological therapy because biologics are extremely expensive. One study modeled that, in the US, the average yearly cost of biological therapy for inflammatory bowel disease was around $36,000. The treatment of inflammatory bowel diseases, with an estimated direct cost of $5.9 billion annually, poses a significant economic burden on the health care system. Recently, the primary treatment cost has shifted from hospitalization to medication. The shift is due to the rising use of these expensive biologics as well as their ability to reduce the need for hospitalization. Overtime, patients can lose response to biologics even after an initial positive response. Because biologics are foreign substances to the body, they can prompt an immunological response causing the development of anti-drug antibodies. Anti-drug antibodies can cause negative side effects, accelerate the rate of drug clearance, and reduce the therapeutic effects of the biologic. In clinical practice, less than 50% of patients who showed an initial positive response to biological therapy were in remission after one year. The development of anti-drug antibodies can be reduced by limiting any times when there is no biologic present in the body and by taking other immunosuppressants (such as thiopurines or methotrexate) in combination. == Research == New biologic therapies that target both existing cellular targets (including IL-12 and IL-23) and new cellular targets are being developed. Brazikumab and risankizumab are both IL-23 specific antagonists, opposed to ustekinumab which targets both IL-12 and IL-23, that have shown efficacy in phase 2 trials for Crohn's disease. Etrolizumab is an integrin receptor antagonist that targets beta 7 integrins. Etrolizumab has shown efficacy in phase 2 trials as well. The hope is that etrolizumab can show similar efficacy to natalizumab while avoiding the specific cellular target that is believed to have caused the instances of progressive multifocal leukoencephalopathy. Another area of research is focusing on the personalization of biological therapy. The idea is to use a specific patient's biochemical or genetic profile to predict how a patient will respond to a biological therapy. The information could help inform which class of biologics to use first. Personalized medicine is already being used in practice in the oncology field. A lot of research is being done to develop a biologic that can be delivered orally to address the many drawbacks associated with systemic administration. The general consensus in the field is that oral delivery of biologics directly to the diseased tissue could greatly reduce side effects, the development of anti-drug antibodies, and the cost of treatment. == See also == Treatment of Crohn's disease Essential fatty acid interactions == References ==	Wikipedia/Biological_therapy_for_inflammatory_bowel_disease
Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of the adaptive immune system, people with autoinflammatory diseases do not produce autoantibodies or antigen-specific T or B cells. Instead, the autoinflammatory diseases are characterized by errors in the innate immune system. The syndromes are diverse, but tend to cause episodes of fever, joint pains, skin rashes, abdominal pains and may lead to chronic complications such as amyloidosis. Most autoinflammatory diseases are genetic and present during childhood. The most common genetic autoinflammatory syndrome is familial Mediterranean fever, which causes short episodes of fever, abdominal pain, serositis, lasting less than 72 hours. It is caused by mutations in the MEFV gene, which codes for the protein pyrin. Pyrin is a protein normally present in the inflammasome. The mutated pyrin protein is thought to cause inappropriate activation of the inflammasome, leading to release of the pro-inflammatory cytokine IL-1β. Most other autoinflammatory diseases also cause disease by inappropriate release of IL-1β. Thus, IL-1β has become a common therapeutic target, and medications such as anakinra, rilonacept, and canakinumab have revolutionized the treatment of autoinflammatory diseases. However, there are some autoinflammatory diseases that are not known to have a clear genetic cause. This includes PFAPA, which is the most common autoinflammatory disease seen in children, characterized by episodes of fever, aphthous stomatitis, pharyngitis, and cervical adenitis. Other autoinflammatory diseases that do not have clear genetic causes include adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, Schnitzler syndrome, and chronic recurrent multifocal osteomyelitis. It is likely that these diseases are multifactorial, with genes that make people susceptible to these diseases, but they require an additional environmental factor to trigger the disease. == Individual periodic fever syndromes == == See also == Kawasaki disease - possible autoinflammatory mechanism Multisystem inflammatory syndrome in children List of cutaneous conditions == References == == Further reading == Hobart A. Reimann, Periodic Disease: a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. JAMA, 1948. Hobart A Reimann, Periodic Disease: periodic fever, periodic abdominalgia, cyclic neutropenia, intermittent arthralgia, angioneurotic edema, anaphylactoid purpura and periodic paralysis. JAMA, 1949. Hobart A Reimann, Moadié, J; Semerdjian, S; Sahyoun, PF, Periodic Peritonitis—Heredity & Pathology: report of seventy-two cases. JAMA, 1954. Hobart A Reimann, Periodic fever, an entity: A collection of 52 cases. AmJMedSci, 1962. == External links == Understanding Autoinflammatory Diseases - US National Institute of Arthritis and Musculoskeletal and Skin Diseases	Wikipedia/Autoinflammatory_disease
Darier's disease (DD) is a rare, genetic skin disorder. It is an autosomal dominant disorder, that is, if one parent has DD, there is a 50% chance than a child will inherit DD. It was first reported by French dermatologist Ferdinand-Jean Darier in 1889. Mild forms of the disease are the most common, consisting of skin rashes that flare up under conditions such as high humidity, high stress, or tight-fitting clothes. Short stature, combined with poorly-formed fingernails that contain vertical striations, is diagnostic even for mild forms. Symptoms usually appear in late childhood or early adulthood between the ages of about 15 and 30 years and will vary over the lifespan in an intermittent pattern of relapse (flareups) and remit. More severe cases are characterized by dark crusty patches on the skin that are mildly greasy and that can emit a strong odor. These patches, also known as keratotic papules, keratosis follicularis, or dyskeratosis follicularis, most often appear on the arms, chest, back and legs. DD was initially studied by dermatologists. Recent research however shows DD has a whole-body effect, including cognitive (learning and intellectual) deficits, and mental health issues, particularly depression. == Diagnosis and symptoms == Diagnosis of Darier disease is often made by the appearance of the skin and nails, family history, and/or genetic testing for the mutation in the ATP2A2 gene. However, many individuals are never diagnosed because of the mildness of their symptoms. Mild cases present clinically as minor rashes (without odor) that can become exacerbated by heat, humidity, stress, and sunlight. Clinical symptoms of the disease: Fragile or poorly formed fingernails with vertical striations (as distinct from nail biting). The malformed nails often have V-shaped nicks at the edge of the nail. Rash that covers many areas of the body, sometimes with weeping. In severe cases, it is often associated with an unpleasant odor. The rash can be aggravated by heat, humidity, and exposure to sunlight. Seborrhoeic areas. Areas where excess oil and sebum is released. Overall greasy or scaly skin either in the central chest and back or in the folds of the skin. Painful skin and itching (pruritus). Other less common or less noticed symptoms are: Acrokeratosis verruciformis. Acrokeratosis (AKV) is characterized by several small wart-like and flat-topped bumps that line the skin on typically the hand and feet. Hypermelanotic macule. Dark patches on the skin that contain excess pigment. Subungual hyperkeratotic fragments. Thickened skin that is often discolored, under nails, on either hands or feet. == Epidemiology and mental health == Worldwide prevalence of DD is estimated as between 1:30,000 and 1:100,000. Case studies have shown estimated prevalence by country to be 3.8:100,000 in Slovenia, 1:36,000 in north-east England, 1:30,000 in Scotland, and 1:100,000 in Denmark. DD is seen in males and females equally. Symptoms typically arise between the ages of about 15 and 30, and vary over the lifetime in a relapse and remit pattern, in particular flareups that need to be managed. DD is inherited (genetic), and in particular can be traced in family groups in specific geographic localities. Darier's disease is a non-communicable disorder, but secondary infections by bacteria and viruses can be spread to others. DD was initially identified and studied by dermatologists (skin specialists) as a purely skin disease. Recent research however suggests DD has a whole-body effect, including cognitive and mental health issues. A study of 100 British individuals diagnosed with Darier's disease reported that affected individuals display elevated frequencies of neuropsychiatric conditions. They had high lifetime rates for mood disorders (50%), including depression (30%), bipolar disorder (4%), suicidal thoughts (31%), and suicide attempts (13%). A Swedish study of 770 individuals with DD showed a six-fold risk of being diagnosed with an intellectual disability, compared to matched Swedish population controls. A study of 76 DD patients found that 41% reported learning difficulties, notably reading difficulties, and 74% reported a family history of learning disabilities. The full range of learning difficulties is not known. == Etiology and genetics == Skin changes in Darier's disease are related to a type of nutritional vitamin A deficiency that is caused by genetic mutations (thtat is, DD is a systemic Vitamin A deficiency). The skin displays follicular dyskeratosis (degeneration of the skin in hair follicules), which reflects as hypovitaminosis A. The skin reactions are caused by an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion. Mutations in a single gene, ATP2A2, are the ultimate cause for the development of Darier's disease. It is an autosomal dominant disorder, that is, if one parent has DD, there is a 50% chance than a child will inherit DD. === Subtypes of Darier's disease === Subtypes of DD have been preliminarily suggested. A large number of mutant alleles of ATP2A2 have been identified in association with Darier's Disease. One study of 19 families and 6 sporadic cases found 24 specific, novel mutations associated with DD symptoms. This study reported a loose, imperfect correlation between the severity of ATP2A2 mutations with the severity of the condition. Significant variability in disease severity between members of the same family carrying the same mutation was also reported by this study, suggesting that genetic modifiers contribute to the phenotypic penetrance of certain mutations. One subtype is linear Darier's disease. These cases result from somatic mutations to ATP2A2 in epidermal stem cells. Such individuals display phenotypic mosaicism, where the Darier's phenotype only affects the subset of epidermal tissue arising from the mutated progenitor cell. Somatic mutations are not inherited by the offspring of such individuals. == Treatment == Two recent reviews of the medical literature have evaluated treatment strategies for DD. Management and treatment of Darier disease depends on the severity of the presented clinical symptoms. Mild symptoms are often treated with moisturising creams, and more severe symptoms with topical and oral retinol or other medications (oral medications having higher strength than topical equivalents), and medical procedures. In many mild cases, DD can be managed by avoiding excessive perspiration and non-breathable and abrasive clothing (producing contact dermatitis), washing with salty water, and gentle abrasion with a gauze pad. This is supplemented by moisturising lotions and topical sunscreens. Most patients with Darier's disease can live normal healthy lives. In more severe cases of DD, application of topical and oral medications, particularly retinoids, is prescribed. Hospitalisation may be required for seriously affected individuals who display frequent relapse and remit patterns and severe infections. Rapid resolution of rash symptoms can be complicated by the increased vulnerability of affected skin surfaces to secondary bacterial or viral infections. Bacterial overgrowth can produce an odour. The main bacteria is epidermal Staphylococcus aureus. The main viruses are human papillomavirus (HPV) and herpes simplex virus (HSV). Infections are treated with antibiotics (for bacteria) and antiviral medications (for viruses). Treatments that have evidence-based support (though not for all persons treated) can be classified into a number of groups. Because DD is a product of systemic Vitamin A deficiency, retinoids, chemical compounds (molecules) that are forms of (or related to) Vitamin A, are often recommended. Vitamin A acid compounds are often preferred as being less toxic than Vitamin A itself. 1. Topical medications: Retinoids (Adapalene, Tretinoin, Isotretinoin, Tazarotene gel). Topical retinoids help in the reduction of hyperkeratosis. They work by causing the skin cells in the top layers to die and be shed off. Vitamin A analogs (Calciptriol, Tacalitol). 2. Other topical medications. 5-fluouracil, a chemotherapeutic agent. Benzoyal peroxide 5% gel. Antibacterial effect and removes dead skin, but frequent use can cause skin irritation and other side effects, as well as bleaching of hair and clothes. Topical corticosteroids. 3. Oral medications: Retinoids (Acitretin, Isotretinoin). If symptoms are severe, oral retinoids have been proven to be very effective. However, there can be many adverse (and sometimes serious) side-effects associated with prolonged use. Systemic Vitamin A analogs. 4. Medical Procedures: Surgical excision and dermabrasion, laser procedures, radiation procedures (grenz-ray, X-ray, radiology). Dermabrasion. Removal of the top layer of skin to help smooth and stimulate new growth of the skin. Electrosurgery. Used to help stop bleeding and remove abnormal skin growths. == Support groups == Further information on and advocacy work for Darier's disease are provided by support groups. FIRST Skin Foundation (Foundation for Ichthyosis and Related Skin Disorders, Colmar, Pennsylvania). Ichthyosis refers to a group of skin disorders characterised by dry, scaly or thickened skin (mostly inherited, including DD). == History == Darier's disease was first described by the French dermatologist Ferdinand-Jean Darier in the journal Annales de dermatologie et de syphilographie. Darier was a well-regarded dermatologist of the time who was the head of the medical department at the Hôpital Saint-Louis. Darier was an early proponent of histopathology, or the examination of samples of diseased flesh under a microscope to determine the cause of illnesses. Using this technique, he was able to uncover the origins of Darier's disease and a host of others that also bear his name. James Clarke White, a dermatologist at Harvard Medical School, independently characterized and published his observations on this dermatological disorder in the same year as Darier (1889), which is why DD is sometimes referred to as Darier-White disease. === Court case === In Singapore, a man escaped the death penalty for murder as a result of Darier's disease. Ong Teng Siew, a Malaysian chicken slaughterer aged 27, was charged with murdering an 82-year-old opium addict Ng Gee Seh in December 1995. Ong was sentenced to death in August 1996 after the trial court found him guilty of murder, and while he was appealing against his conviction, Ong was hospitalized in September 1996 for an outbreak of Darier's disease, which had previously went undiagnosed. After his lawyer discovered that the disease had a causal link to psychiatric disorders, this new evidence enabled Ong to successfully apply for a re-trial. The court accepted the new evidence and that Ong was suffering from diminished responsibility as a result of Darier's disease, and therefore he was found guilty of a lesser offence of manslaughter and was re-sentenced to life imprisonment. == See also == Linear Darier disease List of cutaneous conditions Darier's sign Familial disseminated comedones without dyskeratosis == Notes == === References === === Sources === Cardoso, Camila Lopes; Freitas, Patrícia; Taveira, Luís Antônio de Assis; Consolaro, Alberto (2006). "Darier disease: case report with oral manifestations" (PDF). Medicina Oral Patologia Oral y Cirugia Bucal. 11 (E404-6): E404-6. eISSN 1698-6946. PMID 16878056.	Wikipedia/Darier's_disease
In evolutionary biology, function is the reason some object or process occurred in a system that evolved through natural selection. That reason is typically that it achieves some result, such as that chlorophyll helps to capture the energy of sunlight in photosynthesis. Hence, the organism that contains it is more likely to survive and reproduce, in other words the function increases the organism's fitness. A characteristic that assists in evolution is called an adaptation; other characteristics may be non-functional spandrels, though these in turn may later be co-opted by evolution to serve new functions. In biology, function has been defined in many ways. In physiology, it is simply what an organ, tissue, cell or molecule does. In the philosophy of biology, talk of function inevitably suggests some kind of teleological purpose, even though natural selection operates without any goal for the future. All the same, biologists often use teleological language as a shorthand for function. In contemporary philosophy of biology, there are three major accounts of function in the biological world: theories of causal role, selected effect, and goal contribution. == In pre-evolutionary biology == In physiology, a function is an activity or process carried out by a system in an organism, such as sensation or locomotion in an animal. This concept of function as opposed to form (respectively Aristotle's ergon and morphê) was central in biological explanations in classical antiquity. In more modern times it formed part of the 1830 Cuvier–Geoffroy debate, where Cuvier argued that an animal's structure was driven by its functional needs, while Geoffroy proposed that each animal's structure was modified from a common plan. == In evolutionary biology == Function can be defined in a variety of ways, including as adaptation, as contributing to evolutionary fitness, in animal behaviour, and, as discussed below, also as some kind of causal role or goal in the philosophy of biology. === Adaptation === A functional characteristic is known in evolutionary biology as an adaptation, and the research strategy for investigating whether a character is adaptive is known as adaptationism. Although assuming that a character is functional may be helpful in research, some characteristics of organisms are non-functional, formed as accidental spandrels, side effects of neighbouring functional systems. === Natural selection === From the point of view of natural selection, biological functions exist to contribute to fitness, increasing the chance that an organism will survive to reproduce. For example, the function of chlorophyll in a plant is to capture the energy of sunlight for photosynthesis, which contributes to evolutionary success. == In ethology == The ethologist Niko Tinbergen named four questions, based on Aristotle's Four Causes, that a biologist could ask to help explain a behaviour, though they have been generalised to a wider scope. 1) Mechanism: What mechanisms cause the animal to behave as it does? 2) Ontogeny: What developmental mechanisms in the animal's embryology (and its youth, if it learns) created the structures that cause the behaviour? 3) Function/adaptation: What is the evolutionary function of the behaviour? 4) Evolution: What is the phylogeny of the behaviour, or in other words, when did it first appear in the evolutionary history of the animal? The questions are interdependent, so that, for example, adaptive function is constrained by embryonic development. == In philosophy of biology == Function is not the same as purpose in the teleological sense, that is, possessing conscious mental intention to achieve a goal. In the philosophy of biology, evolution is a blind process which has no 'goal' for the future. For example, a tree does not grow flowers for any purpose, but does so simply because it has evolved to do so. To say 'a tree grows flowers to attract pollinators' would be incorrect if the 'to' implies purpose. A function describes what something does, not what its 'purpose' is. However, teleological language is often used by biologists as a shorthand way of describing function, even though its applicability is disputed. In contemporary philosophy of biology, there are three major accounts of function in the biological world: theories of causal role, selected effect, and goal contribution. === Causal role === Causal role theories of biological function trace their origin back to a 1975 paper by Robert Cummins. Cummins defines the functional role of a component of a system to be the causal effect that the component has on the larger containing system. For example, the heart has the actual causal role of pumping blood in the circulatory system; therefore, the function of the heart is to pump blood. This account has been objected to on the grounds that it is too loose a notion of function. For example, the heart also has the causal effect of producing a sound, but we would not consider producing sound to be the function of the heart. === Selected effect === Selected effect theories of biological functions hold that the function of a biological trait is the function that the trait was selected for, as argued by Ruth Millikan. For example, the function of the heart is pumping blood, for that is the action for which the heart was selected for by evolution. In other words, pumping blood is the reason that the heart has evolved. This account has been criticized for being too restrictive a notion of function. It is not always clear which behavior has contributed to the selection of a trait, as biological traits can have functions, even if they have not been selected for. Beneficial mutations are initially not selected for, but they do have functions. === Goal contribution === Goal contribution theories seek to carve a middle ground between causal role and selected effect theories, as with Boorse (1977). Boorse defines the function of a biological trait to be the statistically typical causal contribution of that trait to survival and reproduction. So for example, zebra stripes were sometimes said to work by confusing predators. This role of zebra stripes would contribute to the survival and reproduction of zebras, and that is why confusing predators would be said to be the function of zebra stripes. Under this account, whether or not a particular causal role of a trait is its function depends on whether that causal role contributes to the survival and reproduction of that organism. == See also == Preadaptation == References ==	Wikipedia/Biological_function
Protein losing enteropathy (PLE) is a syndrome in which blood proteins are lost excessively via the gastrointestinal (GI) tract. It may be caused by many different underlying diseases that damage the lining of the GI tract (mucosa) or cause blockage of its lymphatic drainage. == Signs and symptoms == The signs and symptoms of protein losing enteropathy include diarrhea, fever, and general abdominal discomfort. Swelling of the legs due to peripheral edema can also occur; however, if the PLE is related to a systemic disease such as congestive heart failure or constrictive pericarditis, then these symptoms could be due directly to the underlying illness. In severe cases, anasarca, a generalized form of edema, may develop. == Causes == The causes of protein-losing enteropathy can include GI conditions (among other causes), like the following: == Mechanism == The pathophysiology of protein losing enteropathy is a result of plasma protein loss to the GI tract lumen. PLE is a complication of a disorder, be it lymphatic obstruction or mucosal injury. Protein losing enteropathy is a syndrome, characterized by a collection of signs and symptoms that are due to an underlying primary medical condition. Thus, there are many different pathophysiologic mechanisms of intestinal protein loss. Erosive disease, is characterized by mucosal damage or erosions of the colon intestinal epithelium and capillary bed underlying the epithelium, leading to a leakage of proteins from the capillaries into the interstitial space and then into the intestinal lumen where they are lost from the body. This type of inflammation may be seen in inflammatory bowel diseases, peptic ulcers and infections. A second pathological mechanism, the non-erosive type, is characterized by increased intestinal permeability causing protein to be lost from the interstitium into the intestinal lumen. This increased intestinal permeability may be seen in eosinophilic gastroenteritis and other conditions causing increased inflammation in the gut, or certain genetic disorders affecting the cell adhesions between gut enterocytes. And a third type is due to intestinal lymphangiectasia in which the lymphatic vessels that drain interstitial fluid from the gut are damaged, leading to a blockage of lymphatic drainage and a buildup of interstitial fluid near the gut, thus causing leakage of proteins into the gut. This may be due to primary or congenital disease states of the lymphatic system or secondary (acquired) damage to the lymphatic system. Possible secondary causes of lymphangiectasis include congestive heart failure or constrictive pericarditis. These conditions cause an increase in the central venous pressure. The lymphatic system drains into the central venous system following a negative pressure gradient to the subclavian vein via the thoracic duct or right lymphatic duct. However, any pathological mechanism that leads to increased central venous pressure may also cause increased lymphatic pressure, thus impairing lymphatic drainage at the gut and lead to protein losing enteropathy. Certain infections such as Whipple disease can also lead to impaired lymphatic drainage by destroying the lymphatic lacteals, which are lymphatic capillaries underlying intestinal villi and facilitating the drainage of lymph from the gut. Congenital disorders of the lymphatic system such as Primary Intestinal Lymphangiectasia are due to congenitally dilated or malformed lacteals that lead to lymph leakage into the small bowel, causing protein loss and protein losing enteropathy. The widespread hypoproteinemia seen in protein losing enteropathy may present with complications related to the specific proteins lost, especially in severe disease. A decrease in antibodies (also known as immune globulins) may lead to an increased susceptibility to infections. And the loss of inhibitory coagulation factors may lead to a hypercoagulable state. In pediatric protein losing enteropathy, changes in epithelial cells contribute to the pathogenesis of PLE by augmenting the rate of efflux of serum proteins. Congenital molecular mutations, poor lymphatic drainage and/or inflammation may cause epithelial matrix changes. The absence of proteoglycans, which are glycosaminoglycan chains attached to protein, may contribute to PLE and augment inflammatory cytokines. Children who have certain congenital glycosylation defects may have protein losing enteropathy. == Diagnosis == The diagnosis of protein losing enteropathy is made by excluding other causes of protein loss. Endoscopy can be used to localize the cause of the protein loss in the bowel. Different methods of quantifying protein loss in the bowel include faecal excretion of alpha 1-antitrypsin, a marker of protein losing enteropathy, as well as viral serologies, which may be useful to determine the cause of the PLE. Alpha 1-antitrypsin is a blood protein that is lost in the gut, however, it is not actively secreted or absorbed by the gut, and it resists proteolysis in the gut lumen, thus making it a preferred protein for quantification of gut protein loss in protein losing enteropathy. Fecal alpha 1-antitrypsin may be quantified in a random stool sample, or more accurately, in a 24-hour stool sampling to quantify the amount of protein loss in PLE. In suspected cases of local disease, or when PLE is suspected to be due to lymph drainage abnormalities, lymphangiography may be used to localize the areas of lymphatic leakage. Imaging of the thoracic or abdominopelvic cavities may also aid in the diagnosis, possibly by identifying masses impairing lymphatic and venous drainage from the intestines and thus contributing to PLE. == Treatment == Treatment for protein losing enteropathy depends upon the underlying condition; according to Rychik and Spray (2002) this could mean treatment of hypoproteinemia or of the intestinal mucosa. For causes related to the heart, treatment for PLE after the Fontan operation treatment must be equal to the level of hypoproteinemia present. Therefore, it is useful to categorize patients based on their serum albumin levels, if less than normal (typically less than 3.5 g/dL) but greater than 2.5 g/dL, this can be seen as a mild form of protein losing enteropathy. Symptomatic management of edema with furosemide (and aldactone) can provide relief for the individual with mild hypoproteinemia. == In animals == Dogs can also suffer from PLE. Because the proteins are lost from the intestine, these dogs have low levels of albumin in the blood. Chronic enteropathy is one of the possible reasons for PLE and it has been shown in a study that hypoalbuminaemia is a risk factor for negative outcome and the prognosis is guarded for these dogs. Gastrointestinal lymphoma and intestinal lymphangiectasia are other diseases that can cause protein losing enteropathy in dogs. The Breed Lundehunds seem to be predisposed for PLE. == References == == Further reading == Umar, Sarah B; DiBaise, John K (January 2010). "Protein-Losing Enteropathy: Case Illustrations and Clinical Review". American Journal of Gastroenterology. 105 (1): 43–49. doi:10.1038/ajg.2009.561. PMID 19789526. Nikolaidis, Nikolaos; Tziomalos, Konstantinos; Giouleme, Olga; Gkisakis, Dimitrios; Kokkinomagoulou, Amalia; Karatzas, Nikolaos; Papanikolaou, Athanassios; Tsitourides, Ioannis; Eugenidis, Nikolaos; Kontopoulos, Athanassios (October 2005). "Protein-losing enteropathy as the principal manifestation of constrictive pericarditis". Journal of General Internal Medicine. 20 (10): C5-7. doi:10.1111/j.1525-1497.2005.0202_3.x (inactive 1 November 2024). PMC 1490237. PMID 16191147.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link) == External links ==	Wikipedia/Protein_losing_enteropathy
Gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD) is a chronic upper gastrointestinal disease in which stomach content persistently and regularly flows up into the esophagus, resulting in symptoms and/or complications. Symptoms include dental corrosion, dysphagia, heartburn, odynophagia, regurgitation, non-cardiac chest pain, extraesophageal symptoms such as chronic cough, hoarseness, reflux-induced laryngitis, or asthma. In the long term, and when not treated, complications such as esophagitis, esophageal stricture, and Barrett's esophagus may arise. Risk factors include obesity, pregnancy, smoking, hiatal hernia, and taking certain medications. Medications that may cause or worsen the disease include benzodiazepines, calcium channel blockers, tricyclic antidepressants, NSAIDs, and certain asthma medicines. Acid reflux is due to poor closure of the lower esophageal sphincter, which is at the junction between the stomach and the esophagus. Diagnosis among those who do not improve with simpler measures may involve gastroscopy, upper GI series, esophageal pH monitoring, or esophageal manometry. Treatment options include lifestyle changes, medications, and sometimes surgery for those who do not improve with the first two measures. Lifestyle changes include not lying down for three hours after eating, lying down on the left side, raising the pillow or bedhead height, losing weight, and stopping smoking. Foods that may precipitate GERD symptoms include coffee, alcohol, chocolate, fatty foods, acidic foods, and spicy foods. Medications include antacids, H2 receptor blockers, proton pump inhibitors, and prokinetics. In the Western world, between 10 and 20% of the population is affected by GERD. It is highly prevalent in North America with 18% to 28% of the population suffering from the condition. Occasional gastroesophageal reflux without troublesome symptoms or complications is even more common. The classic symptoms of GERD were first described in 1925, when Friedenwald and Feldman commented on heartburn and its possible relationship to a hiatal hernia. In 1934 gastroenterologist Asher Winkelstein described reflux and attributed the symptoms to stomach acid. == Signs and symptoms == === Adults === The most common symptoms of GERD in adults are an acidic taste in the mouth, regurgitation, and heartburn. Less common symptoms include pain with swallowing/sore throat, increased salivation (also known as water brash), nausea, chest pain, coughing, and globus sensation. The acid reflux can induce asthma attack symptoms like shortness of breath, cough, and wheezing in those with underlying asthma. GERD sometimes causes injury to the esophagus. These injuries may include one or more of the following: Reflux esophagitis – inflammation of esophageal epithelium which can cause ulcers near the junction of the stomach and esophagus Esophageal strictures – the persistent narrowing of the esophagus caused by reflux-induced inflammation Barrett's esophagus – intestinal metaplasia (changes of the epithelial cells from squamous to intestinal columnar epithelium) of the distal esophagus Esophageal adenocarcinoma – a form of cancer GERD sometimes causes injury of the larynx (LPR). Other complications can include aspiration pneumonia. === Children and babies === GERD may be difficult to detect in infants and children since they cannot describe what they are feeling and indicators must be observed. Symptoms may vary from typical adult symptoms. GERD in children may cause repeated vomiting, effortless spitting up, coughing, and other respiratory problems, such as wheezing. Inconsolable crying, refusing food, crying for food and then pulling off the bottle or breast only to cry for it again, failure to gain adequate weight, bad breath, and burping are also common. Children may have one symptom or many; no single symptom is universal in all children with GERD. Of the estimated 4 million babies born in the US each year, up to 35% of them may have difficulties with reflux in the first few months of their lives, known as 'spitting up'. About 90% of infants will outgrow their reflux by their first birthday. === Mouth === Acid reflux into the mouth can cause breakdown of the enamel, especially on the inside surface of the teeth. A dry mouth, acid or burning sensation in the mouth, bad breath and redness of the palate may occur. Less common symptoms of GERD include difficulty in swallowing, water brash, chronic cough, hoarse voice, nausea and vomiting. Signs of enamel erosion are the appearance of a smooth, silky-glazed, sometimes dull, enamel surface with the absence of perikymata, together with intact enamel along the gum margin. It will be evident in people with restorations as tooth structure typically dissolves much faster than the restorative material, causing it to seem as if it "stands above" the surrounding tooth structure. === Barrett's esophagus === GERD may lead to Barrett's esophagus, a type of intestinal metaplasia, which is in turn a precursor condition for esophageal cancer. The risk of progression from Barrett's to dysplasia is uncertain, but is estimated at 20% of cases. Due to the risk of chronic heartburn progressing to Barrett's, EGD every five years is recommended for people with chronic heartburn, or who take drugs for chronic GERD. == Causes == A small amount of acid reflux is typical even in healthy people (as with infrequent and minor heartburn), but gastroesophageal reflux becomes gastroesophageal reflux disease when signs and symptoms develop into a recurrent problem. Frequent acid reflux is due to poor closure of the lower esophageal sphincter, which is at the junction between the stomach and the esophagus. Factors that can contribute to GERD: Hiatal hernia, which increases the likelihood of GERD due to mechanical and motility factors. Obesity: increasing body mass index is associated with more severe GERD. In a large series of 2,000 patients with symptomatic reflux disease, it has been shown that 13% of changes in esophageal acid exposure is attributable to changes in body mass index. GERD can be a symptom of mast cell activation syndrome (MCAS). Factors that have been linked with GERD, but not conclusively: Obstructive sleep apnea Gallstones, which can impede the flow of bile into the duodenum, which can affect the ability to neutralize gastric acid In 1999, a review of existing studies found that, on average, 40% of GERD patients also had H. pylori infection. The eradication of H. pylori can lead to an increase in acid secretion, leading to the question of whether H. pylori-infected GERD patients are any different from non-infected GERD patients. A double-blind study, reported in 2004, found no clinically significant difference between these two types of patients with regard to the subjective or objective measures of disease severity. The etiology of GERD appears to include the reflux of bile from the stomach into the esophagus leading to the production of reactive oxygen species and oxidative stress and then inflammation and induction of DNA damage. In experimental models of GERD it was found that Lactobacilli facilitate the repair of such DNA damage indicating that administration of these potentially probiotic bacteria may be useful in patients suffering with GERD for preventing progression to Barrett’s esophagus and esophageal adenocarcinoma. == Diagnosis == The diagnosis of GERD is usually made when typical symptoms are present. Reflux can be present in people without symptoms and the diagnosis requires both symptoms or complications and reflux of stomach content. Other investigations may include esophagogastroduodenoscopy (EGD). Barium swallow X-rays should not be used for diagnosis. Esophageal manometry is not recommended for use in the diagnosis, being recommended only prior to surgery. Ambulatory esophageal pH monitoring may be useful in those who do not improve after PPIs and is not needed in those in whom Barrett's esophagus is seen. Investigation for H. pylori is not usually needed. The current gold standard for diagnosis of GERD is esophageal pH monitoring. It is the most objective test to diagnose the reflux disease and allows monitoring GERD patients in their response to medical or surgical treatment. One practice for diagnosis of GERD is a short-term treatment with proton-pump inhibitors, with improvement in symptoms suggesting a positive diagnosis. Short-term treatment with proton-pump inhibitors may help predict abnormal 24-hour pH monitoring results among patients with symptoms suggestive of GERD. === Endoscopy === Endoscopy, the examination of the stomach with a fibre-optic scope, is not routinely needed if the case is typical and responds to treatment. It is recommended when people either do not respond well to treatment or have alarm symptoms, including dysphagia, anemia, blood in the stool (detected chemically), wheezing, weight loss, or voice changes. Some physicians advocate either once-in-a-lifetime or 5- to 10-yearly endoscopy for people with longstanding GERD, to evaluate the possible presence of dysplasia or Barrett's esophagus. Biopsies performed during gastroscopy may show: Edema and basal hyperplasia (nonspecific inflammatory changes) Lymphocytic inflammation (nonspecific) Neutrophilic inflammation (usually due to reflux or Helicobacter gastritis) Eosinophilic inflammation (usually due to reflux): The presence of intraepithelial eosinophils may suggest a diagnosis of eosinophilic esophagitis (EE) if eosinophils are present in high enough numbers. Less than 20 eosinophils per high-power microscopic field in the distal esophagus, in the presence of other histologic features of GERD, is more consistent with GERD than EE. Goblet cell intestinal metaplasia or Barrett's esophagus Elongation of the papillae Thinning of the squamous cell layer Dysplasia Carcinoma Reflux changes that are not erosive in nature lead to "nonerosive reflux disease". === Severity === Severity may be documented with the Johnson-DeMeester's scoring system: 0 – None 1 – Minimal – occasional episodes 2 – Moderate – medical therapy visits 3 – Severe – interference with daily activities === Differential diagnosis === Other causes of chest pain such as heart disease should be ruled out before making the diagnosis. Another kind of acid reflux, which causes respiratory and laryngeal signs and symptoms, is called laryngopharyngeal reflux (LPR) or extraesophageal reflux disease (EERD). Unlike GERD, LPR rarely produces heartburn, and is sometimes called silent reflux. Differential diagnosis of GERD can also include dyspepsia, peptic ulcer disease, esophageal and gastric cancer, and food allergies. == Treatment == The treatments for GERD may include food choices, lifestyle changes, medications, and possibly surgery. Initial treatment is frequently with a proton-pump inhibitor such as omeprazole. In some cases, a person with GERD symptoms can manage them by taking over-the-counter drugs. This is often safer and less expensive than taking prescription drugs. Some guidelines recommend trying to treat symptoms with an H2 antagonist before using a proton-pump inhibitor because of cost and safety concerns. === Medical nutrition therapy and lifestyle changes === Medical nutrition therapy plays an essential role in managing the symptoms of the disease by preventing reflux, preventing pain and irritation, and decreasing gastric secretions. Some foods such as chocolate, mint, high-fat food, and alcohol have been shown to relax the lower esophageal sphincter, increasing the risk of reflux. Weight loss is recommended for the overweight or obese, as well as avoidance of bedtime snacks or lying down immediately after meals (meals should occur at least 2–3 hours before bedtime), elevation of the head of the bed on 6-inch blocks, avoidance of smoking, and avoidance of tight clothing that increases pressure in the stomach. It may be beneficial to avoid spices, citrus juices, tomatoes and soft drinks, and to consume small frequent meals and drink liquids between meals. Some evidence suggests that reduced sugar intake and increased fiber intake can help. Although moderate exercise may improve symptoms in people with GERD, vigorous exercise may worsen them. Breathing exercises may relieve GERD symptoms. === Medications === The primary medications used for GERD are proton-pump inhibitors, H2 receptor blockers and antacids with or without alginic acid. The use of acid suppression therapy is a common response to GERD symptoms and many people get more of this kind of treatment than their case merits. The overuse of acid suppression is a problem because of the side effects and costs. ==== Proton-pump inhibitors ==== Proton-pump inhibitors (PPIs), such as omeprazole, are the most effective, followed by H2 receptor blockers. If a once-daily PPI is only partially effective they may be used twice a day. They should be taken one half to one hour before a meal. There is no significant difference between PPIs. When these medications are used long-term, the lowest effective dose should be taken. They may also be taken only when symptoms occur in those with frequent problems. H2 receptor blockers lead to roughly a 40% improvement. ==== Antacids ==== The evidence for antacids is weaker with a benefit of about 10% (NNT=13) while a combination of an antacid and alginic acid (such as Gaviscon) may improve symptoms by 60% (NNT=4). Metoclopramide (a prokinetic) is not recommended either alone or in combination with other treatments due to concerns around adverse effects. The benefit of the prokinetic mosapride is modest. ==== Other agents ==== Sucralfate has similar effectiveness to H2 receptor blockers; however, sucralfate needs to be taken multiple times a day, thus limiting its use. Baclofen, an agonist of the GABAB receptor, while effective, has similar issues of needing frequent dosing in addition to greater adverse effects compared to other medications. === Surgery === The standard surgical treatment for severe GERD is the Nissen fundoplication. In this procedure, the upper part of the stomach is wrapped around the lower esophageal sphincter to strengthen the sphincter and prevent acid reflux and to repair a hiatal hernia. It is recommended only for those who do not improve with PPIs. Quality of life is improved in the short term compared to medical therapy, but there is uncertainty in the benefits of surgery versus long-term medical management with proton pump inhibitors. When comparing different fundoplication techniques, partial posterior fundoplication surgery is more effective than partial anterior fundoplication surgery, and partial fundoplication has better outcomes than total fundoplication. Esophagogastric dissociation is an alternative procedure that is sometimes used to treat neurologically impaired children with GERD. Preliminary studies have shown it may have a lower failure rate and a lower incidence of recurrent reflux. In 2012 the U.S. Food and Drug Administration (FDA) approved a device called the LINX, which consists of a series of metal beads with magnetic cores that are placed surgically around the lower esophageal sphincter, for those with severe symptoms that do not respond to other treatments. Improvement of GERD symptoms is similar to those of the Nissen fundoplication, although there is no data regarding long-term effects. Compared to Nissen fundoplication procedures, the procedure has shown a reduction in complications such as gas bloat syndrome that commonly occur. Adverse responses include difficulty swallowing, chest pain, vomiting, and nausea. Contraindications that would advise against use of the device are patients who are or may be allergic to titanium, stainless steel, nickel, or ferrous iron materials. A warning advises that the device should not be used by patients who could be exposed to, or undergo, magnetic resonance imaging (MRI) because of serious injury to the patient and damage to the device. Some patients who are at an increased surgical risk or do not tolerate PPIs may qualify for a more recently developed incisionless procedure known as a TIF transoral incisionless fundoplication. Benefits of this procedure may last for up to six years. === Special populations === ==== Pregnancy ==== GERD is a common condition that develops during pregnancy, but usually resolves after delivery. The severity of symptoms tend to increase throughout the pregnancy. In pregnancy, dietary modifications and lifestyle changes may be attempted, but often have little effect. Some lifestyle changes that can be implemented are elevating the head of the bed, eating small portions of food at regularly scheduled intervals, reduce fluid intake with a meal, avoid eating three hours before bedtime, and refrain from lying down after eating. Calcium-based antacids are recommended if these changes are not effective; aluminum- and magnesium hydroxide-based antacids are also safe. Antacids that contain sodium bicarbonate or magnesium trisilicate should be avoided in pregnancy. Sucralfate has been studied in pregnancy and proven to be safe as is cimetidine and PPIs. ==== Babies ==== Babies may see relief with smaller, more frequent feedings, more frequent burping during feedings, holding the baby in an upright position 30 minutes after feeding, keeping the baby's head elevated while laying on the back, removing milk and soy from the mother's diet or feeding the baby milk protein-free formula. They may also be treated with medicines such as PPIs or H2 receptor blockers. PPIs, however, have not been found to be effective in this population and there is a lack of evidence for safety. The role of an occupational therapist with an infant with GERD includes positioning during and after feeding. One technique used is called the log-roll technique, which is practiced when changing an infant's clothing or diapers. Placing an infant on their back while having their legs lifted is not recommended since it causes the acid to flow back up the esophagus. Instead, the occupational therapist would suggest rolling the child on the side, keeping the shoulders and hips aligned to avoid acid rising up the baby's esophagus. Another technique used is feeding the baby on their side with an upright position instead of lying flat on their back. The final positioning technique used for infants is to keep them on their stomach or upright for 20 minutes after feeding. == Epidemiology == In Western populations, GERD affects approximately 10% to 20% of the population and 0.4% newly develop the condition. For instance, an estimated 3.4 million to 6.8 million Canadians have GERD. The prevalence rate of GERD in developed nations is also tightly linked with age, with adults aged 60 to 70 being the most commonly affected. In the United States 20% of people have symptoms in a given week and 7% every day. No data supports sex predominance with regard to GERD. == History == An obsolete treatment is vagotomy ("highly selective vagotomy"), the surgical removal of vagus nerve branches that innervate the stomach lining. This treatment has been largely replaced by medication. Vagotomy by itself tended to worsen contraction of the pyloric sphincter of the stomach, and delayed stomach emptying. Historically, vagotomy was combined with pyloroplasty or gastroenterostomy to counter this problem. == Research == A number of endoscopic devices have been tested to treat chronic heartburn. Endocinch puts stitches in the lower esophogeal sphincter (LES) to create small pleats to help strengthen the muscle. However, long-term results were disappointing, and the device is no longer sold by Bard. The Stretta procedure uses electrodes to apply radio-frequency energy to the LES. A 2015 systematic review and meta-analysis in response to the systematic review (no meta-analysis) conducted by SAGES did not support the claims that Stretta was an effective treatment for GERD. A 2012 systematic review found that it improves GERD symptoms. NDO Surgical Plicator creates a plication, or fold, of tissue near the gastroesophageal junction, and fixates the plication with a suture-based implant. The company ceased operations in mid-2008, and the device is no longer on the market. Transoral incisionless fundoplication, which uses a device called Esophyx, may be effective. == See also == Acid perfusion test EndoStim Electrical Stimulation Therapy Esophageal motility disorder Esophageal motility study == References == == Further reading == Lichtenstein DR, Cash BD, Davila R, et al. (August 2007). "Role of endoscopy in the management of GERD" (PDF). Gastrointestinal Endoscopy. 66 (2): 219–24. doi:10.1016/j.gie.2007.05.027. PMID 17643692. Lay summary in: "Role of endoscopy in the management of GERD". National Guideline Clearinghouse. Archived from the original on 28 September 2010. Hirano I, Richter JE (March 2007). "ACG practice guidelines: esophageal reflux testing". American Journal of Gastroenterology. 102 (3): 668–85. CiteSeerX 10.1.1.619.3818. doi:10.1111/j.1572-0241.2006.00936.x. PMID 17335450. S2CID 10854440. Katz PO, Gerson LB, Vela MF (March 2013). "Guidelines for the diagnosis and management of gastroesophageal reflux disease". American Journal of Gastroenterology. 108 (3): 308–28. doi:10.1038/ajg.2012.444. PMID 23419381.	Wikipedia/Gastroesophageal_reflux_disease
Management of Crohn's disease involves first treating the acute symptoms of the disease, then maintaining remission. Since Crohn's disease is an immune system condition, it cannot be cured by medication or surgery. Treatment initially involves the use of medications to eliminate infections (generally antibiotics) and reduce inflammation (generally aminosalicylate anti-inflammatory drugs and corticosteroids). Surgery may be required for complications such as obstructions, fistulae, abscesses, or if the disease does not respond to drugs within a reasonable time. However, surgery cannot cure Crohn's disease. It involves removing the diseased part of the intestine and rejoining the healthy ends, but the disease tends to recur after surgery. Once remission is induced, the goal of treatment becomes maintenance of remission: avoiding the return of active disease, or "flares". Because of side effects, the prolonged use of corticosteroids is avoided. Although some people are able to maintain remission spontaneously, many require immunosuppressive drugs. == Aminosalicylates == 5-ASA compounds, such as mesalazine and sulfasalazine, have shown to be of very little efficacy in the treatment of Crohn's disease, either for induction or for maintenance of remission. Current guidelines do not advise the use of 5-ASA compounds in Crohn's disease. == Corticosteroids == Corticosteroids are a class of anti-inflammatory drugs used to treat moderate to severe flares of Crohn's disease. However, they are used sparingly because they can cause serious side effects, including Cushing's syndrome, mania, insomnia, hypertension, high blood glucose, osteoporosis, and avascular necrosis of long bones. Corticosteroids should not be confused with the anabolic steroids used to enhance athletic performance. The most commonly prescribed oral steroid is prednisone, which is typically dosed at 0.5 mg/kg for induction of remission in Crohn's disease. Intravenous steroids, administered in a hospital setting, are used when oral steroids do not work or cannot be taken. Because corticosteroids reduce the body's ability to fight infection, care must be taken to ensure that there is no active infection, particularly an intra-abdominal abscess, before the initiation of steroids. Another oral corticosteroid, budesonide (trade name Entocort), has limited absorption and a high level of first-pass metabolism, meaning that lower quantities of the drug enter the bloodstream. It has been shown to be useful in the treatment of mild to moderate Crohn's disease, and in maintaining remission. It is also effective when used in combination with antibiotics to treat active Crohn's disease. Budesonide is released in the ileum and right colon, and therefore has a topical effect against disease in that area. Steroid enemas can also be used to treat symptoms in the lower colon and rectum. Hydrocortisone and budesonide liquid and foam enemas are marketed for this purpose. == Mercaptopurine immunosuppressing drugs == Azathioprine and 6-mercaptopurine (6-MP) are the most commonly used immunosuppressants for maintenance therapy of Crohn's disease. They are purine anti-metabolites, meaning that they interfere with the synthesis of purines required for inflammatory cells. They have a duration of action of months (slow-acting). Both drugs are dosed at 1.5 to 2.5 mg/kg, with literature supporting the use of higher doses. A Cochrane systematic review that included 13 randomized controlled trials, concluded that azathioprine and 6-mercaptopurine are not effective for inducing remission when a person has Crohn's disease. Azathioprine and 6-MP may be useful for the following indications: Maintenance therapy with azathioprine or 6-mercaptopurine may lead people with active Crohn's to take less steroid medication. This may lower side effects related to steroid treatments. Fistulizing disease Maintenance of remission after surgery for Crohn's disease A combination of azathioprine and infliximab treatment may be more effective than a single dose of infliximab to induce steroid-free remission for people with active Crohn's disease. Azathioprine treatment may lead to rare but life-threatening side effects. The rare side effects include leukopenia or pancreatitis. There may also be an increased risk of lymphoma that is associated with azathioprine or 6-mercaptopurine treatment. Azathioprine is listed by the United States FDA as a human carcinogen. However, it confers considerably less morbidity and mortality than corticosteroids. == Biologic therapies == === Infliximab === Infliximab (trade name Remicade, among others) is a mouse-human chimeric antibody that targets tumor necrosis factor alpha (TNFα), a cytokine in the inflammatory response. It is a monoclonal antibody that inhibits the pro-inflammatory cytokine TNFα. It is administered intravenously and dosed per weight starting at 5 mg/kg and increasing according to character of disease. Infliximab has found utility as follows: Induction and maintenance of remission for people with Crohn's disease Maintenance for fistulizing Crohn's disease Side effects of infliximab, like other immunosuppressants of the TNF class, can be serious and potentially fatal, and infliximab carries an FDA black-box warning on the label. Listed side effects include hypersensitivity and allergic reactions, risk of re-activation of tuberculosis, serum sickness, and risk of multiple sclerosis. Serious side effect also include lymphoma and severe infections. === Adalimumab === Adalimumab, like infliximab, is an antibody that targets tumor necrosis factor. It has been shown to reduce the signs and symptoms of, and is approved for treatment of, moderate to severe Crohn's disease in adults who have not responded well to conventional treatments and who have lost response to or are unable to tolerate infliximab. Adalimumab also has a number of serious, potentially fatal, safety concerns characteristic of the anti-TNFα drugs. It, too, has a black-box warning on its FDA label. Listed potential side effects include serious and sometimes fatal blood disorders; serious infections including tuberculosis and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma and solid tissue cancers; rare reports of serious liver injury; and rare reports of demyelinating central nervous system disorders; and rare reports of cardiac failure. === Natalizumab === Natalizumab is an anti-integrin monoclonal antibody that has shown utility as induction and maintenance treatment for moderate to severe Crohn's disease. Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha, such as infliximab. In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease. A total of 3 large randomized controlled trials have demonstrated that natalizumab is effective in increasing rates of remission and maintaining symptom-free status in patients with Crohn's disease. Natalizumab has also been linked to PML (though only when used in combination with interferon beta-1a). The label also recommends monitoring of liver enzymes due to concerns over possible damage or failure. Also associated with a rare but serious risk of multifocal leukoencephalopathy (brain infection leading to death or severe disability). Therefore, a specific program exists in which prescribers must be enrolled, CD-TOUCH (Crohn's Disease-Tysabri Outreach Unified Commitment to Health) Prescribing Program. === Ustekinumab === Ustekinumab (CNTO 1275) is a monoclonal antibody that suppresses cytokines IL-12 and IL-23. Originally designed to treat psoriasis, ustekinumab was approved by the FDA for the treatment of Crohn's disease in 2016. Evidence from four quality randomized control trials suggest that ustekinumab is effective for induction of clinical remission and clinical improvement in patients with moderate to severe Crohn's disease. Based on these studies, ustekinumab appears to be safe, but the implications of longer-term drug administration needs to be studied. === Vedolizumab === Vedolizumab is a gut-selective, Alpha-4 Beta-7 anti-integrin, monoclonal antibody that was approved by the U.S. Food and Drug Administration (FDA) to treat Crohn's disease in 2014. It is indicated for management of moderate-to-severe, active Crohn's disease patients and it works by inhibiting the trafficking of pro-inflammatory immune cells to the site of inflammation. Evidence from three randomized control trials, including an international, multi-center, randomized, parallel-group, double-blind clinical trial, GEMINI 2 (NCT00783692), demonstrated that Vedolizumab is effective for induction and maintenance of remission in patients with active Crohn's disease. == Surgery == Surgery is normally reserved for complications of Crohn's disease or when disease that resists treatment with drugs is confined to one location that can be removed. Surgery is often used to manage complications of Crohn's disease, including fistulae, small bowel obstruction, colon cancer, small intestine cancer and fibrostenotic strictures, when strictureplasty (expansion of the stricture) is sometimes performed. Otherwise, and for other complications, resection and anastomosis – the removal of the affected section of intestine and the rejoining of the healthy sections – is the surgery usually performed for Crohn's disease (e.g., ileocolonic resection). None of these surgeries cure or eliminate Crohn's disease, as the disease eventually comes back in healthy segments of the intestine, although when Crohn's disease recurs after surgery, it usually comes back at the site of the surgery. Small intestine transplants are becoming less experimental, but are still mainly performed in response to short bowel syndrome due to a high rate of transplant rejection. == Diet and lifestyle == Many diets have been proposed for the management of Crohn's disease, and many do improve symptoms, but none have been proven to cure the disease. The specific carbohydrate diet usually requires adjustments by patients; if a patient finds that certain foods increase or decrease symptoms, they may adjust their diet accordingly. A food diary is recommended to see what positive or negative effects particular foods have. A low residue diet may be used to reduce the volume of stools excreted daily. People with lactose intolerance due to small bowel disease may benefit from avoiding lactose-containing foods. Patients who cannot eat may be given total parenteral nutrition (TPN), a source of vitamins and nutrients. Fish oil may be effective in reducing the chance of relapse in less severe cases. Because the terminal ileum is the most common site of involvement and is the site for vitamin B12 absorption, people with Crohn's disease are at risk for B12 deficiency and may need supplementation. In cases with extensive small intestine involvement, the fat-soluble vitamins A, D, E and K may be deficient. Folate deficiency is a risk for patients treated with methotrexate who do not simultaneously receive folate supplementation. Stress can influence the course of Crohn's disease. Smoking has also been associated with the disease, and smokers with Crohn's are encouraged to explore smoking cessation programs. Smoking can not only make Crohn's disease worse in people who do it, but also increase the risk of recurrence after surgery. If a Crohn's disease patient who undergoes surgery does not quit smoking, the disease is likely to recur more aggressively. == Microbiome Modification == The use of oral probiotic supplements to modify the composition and behaviour of the gastrointestinal microbiome has been researched recently to understand whether it may help to improve remission rate in people with Crohn's disease. However only 2 controlled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation. == Helminthic therapy == In an experimental idea called helminthic therapy, moderate hookworm infections have been demonstrated to have beneficial effects on hosts who have diseases linked to overactive immune systems. This may be explained by the hygiene hypothesis. Hookworm therapy is currently in the trial stage at the University of Nottingham. Due to the unconventional nature of this therapy, it is not widely used. == Alternative medicine == More than half of people with Crohn's disease have tried complementary or alternative therapy. These include diets, probiotics, fish oil and other herbal and nutritional supplements. The benefit, if any, and risks of these therapies is uncertain. === Acupuncture === Acupuncture is used to treat inflammatory bowel disease in China, and is being used more frequently in Western society. Evidence has been put forth suggesting that acupuncture can have benefits beyond the placebo effect, improving quality of life, general well-being and a small decrease in blood-bound inflammatory markers. This study however had a very small test set and did not reach the threshold for benefit. === Herbal === Boswellia is an ayurvedic (Indian traditional medicine) herb, used as a natural alternative to drugs. One study has found that the effectiveness of H-15 extract is not inferior to mesalazine: "Considering both safety and efficacy of Boswellia serrata extract H15, it appears to be superior over mesalazine in terms of a benefit-risk-evaluation." Yunnan Baiyao == Other medications == Methotrexate is a folate anti-metabolite drug that is also used for chemotherapy. It is useful in maintenance of remission for those no longer taking corticosteroids. The antibiotics Metronidazole and ciprofloxacin may be used to treat Crohn's disease with colonic or perianal involvement, although this usage has not been approved by the Food and Drug Administration. They are also used to treat complications, including abscesses and other infections. Thalidomide has shown efficacy in reversing endoscopic evidence of disease. Cannabis may be used to treat Crohn's disease because of its anti-inflammatory properties. Cannabis and cannabis-derived drugs may also help to heal the gut lining, and may reduce the need for surgery and other medications. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, can cause flares of inflammatory bowel disease in approximately 25% of patients. These flares tend to occur within one week after starting regular use of the NSAID. In contrast, acetaminophen (paracetamol) and aspirin appear to be safe. Celecoxib (Celebrex), a cox-2 inhibitor, also appears to be safe, at least in short-term studies of patients in remission and on medication for their Crohn's disease. == Research == Many clinical trials have been recently completed or are ongoing for new therapies for Crohn's disease. They include the following: Certolizumab is a PEGylated Fab fragment of a humanized anti-TNFα monoclonal antibody that was found to have efficacy over placebo in one large trial. Traficet-EN/CCX282/GSK'786/vercirnon is a CCR9 chemokine receptor antagonist intended to modulate immune response. It failed in Phase III clinical trials, showing no improvement over a placebo. ABT-874 is a human anti-IL-12 monoclonal antibody being developed by Abbott Laboratories in conjunction with Cambridge Antibody Technology for the treatment of multiple autoimmune diseases, including Crohn's disease. Phase II trials showed promising results, Sargramostim, or granulocyte-monocyte colony stimulating factor (GM-CSF), has been shown to substantially improve health-related quality of life in pilot studies, measured by an increase in score on a 32-item IBD questionnaire. A recent Phase II trial showed that Sargramostim significantly decreased CD severity (48%, compared with 26% in the placebo group) and improved quality of life (40%, versus 19% for placebo). Trichuris suis is a pig whipworm that been shown in one study to improve Crohn's disease symptoms. Autologous stem cell transplants have also been evaluated. Rifabutin, clarithromycin and clofazimine are antibiotics designed to attack mycobacterium avium subsp. paratuberculosis, which may be a cause of Crohn's disease. This treatment, called Myoconda, is being tested by Giaconda. A pilot study found that Low-dose naltrexone, a very inexpensive drug, helped patients with active Crohn's disease. In the study, 89% of patients exhibited a response to therapy, and 67% achieved remission within four weeks. == See also == Biological therapy for inflammatory bowel disease Cholestyramine (Bile acid sequestrant) Essential fatty acid interactions == References ==	Wikipedia/Treatment_of_Crohn's_disease
Industrialisation (UK) or industrialization (US) is the period of social and economic change that transforms a human group from an agrarian society into an industrial society. This involves an extensive reorganisation of an economy for the purpose of manufacturing. Industrialisation is associated with increase of polluting industries heavily dependent on fossil fuels. With the increasing focus on sustainable development and green industrial policy practices, industrialisation increasingly includes technological leapfrogging, with direct investment in more advanced, cleaner technologies. The reorganisation of the economy has many unintended consequences both economically and socially. As industrial workers' incomes rise, markets for consumer goods and services of all kinds tend to expand and provide a further stimulus to industrial investment and economic growth. Moreover, family structures tend to shift as extended families tend to no longer live together in one household, location or place. == Background == The first transformation from an agricultural to an industrial economy is known as the Industrial Revolution and took place from the mid-18th to early 19th century. It began in Great Britain, spreading to Belgium, Switzerland, Germany, and France and eventually to other areas in Europe and North America. Characteristics of this early industrialisation were technological progress, a shift from rural work to industrial labour, and financial investments in new industrial structures. Later commentators have called this the First Industrial Revolution. The "Second Industrial Revolution" labels the later changes that came about in the mid-19th century after the refinement of the steam engine, the invention of the internal combustion engine, the harnessing of electricity and the construction of canals, railways, and electric-power lines. The invention of the assembly line gave this phase a boost. Coal mines, steelworks, and textile factories replaced homes as the place of work. By the end of the 20th century, East Asia had become one of the most recently industrialised regions of the world. There is considerable literature on the factors facilitating industrial modernisation and enterprise development. == Social consequences == The Industrial Revolution was accompanied by significant changes in the social structure, the main change being a transition from farm work to factory-related activities. This has resulted in the concept of Social class, i.e., hierarchical social status defined by an individual's economic power. It has changed the family system as most people moved into cities, with extended family living apart becoming more common. The movement into more dense urban areas from less dense agricultural areas has consequently increased the transmission of diseases. The place of women in society has shifted from primary caregivers to breadwinners, thus reducing the number of children per household. Furthermore, industrialisation contributed to increased cases of child labour and thereafter education systems. === Urbanisation === As the Industrial Revolution was a shift from the agrarian society, people migrated from villages in search of jobs to places where factories were established. This shifting of rural people led to urbanisation and an increase in the population of towns. The concentration of labour in factories has increased urbanisation and the size of settlements, to serve and house the factory workers. === Exploitation === === Changes in family structure === Family structure changes with industrialisation. Sociologist Talcott Parsons noted that in pre-industrial societies there is an extended family structure spanning many generations who probably remained in the same location for generations. In industrialised societies the nuclear family, consisting of only parents and their growing children, predominates. Families and children reaching adulthood are more mobile and tend to relocate to where jobs exist. Extended family bonds become more tenuous. One of the most important criticisms of industrialisation is that it caused children to stay away from home for many hours and to use them as cheap workers in factories. == Industrialisation in East Asia == Between the early 1960s and 1990s, the Four Asian Tigers underwent rapid industrialisation and maintained exceptionally high growth rates. == Current situation == As of 2018 the international development community (World Bank, Organisation for Economic Co-operation and Development (OECD), many United Nations departments, FAO WHO ILO and UNESCO, endorses development policies like water purification or primary education and co-operation amongst third world communities. Some members of the economic communities do not consider contemporary industrialisation policies as being adequate to the global south (Third World countries) or beneficial in the longer term, with the perception that they may only create inefficient local industries unable to compete in the free-trade dominated political order which industrialisation has fostered. Environmentalism and Green politics may represent more visceral reactions to industrial growth. Nevertheless, repeated examples in history of apparently successful industrialisation (Britain, Soviet Union, South Korea, China, etc.) may make conventional industrialisation seem like an attractive or even natural path forward, especially as populations grow, consumerist expectations rise and agricultural opportunities diminish. The relationships among economic growth, employment, and poverty reduction are complex, and higher productivity can sometimes lead to static or even lower employment (see jobless recovery). There are differences across sectors, whereby manufacturing is less able than the tertiary sector to accommodate both increased productivity and employment opportunities; more than 40% of the world's employees are "working poor", whose incomes fail to keep themselves and their families above the $2-a-day poverty line. There is also a phenomenon of deindustrialisation, as in the former USSR countries' transition to market economies, and the agriculture sector is often the key sector in absorbing the resultant unemployment. == See also == == References == == Further reading == Ahmady, Kameel (2021). Traces of Exploitation in the World of Childhood (A Comprehensive Research on Forms, Causes and Consequences of Child Labour in Iran). Denmark: Avaye Buf. ISBN 9788793926646. Chandler Jr., Alfred D. (1993). The Visible Hand: The Management Revolution in American Business. Belknap Press of Harvard University Press. ISBN 978-0674940529. Hewitt, T., Johnson, H. and Wield, D. (Eds) (1992) industrialisation and Development, Oxford University Press: Oxford. Hobsbawm, Eric (1962): The Age of Revolution. Abacus. Kemp, Tom (1993) Historical Patterns of Industrialisation, Longman: London. ISBN 0-582-09547-6 Kiely, R (1998) industrialisation and Development: A comparative analysis, UCL Press:London. Landes, David. S. (1969). The Unbound Prometheus: Technological Change and Industrial Development in Western Europe from 1750 to the Present. Cambridge, New York: Press Syndicate of the University of Cambridge. ISBN 0-521-09418-6. Pomeranz, Ken (2001)The Great Divergence: China, Europe and the Making of the Modern World Economy (Princeton Economic History of the Western World) by (Princeton University Press; New Ed edition, 2001) Tilly, Richard H.: Industrialization as an Historical Process, European History Online, Main: Institute of European History, 2010, retrieved: 29 February 2011. == External links ==	Wikipedia/Industrialized
An immune-mediated inflammatory disease (IMID) is any of a group of conditions or diseases that lack a definitive etiology, but which are characterized by common inflammatory pathways leading to inflammation, and which may result from, or be triggered by, a dysregulation of the normal immune response. All IMIDs can cause end organ damage, and are associated with increased morbidity and/or mortality. Inflammation is an important and growing area of biomedical research and health care because inflammation mediates and is the primary driver of many medical disorders and autoimmune diseases, including ankylosing spondylitis, psoriasis, psoriatic arthritis, Behçet's disease, rheumatoid arthritis, inflammatory bowel disease (IBD), and allergy, as well as many cardiovascular, neuromuscular, and infectious diseases. Some current research even suggests that aging is a consequence, in part, of inflammatory processes. == Characterization == IMID is characterized by immune disregulation, and one underlying manifestation of this immune disregulation is the inappropriate activation of inflammatory cytokines, such as IL-12, IL-6 or TNF alpha, whose actions lead to pathological consequences. == See also == Immune mediated polygenic arthritis == Bibliography == Shurin, Michael R. and Yuri S. Smolkin (editors). Immune Mediated Diseases: From Theory to Therapy (Advances in Experimental Medicine and Biology). Springer, 2007. == References == idid.us: immune mediated inflammatory diseases, inflammatory diseases of immune dysregulation Archived 2018-03-08 at the Wayback Machine	Wikipedia/Immune-mediated_inflammatory_diseases
Functional gastrointestinal disorders (FGID), also known as disorders of gut–brain interaction, include a number of separate idiopathic disorders which affect different parts of the gastrointestinal tract and involve visceral hypersensitivity and motility disturbances. == Definition == Using the Delphi method, the Rome Foundation and its board of directors, chairs and co-chairs of the ROME IV committees developed the current definition for disorders of gut-brain interaction. A group of disorders classified by GI symptoms related to any combination of: Motility disturbance Visceral hypersensitivity Altered mucosal and immune function Altered gut microbiota Altered central nervous system (CNS) processing == Classification == Terms such as functional colonic disease (or functional bowel disorder) refer in medicine to a group of bowel disorders which are characterized by chronic abdominal complaints without a structural or biochemical cause that could explain symptoms. Other functional disorders relate to other aspects of the process of digestion. The consensus review process of meetings and publications organised by the Rome Foundation, known as the Rome process, has helped to define the functional gastrointestinal disorders. Successively, the Rome I, Rome II, Rome III and Rome IV proposed consensual classification system and terminology, as recommended by the Rome Coordinating Committee. These now include classifications appropriate for adults, children and neonates/toddlers. The current ROME IV classification, published in 2016, is as follows: A. Esophageal disorders A1. Functional chest pain A2. Functional heartburn A3. Reflux hypersensitivity A4. Globus A5. Functional dysphagia B. Gastroduodenal disorders B1. Functional dyspepsia B1a. Postprandial distress syndrome (PDS) B1b. Epigastric pain syndrome (EPS) B2. Belching disorders B2a. Excessive supragastric belching B2b. Excessive gastric belching B3. Nausea and vomiting disorders B3a. Chronic nausea vomiting syndrome (CNVS) B3b. Cyclic vomiting syndrome (CVS) B3c. Cannabinoid hyperemesis syndrome (CHS) B4. Rumination syndrome C. Bowel disorders C1. Irritable bowel syndrome (IBS) IBS with predominant constipation (IBS-C) IBS with predominant diarrhea (IBS-D) IBS with mixed bowel habits (IBS-M) IBS unclassified (IBS-U) C2. Functional constipation C3. Functional diarrhea C4. Functional abdominal bloating/distension C5. Unspecified functional bowel disorder C6. Opioid-induced constipation D. Centrally mediated disorders of gastrointestinal pain D1. Centrally mediated abdominal pain syndrome (CAPS) D2. Narcotic bowel syndrome (NBS)/ Opioid-induced GI hyperalgesia E. Gallbladder and sphincter of Oddi disorders E1. Biliary pain E1a. Functional gallbladder disorder E1b. Functional biliary sphincter of Oddi disorder E2. Functional pancreatic sphincter of Oddi disorder F. Anorectal disorders F1. Fecal incontinence F2. Functional anorectal pain F2a. Levator ani syndrome F2b. Unspecified functional anorectal pain F2c. Proctalgia fugax F3. Functional defecation disorders F3a. Inadequate defecatory propulsion F3b. Dyssynergic defecation G. Childhood functional GI disorders: Neonate/Toddler G1. Infant regurgitation G2. Rumination syndrome G3. Cyclic vomiting syndrome (CVS) G4. Infant colic G5. Functional diarrhea G6. Infant dyschezia G7. Functional constipation H. Childhood functional GI disorders: Child/Adolescent H1. Functional nausea and vomiting disorders H1a. Cyclic vomiting syndrome (CVS) H1b. Functional nausea and functional vomiting H1b1. Functional nauseaH1b2. Functional vomiting H1c. Rumination syndrome H1d. Aerophagia H2. Functional abdominal pain disorders H2a. Functional dyspepsia H2a1. Postprandial distress syndrome H2a2. Epigastric pain syndrome H2b. Irritable bowel syndrome (IBS) H2c. Abdominal migraine H2d. Functional abdominal pain ‒ NOS H3. Functional defecation disorders H3a. Functional constipation H3b. Nonretentive fecal incontinence == Causes == FGIDs share in common any of several physiological features including increased reactivity of gastrointestinal movement, hypersensitivity, altered immune function, inflammatory function (associated with bacterial dysbiosis), and altered central nervous system and enteric nervous system (CNS-ENS) regulation. The pathophysiology of FGID has been best conceptualized using biopsychosocial model help to explain the relationships between an individual factors in their early life that in turn can influence their psychosocial factor and physiological functioning. This model also shows the complex interactions between these factors through the brain-gut axis. These factors affect how FGID manifest in terms of symptoms but also affect the clinical outcome. These factors are interconnected and the influences on these factors are bidirectional and mutually interactive. === Early life factors === Early life factors include genetic factors, psychophysiological and sociocultural factors, and environmental exposures. Genetics – Several polymorphisms and candidate genes may predispose individuals to develop FGID. These include alpha-2 adrenergic and 5-HT receptors; serotonin and norepinephrine transporters (SERT, NET); inflammatory markers interleukin-(IL)10, tumor necrosis factor-(TNF) alpha, and TNF super family member 15 (TNF-SF15); intracellular cell signaling (G proteins); and ion channels (SCN5A). However, the expression of a FGID requires the influence of additional environmental exposures such as infection, illness modeling and other factors. Psychophysiological factors may affect the expression of these genes, thus leading to symptoms production associated with FGID. Sociocultural factors and family interactions have been shown to shape later reporting of symptoms, the development of FGIDs, and health care seeking. The expression of pain varies across cultures as well including denial of symptoms to dramatic expression. Environmental exposures – Prior studies have shown the effect of environmental exposures in relation to the development of FGIDs. Environmental exposures such as childhood salmonella infection can be a risk factor for IBS in adulthood. === Psychosocial factors === There is a strong link between FGIDs and psychosocial factors. Psychosocial factors influence the functioning of the GI tract through the brain-gut axis, including the GI tract's motility, sensitivity, and barrier function. Psychosocial factors also affect experience and behavior, treatment selection, and clinical outcome. Psychological stress or one's emotional response to stress exacerbates gastrointestinal symptoms and may contribute to FGID development and maintenance. Specifically in children and adolescents, anxiety and depression may present as FGID-associated somatic complaints, such as nausea, vomiting, and abdominal pain. Similarly, anxiety in individuals with FGIDs is linked to greater pain severity, frequency, duration, chronicity, and disabling effects. This is because psychological stress can impact the gut's mucosal barrier functions, allowing bacteria and bacterial products to migrate and cause pain, diarrhea, and other GI symptoms. Conversely, since the brain-gut axis is bidirectional, GI inflammation and injury can amplify pain signals to the brain and contribute to worsened mental status, including anxiety and depression symptoms. Individuals with FGIDs may also experience poor socialization. Due to the nature of the disease, individuals with an FGID may have difficulty with regular school or work attendance and participation in extracurricular activities, leading to isolation and a lack of peer support. This lack of peer support may lead to depression and loneliness, conditions which exacerbate FGIDs symptoms. In addition, children with FGIDs are more likely to experience bullying. As such, stressful situations which influence socialization (seen as either a lack thereof or negative experiences) may lead to an impaired functioning in patients with FGIDs. Family interactions may also play a role in the development of FGIDs through their effects on the physical and psychosocial functioning of an individual. Family factors which may influence the development of an FGID include child attachment style, maladaptive parenting behaviors (paternal rejection and hostility), and even the parents' health status, as children of chronically ill parents experience increased somatic symptoms, insecure attachment, and worsened biopsychosocial functioning. Each of these factors leads to the accumulation of stressors, which can ultimately lead to the development of an FGID. In addition, family units which have a member with an FGIDs diagnosis are more likely to face family functioning difficulties, including challenges to familial roles, communication, affective involvement, organization, and cohesion. These challenges arise due to the nature of the disease, and ultimately worsen symptoms for the FGID patient. === Physiology === The physiology of FGID is characterized by abnormal motility, visceral hypersensitivity as well as dysregulation of the immune system and barrier function of the GI tract as well as inflammatory changes. Abnormal motility Studies have shown altered muscle contractility and tone, bowel compliance, and transit may contribute to many of the gastrointestinal symptoms of FGID which may include diarrhea, constipation, and vomiting. Visceral hypersensitivity In FGID there is poor association of pain with GI motility in many functional GI disorders. These patient often have a lower pain threshold with balloon distension of the bowel (visceral hyperalgesia), or they have increased sensitivity even to normal intestinal function; Visceral hypersensitivity may be amplified in patients with FGIDs. Immune dysregulation, inflammation, and barrier dysfunction Studies on postinfectious IBS have shown that factors such as mucosal membrane permeability, the intestinal flora, and altered mucosal immune function. Ultimately leading to visceral hypersensitivity. Factors contributing to this occurrence include genetics, psychological stress, and altered receptor sensitivity at the gut mucosa and myenteric plexus, which are enabled by mucosal immune dysfunction. Microbiome There has been increased attention to the role of bacteria and the microbiome in overall health and disease. There is evidence for a group of microorganisms which play a role in the brain-gut axis. Studies have revealed that the bacterial composition of the gastrointestinal tract in IBS patient differs from healthy individuals (e.g., increased Firmicutes and reduced Bacteroidetes and Bifidobacteria) However, further research is needed to determine the role of the microbiome in FGIDs. Food and diet The types of food consumed and diet consumed plays a role in the manifestation of FGID and also their relationship to intestinal microbiota. Studies have shown that specific changes in diet (e.g., low FODMAP—fermentable oligo-, di-, and monosaccharides and polyols, or gluten restriction in some patients) may help and reduce the symptom burden in FGID. However, no one diet has been shown to be recommended for all people. === Brain-gut axis === The brain-gut axis is a bidirectional mechanism in which psychosocial factors influence the GI tract and vice versa. Specifically, the emotional and cognitive centers of the brain influence GI activity and immune cell function, and the microbes within the gut regulate mood, cognition, and mental health. These two systems interact through several mechanisms. There are direct, physical connections between the central nervous system and nerve plexuses to the visceral muscles. In addition, neurotransmitters send signals related to thoughts, feelings, and pain regulation from the brain to the GI tract. The brain-gut axis influences the entire body through a variety of pathways; it regulates sensory, motor, endocrine, autonomic, immune, and inflammatory reactions. Within the physical and psychological interactions of FGIDs specifically, psychiatric disorders such as anxiety, depression, and even autism are well-linked to GI dysfunction. Conversely, functional GI diseases are linked to several comorbid psychiatric diseases. Negative emotions such as fear, anxiety, anger, stress, and pain may delay gastric emptying, decrease intestinal and colonic transit time, and induce defecation and diarrhea. == Treatments == === Psychotherapeutic treatments === Because FGIDs are known to be multifactorial with external stressors and environmental factors playing a role in their development, current research demonstrates that psychological treatments may be effective in relieving some symptoms of the disease. Interventions such as cognitive behavioral therapy (CBT), hypnotherapy, and biofeedback-assisted relaxation training (BART) each show promise in symptom reduction. Each of these therapies aims to alter an individual's thought patterns and behaviors while improving self-efficacy, which all work together to improve health outcomes. Cognitive behavioral therapy is a treatment based on the theory that thinking affects one's feelings and behaviors. As such, alterations in one's thought process can have a positive or negative effect on actions and perceptions. Through the lens of FGIDs, a negative thought pattern may be associated with a negative physical experience of abdominal pain, discomfort, and general sickness. In theory, retraining the patient's thought patterns can alleviate these symptoms and improve quality of life. In patients with FGIDs, CBT is an effective treatment option; one study found 87.5% of participants to be completely pain-free following treatment. Internet-based CBT (iCBT) is similarly effective, and may be a good treatment option for individuals who either cannot afford or otherwise lack access to traditional CBT. Virtual CBT for FGIDs has become a growing area of interest. In addition to patients being unable to afford or arrange transportation for in-office CBT, patients also face limited availability of providers trained in GI-specific psychotherapy. Part of the interest in virtual CBT for functional gastrointestinal disorders is due to the effectiveness initial studies have reported. When compared to in-office CBT treatment, both telephone-based CBT treatment and web-based CBT treatment show statistically significant improvements in patient symptoms. Additionally, virtual CBT may allow for better adherence to treatment. Currently, Regulora is the only smartphone app that is approved by the FDA for virtual treatment of FGIDs in adults. Regulora was approved for use as a digital therapeutic that is available by prescription only. Although a relatively newer treatment option, initial evidence from app users suggests statistically significant reductions in abdominal pain for some participants. Hypnotherapy, another method for reducing symptoms of FGIDs, teaches users how to alter their perception of uncomfortable sensations in the body. Gut-directed hypnotherapy specifically gives greater improvements in symptoms than standard treatment of the disease. Research demonstrates directed hypnotherapy to be an effective mechanism of reducing visceral hypersensitivity (a low pain threshold of the internal organs) and sympathetic activity, due to the reduced activity of the anterior cingulated cortex and state of relaxation achieved during hypnosis. For patients with irritable bowel syndrome (IBS) and functional abdominal pain (FAP), hypnotherapy reduces pain intensity and frequency. BART therapies monitor the physiological changes occurring with thoughts, feelings, and emotions. These therapies aim to teach patients how to visualize the effects of the interventions they are undergoing. BART is used to improve mood and somatic responses to anxiety disorders, which may relieve some of the psychological and physiological symptoms of FGIDs. The visual, real-time feedback given through BART empowers the patient to see the difference that the therapy is making, thus giving the patient control over the physiological components of the disease. This allows the patient to maximize their mind-body connection and eventually optimize symptom management and quality of life. BART allows the patient to break the positive feedback loop of anxiety and pain, thus reducing disease exacerbations. === Pharmaceutical treatments === Antidepressants have been thoroughly studied as a potential treatment for FGIDs. Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) show the most promise in treating some of the symptoms of FGIDs. TCAs, specifically amitriptyline, show promising results when examining common FGIDs symptoms such as pain and poor quality of life. SNRIs also demonstrate pain-relieving qualities. SSRIs are less effective in pain management, but may reduce symptoms of anxiety and depression, which would, in turn, reduce some FGIDs symptoms. == Pediatric implications == FGIDs are common in children and adolescents, with a prevalence of 23.1%. The most common functional gastrointestinal disorders affecting children are functional abdominal pain and functional defecation disorders. Despite most children with DBGIs having no clear underlying pathology, these disorders can have profound effects on day-to-day life. As mentioned above, family dynamics may influence the development of FGIDs. Children with at least one parent with a mental health condition are more likely to develop a FGID by age 6. Treatment for these disorders is currently in accordance with treatment for adults. This includes CBT, hypnotherapy, and distraction techniques. Overall, prognosis of FGIDs in children is good. Children have better outcomes when there is family support and acceptance of the child's disorder. == Epidemiology == Functional gastrointestinal disorders are very common. Globally, irritable bowel syndrome and functional dyspepsia alone may affect 16–26% of the population. == Research == There is considerable research into the causes, diagnosis and treatments for FGIDs. Diet, microbiome, genetics, neuromuscular function and immunological response all interact. A role for mast cell activation has been proposed as one of the factors. == See also == Allergy Food intolerance Functional indigestion Histamine intolerance == References == == External links ==	Wikipedia/Functional_colonic_disease
Noma (also known as gangrenous stomatitis or cancrum oris) is a rapidly-progressive and often-fatal gangrenous infection of the mouth and face. Noma usually begins as an ulcer on the gums and rapidly spreads into the jawbone, cheek, and facial soft tissues. This is followed by death of the facial tissues and fatal sepsis. Survivors are left with severe facial disfigurement often with impairments in breathing, swallowing, speaking, and vision. In 2023 noma was added to the World Health Organization's list of neglected tropical diseases. This disease is strongly linked to poverty and malnutrition, and predominantly affects children between the ages of two and six years in the least developed countries around the world, primarily in sub-Saharan Africa; noma has also been seen in severely immunocompromised people in the developed world. It is preventable by proper nutrition and oral hygiene. Noma is most common in impoverished environments with poor healthcare infrastructure; as a result, many cases go undiagnosed, untreated, and unreported. There are no reliable estimates of its prevalence – in 1998 WHO estimated that there were 140,000 cases per year with a fatality rate of 90%; no more recent estimates are available. Noma is an opportunistic infection linked to several microbes that take advantage of malnutrition and compromised immunity. There is no evidence of direct transmission from person to person. In the early stages, it can be treated effectively with antibiotics and nutrition supplements. If diagnosed early enough, there can be proper wound healing. After recovering, patients with disfigurement require complex surgical rehabilitation. Noma survivors experience high levels of stigma, social isolation, and discrimination within their communities. These can be countered by education and community outreach programs. == Signs and symptoms == Initially, there may be a small ulcer in the mouth which progresses into necrotizing gingivitis – painful bleeding of the gums and inter-dental papillae. This is followed by a rapid spread of the infection resulting in more general inflammation of the mouth and lips, facial edema, and foul breath. If untreated, within a few days the necrotizing infection progresses into the facial muscles, the skin, and the upper and lower jaw resulting in tissue destruction and sloughing. Many patients die due to sepsis; survivors are left with permanent scarring and disfigurement. Noma neonatorum is a severe infection affecting very young or newborn children in impoverished environments. A gangrenous infection spreads across the oral, nasal, and/or anal areas, and is frequently fatal. The pattern of lesions is similar to those found in noma. === Stages of noma === The World Health Organization divides noma into five stages: Acute necrotizing gingivitis, edema, gangrenous, scarring, and sequelae. ==== Warning-signs ==== Before the development of noma, there may be simple gingivitis: Inflammation and reddening of the gums, which bleed when touched or during toothbrushing. The WHO recommends disinfectant mouthwash; if not available, use warm, salted water that has been boiled. A high-protein diet, Vitamin A supplements, and patient education on oral hygiene are also recommended to prevent noma from progressing to the acute stages. ==== Stage I: Acute necrotizing gingivitis ==== This is the first stage of noma. The gums are red or reddish-purple and bleed spontaneously. The child has fetid breath and may drool. Painful ulcers of the gums develop, causing trouble eating. If the patient is malnourished and has recently been sick with an infectious disease, such as measles or chickenpox, they are at more risk for developing noma. Fever may develop at this stage, which can persist indefinitely. Appropriate treatment at this stage can halt the disease. ==== Stage II: Edema ==== This stage begins the acute phase of noma. The telltale sign is facial edema (swelling) of the lips, cheeks, eyes, etc. Ulceration of the gums worsens during this stage; ulceration may spread to the mucosa (soft, mucus-producing tissue) of the mouth and nose. The patient may feel pain or soreness in their mouth and cheeks. Other symptoms at this stage include fever, drooling, fetid breath, lymphadenopathy (swollen lymph nodes), and difficulty eating. Progression of the disease can be halted with appropriate treatment. ==== Stage III: Gangrene ==== At this and subsequent stages, although the disease can still be treated, sequelae will inevitably set in. In this stage, the infection eats away at the soft tissue of the patient's face. The gangrene may affect the cheeks, lips, nose, mouth, and nasal and oral cavities. Dead tissue sloughs away over time, leaving holes in the face and the soft tissue, possibly exposing bones and teeth. The patient is apathetic, has little appetite, and has great difficulty eating. At this stage, there is a high risk of sepsis leading to death. ==== Stage IV: Scarring ==== The acute phase is over, but the patient's life is still at risk, and treatment is recommended. This stage lasts one to two weeks. The patient may experience trismus (difficulty moving/opening the jaw), scars will form, and any exposed teeth will set in place. ==== Stage V: Sequelae ==== The disease is over, but sequelae from the gangrenous and scarring stages remain. Tissue may be missing, teeth may still be exposed, and the face may be disfigured. The patient may have difficulty eating, drinking, and speaking. Teeth may become set in the wrong places, or be lost altogether. There may still be problems with drooling and with opening/closing the jaw. Reconstructive surgery is an option at this phase. Social reintegration is also very important. == Epidemiology == As of December 2023, most people who acquire this disease are between the ages of two and six years old, living in the poorest countries of the world. Accurate figures for noma prevalence are not available due to difficulties in diagnosis and reporting in the endemic areas. In 1998 The World Health Organization estimated that 140,000 new cases were occurring each year, with a 90% fatality rate, and a total of 770,000 surviving with scarring or disfigurement. Noma is associated with a very high morbidity, and a mortality rate of approximately 90 percent. The prognosis is much better with treatment; if children have access to medical care, the mortality rate drops to under 10 percent. After gangrene sets in, patients are likely to die of sepsis within one to two weeks. === Causes and risks === Noma is an opportunistic rather than contagious infection. No single pathogen has been associated with the disease (the causative organisms are common in many environments) and there are no documented cases of person to person transmission. The underlying causes for this disease are extreme poverty, malnutrition, other causes of immunosuppression, underlying infections, and poor oral health. The disease principally affects extremely impoverished and malnourished children between 2 and 6 years old in tropical regions. Cases of noma have also been reported in malnourished or immunosuppressed adults, and in concentration camps during the Second World War. Predisposing factors include: malnutrition and vitamin deficiency immunodeficiency poor oral hygiene recent illness (especially acute necrotizing ulcerative gingivitis, measles, malaria, or kwashiorkor), social and environmental factors such as maternal malnutrition and closely spaced pregnancies that result in offspring with weakened immune systems === Treatment === When noma is detected early, its progression can be rapidly halted through basic hygiene, antibiotics, and improved nutrition. However, its physical effects are permanent and may require oral and maxillofacial surgery or reconstructive plastic surgery to repair. Treatments for noma in the acute stage include penicillin, sulfonamides, and other antibiotics. In all stages of noma, the World Health Organization encourages antibiotics, vitamin A supplements or other nutritional supplements, a high-protein diet, and proper hydration. The World Health Organization recommends using amoxicillin and metronidazole in tandem to treat stage I noma (acute necrotizing gingivitis), along with the use of chlorhexidine and hydrogen peroxide to clean the mouth and gums. For stage II noma (edema phase), stage III noma (acute/gangrenous stage), and stage IV noma (scarring phase), the WHO recommends either one of two therapies. The first therapy includes the concurrent use of amoxicillin, clavulanic acid, gentamicin, and metronidazole. The second option includes the concurrent use of ampicillin, gentamicin, and metronidazole. For both options, chlorhexidine mouthwash is advised. For stage III and IV noma, the use of ketamine, and honey are both given as options for dressing the lesions. Reconstruction is usually very challenging and should be delayed until full recovery (usually about one year following initial intervention). == History == Known in antiquity to such physicians as Hippocrates and Galen, noma was once reported around the world, including in Europe and the United States. The disease was well-known in the Netherlands in the 1500s and 1600s. The first clinical description of noma was in 1595 by a Dutch man, Carolus Battus. Dutch surgeon Cornelis van de Voorde first used the term "noma" to describe the disease in 1680. A European scientist, Gabriel Lund, attributed noma to poverty, cramped living conditions, and malnutrition in 1765. English physician John Addington Symmonds linked the disease to previous infection with measles. The first surgical treatment for noma sequelae was performed in 1781. Surgical treatments for sequelae developed throughout the 1800s. In the late 1800s, scientists suspected that noma was caused by bacteria. With improvements in hygiene and nutrition, noma has disappeared from industrialized countries since the 20th century, except during World War II when it was endemic to the Auschwitz and Belsen concentration camps. The disease and treatments were studied by Berthold Epstein, a Czech physician and forced-labor prisoner who had recommended the study under Josef Mengele's direction. Since 1970, there has been little research done on noma, with few exceptions. One exception is Cyril Enwonwu, a Nigerian scientist focusing on noma. Nigeria is home to two of the few hospitals in the world that focus on treating noma patients: Sokoto Noma Hospital, in the city of Sokoto and the Noma Centre Abuja (built and funded by the Noma Aid Nigeria Initiative). In January 2023 the Nigerian Ministry of Health submitted to the World Health Organization a request for noma to be added to WHO's list of neglected tropical diseases. This had been endorsed by 31 countries and was accompanied by a dossier of evidence demonstrating that noma fit the criteria for inclusion. In December 2023 WHO conceded the request. It is hoped that this will encourage more research into the disease. === Etymology === The word "noma" derives from the classical Greek word νομή, used to describe the continuing process of a fire or an ulcer. == Society and culture == People with noma and noma survivors may face stigma. Some think that noma is a contagious disease, so they avoid noma sufferers and survivors to avoid contracting it. Parents may hide afflicted children within the home because of social stigma, which can prevent them from getting treatment. Some also believe noma may be caused by witchcraft or a curse on the child's parents. Based on one 1997 estimate, roughly 770,000 people worldwide live with noma sequelae. However, "noma is a disease of shame," and children are sometimes hidden in isolation rather than being sent to receive treatment. In Nigeria, sufferers and their families may seek traditional medicine rather than go to a medical center. In a study of 7,185 noma sufferers across Nigeria, only 19% reported going to a hospital or medical center upon discovering a facial lesion. 47.6% took 1–3 weeks to visit a hospital; the rest took longer to visit a hospital. Children and other noma survivors in Africa are helped by a few international charitable organizations, such as Facing Africa, a UK registered charity that helps affected Ethiopians, and Swiss charity Winds of Hope. The Hilfsaktion Noma E.v is a non-governmental organization that has been involved in the management of Noma survivors for 30 years. They have a presence in 9 countries within the sub-Saharan Noma belt and have two fully funded clinics for the comprehensive management of Noma patients (one in Niger Republic and the other in Guinea Bissau). There are two dedicated Noma hospitals in Nigeria, the first and oldest is the Noma Children Hospital Sokoto, staffed by resident and visiting medical teams supported by Médecins Sans Frontières. Some of the staff are noma survivors. The second and more recently commissioned centre is the Noma Centre Abuja, fully funded and sponsored by the Noma Aid Nigeria Initiative, where holistic and compressive management of the Noma patients is given. The team consists of a resident medical and surgical team and visiting surgeons from Europe. In other countries, such as Ethiopia, international charities work in collaboration with the local health care system to provide complex reconstructive surgery which can give back facial functions such as eating, speaking, and smiling. Teams of volunteer medics coming from abroad are often needed to support the local capacity to address the most severe cases, which can be extremely challenging even for senior maxillofacial surgeons. On 10 June 2010, the work of such volunteer surgeons was featured in a UK BBC Two documentary presented by Ben Fogle, Make Me a New Face: Hope for Africa's Hidden Children. == See also == Necrotizing fasciitis Noma neonatorum == References == == Further reading == == External links == Short documentary on noma in Nigeria	Wikipedia/Noma_(disease)
Pancreatic diseases are diseases that affect the pancreas, an organ in most vertebrates and in humans and other mammals located in the abdomen. The pancreas plays a role in the digestive and endocrine system, producing enzymes which aid the digestion process and the hormone insulin, which regulates blood sugar levels. The most common pancreatic disease is pancreatitis, an inflammation of the pancreas which could come in acute or chronic form. Other pancreatic diseases include diabetes mellitus, exocrine pancreatic insufficiency, cystic fibrosis, pseudocysts, cysts, congenital malformations, tumors including pancreatic cancer, and hemosuccus pancreaticus. == Pancreatitis == Pancreatitis is inflammation of the pancreas. There are two forms of pancreatitis, which are different in causes and symptoms, and require different treatment: Acute pancreatitis is a rapid-onset inflammation of the pancreas, most frequently caused by alcoholism or gallstones. Less frequent but important causes are hypertriglyceridemia, drugs, infections. Chronic pancreatitis is a long-standing inflammation of the pancreas. == Diabetes mellitus == The pancreas is central in the pathophysiology of both major types of diabetes mellitus. In type 1 diabetes mellitus, there is direct damage to the endocrine pancreas that results in insufficient insulin synthesis and secretion. Type 2 diabetes mellitus, which begins with insulin resistance, is characterized by the ultimate failure of pancreatic β cells to match insulin production with insulin demand. == Exocrine pancreatic insufficiency == Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans affected by cystic fibrosis and Shwachman–Diamond syndrome. It is caused by a progressive loss of the pancreatic cells that make digestive enzymes. Chronic pancreatitis is the most common cause of EPI in humans. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients. == Cystic fibrosis == Cystic fibrosis, is a hereditary disease that affects the entire body, causing progressive disability and early death. It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The product of this gene helps create sweat, digestive juices, and mucus. The name cystic fibrosis refers to the characteristic 'fibrosis' (tissue scarring) and cyst formation within the pancreas, causing irreversible damage, and often resulting in painful inflammation (pancreatitis). == Pseudocysts == A pancreatic pseudocyst is a circumscribed collection of fluid rich in amylase and other pancreatic enzymes, blood and necrotic tissue, typically located in the lesser sac. == Cysts == A pancreatic cyst is a fluid filled sac within the pancreas. They can be benign or malignant. X-ray computed tomography (CT scan) findings of cysts in the pancreas are common, and often are benign. In a study of 2,832 patients without pancreatic disease, 73 patients (2.6%) had cysts in the pancreas. About 85% of these patients had a single cyst. Cysts ranged in size from 2 to 38 mm (mean, 8.9 mm). There was a strong correlation between the presence of cysts and age. No cysts were identified among patients less than 40 years of age, while 8.7 percent of the patients aged 80 to 89 years had a pancreatic cyst. Cysts also may be present due to intraductal papillary mucinous neoplasm. == Congenital malformations == === Pancreas divisum === Pancreas divisum is a malformation in which the pancreas fails to fuse. It is a rare condition that affects only 6% of the world's population, and of these few, only 1% ever have symptoms that require surgery. === Annular pancreas === Annular pancreas is characterized by a pancreas that encircles the duodenum. It results from an embryological malformation in which the early pancreatic buds undergo inappropriate rotation and fusion, which can lead to small bowel obstruction. == Tumors and cancer == Pancreatic tumors (masses) including pancreatic cancer === Benign === Serous cystadenoma of the pancreas Solid pseudopapillary neoplasm === Tumor predisposition === ==== Zollinger-Ellison syndrome ==== Zollinger-Ellison syndrome is a collection of findings in individuals with gastrinoma, a tumor of the gastrin-producing cells of the pancreas. Unbridled gastrin secretion results in elevated levels of the hormone, and increased hydrochloric acid secretion from parietal cells of the stomach. It can lead to ulceration and scarring of the stomach and intestinal mucosa. == Hemosuccus pancreaticus == Hemosuccus pancreaticus, also known as pseudohematobilia or Wirsungorrhage, is a rare cause of hemorrhage in the gastrointestinal tract. It is caused by a bleeding source in the pancreas, pancreatic duct, or structures adjacent to the pancreas, such as the splenic artery, that bleed into the pancreatic duct. Patients with hemosuccus may develop symptoms of gastrointestinal hemorrhage, such as blood in the stools, maroon stools, or melena. They may also develop abdominal pain. Hemosuccus pancreaticus is associated with pancreatitis, pancreatic cancer and aneurysms of the splenic artery. Angiography may be used to diagnose hemosuccus pancreaticus, where the celiac axis is injected to determine the blood vessel that is bleeding. Concomitant embolization of the end vessel may terminate the hemorrhage. Alternatively, a distal pancreatectomy may be required to stop the hemorrhage. == References == == External links ==	Wikipedia/Pancreatic_disease
Gallbladder diseases are diseases involving the gallbladder and is closely linked to biliary disease, with the most common cause being gallstones (cholelithiasis). The gallbladder is designed to aid in the digestion of fats by concentrating and storing the bile made in the liver and transferring it through the biliary tract to the digestive system through bile ducts that connect the liver, gallbladder, and the Sphincter of Oddi. The gallbladder is controlled on a neurohormonal basis, with Cholecystokinin (CCK) leading to the contraction and release of bile into the bile ducts. Other hormones allow for the relaxation and further storing of bile. A disruption in the hormones, ducts, or gallbladder can lead to disease. Gallstones are the most common disease and can lead to other diseases, including Cholecystitis, inflammation of the gallbladder, and gallstone pancreatitis when the gallstone blocks the pancreatic duct. Treatment is considered for symptomatic disease and can vary from surgical to non-surgical treatment. About 104 million new cases of gallbladder and biliary disease occurred in 2013. == Signs and symptoms == Gallbladder disease presents chiefly with abdominal pain located in the right upper abdomen. This pain is described as biliary colic. Pain typically occurs suddenly and radiates to the right shoulder and back, depending on several factors, including specific diseases. It can either be constant or episodic and last from minutes to hours. This pain is described as biliary colic pain. Other common symptoms with gallbladder disease and biliary colic are nausea and vomiting. With conditions such as cholecystitis and choledocholithiasis, fever may be present. During the physical examination, the patient will present with Murphy's sign. This maneuver requires the physician to grab the lower part of the right ribs and curl their fingers under them. A positive test elicits pain with deep inspiration and is indicative of inflammation of the gallbladder, cholecystitis. With positive Murphy's sign, deep palpation of the abdomen also elicits pain. In these cases, physicians will need to rule out peritonitis, inflammation of the abdominal cavity. A negative Murphy's sign does not rule out all gallbladder diseases such as ascending cholangitis. Using an ultrasound transducer supplanting a physician's hands during an abdominal ultrasound can detect a positive Murphy's sign. The sign also has over a 90% positive and negative predictive value for acute cholecystitis === Gallstones === Gallstones may develop in the gallbladder as well as elsewhere in the biliary tract. If gallstones in the gallbladder are symptomatic, surgical removal of the gallbladder, known as cholecystectomy may be indicated. Gallstones form when the tenuous balance of solubility of biliary lipids tips in favor of precipitation of cholesterol, unconjugated bilirubin, or bacterial degradation products of biliary lipids. For cholesterol gallstones, metabolic alterations in hepatic cholesterol secretion combine with changes in gallbladder motility and intestinal bacterial degradation of bile salts to destabilize cholesterol carriers in bile and produce cholesterol crystals. For black pigment gallstones, changes in heme metabolism or bilirubin absorption lead to increased bilirubin concentrations and precipitation of calcium bilirubinate. In contrast, mechanical obstruction of the biliary tract is the major factor leading to bacterial degradation and precipitation of biliary lipids in brown pigment stones. == Risk factors == === Pregnancy === During pregnancy when female sex hormones are naturally raised, biliary sludge (particulate material derived from bile that is composed of cholesterol, calcium bilirubinate, and mucin) appears in 5% to 30% of women. Resolution frequently transpires during the post-partum period: sludge disappears in two-thirds; small (<1 cm) gallstones (microlithiasis) vanish in one-third, but definitive gallstones become established in ~5%. Additional risk factors for stone formation during pregnancy include obesity (prior to the pregnancy), reduced high density lipoprotein (HDL) cholesterol and the metabolic syndrome. === Hormonal contraceptives === Women are almost twice as likely as men to form gallstones especially during the fertile years; the gap narrows after the menopause. The underlying mechanism is female sex hormones; parity, oral contraceptive use and estrogen replacement therapy are established risk factors for cholesterol gallstone formation. Female sex hormones adversely influence hepatic bile secretion and gallbladder function. Estrogens increase cholesterol secretion and diminish bile salt secretion, while progestins act by reducing bile salt secretion and impairing gallbladder emptying leading to stasis. A new 4th generation progestin, drospirenone, used in some oral contraceptives may further heighten the risk of gallstone disease and cholecystectomy; however, the increased risk is quite modest and not likely to be clinically meaningful. A retrospective (historical) cohort study was performed on a very large data base including 1980 and 1981 Medicaid billing data from the states of Michigan and Minnesota in which 138,943 users of OCs were compared with 341,478 nonusers. Oral contraceptives were shown as risk factors for gallbladder disease, although the risk is of sufficient magnitude to be of potential clinical importance only in young women. The 1984 Royal College of General Practitioners' Oral Contraception Study suggests that, in the long-term, oral contraceptives are not associated with any increased risk of gallbladder disease, although there is an acceleration of the disease in those women susceptible to it. Newer research suggests otherwise. A 1993 meta-analysis concludes that oral contraceptive use is associated with a slightly and transiently increased rate of gallbladder disease, but laters confirms that modern low-dose oral contraceptives are safer than older formulas, though an effect cannot be excluded. A 2001 comparative study of the IMS LifeLink Health Plan Claims Database interpreted that in a large cohort of women using oral contraceptives, there was found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethisterone compared with levonorgestrel. No statistically significant increase in risk was associated with the other formulations of oral contraceptive (etynodiol diacetate, norgestrel and norgestimate). === Menopausal hormone therapy === While some observational studies had suggested that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold, such an association had not been reported consistently. More recent randomized clinical trial data among postmenopausal women now support a causal role for oral menopausal hormone therapy estrogens. Confirming the positive finding of another large study, the landmark Women's Health Initiative (WHI) reported very significant increases (p < 0.001) for risk of gallbladder disease or surgery attributed to treatments with both estrogen alone (conjugated equine estrogen; CEE) and estrogen-plus-progestin (conjugated equine estrogen with medroxyprogesterone; CEE+MPA ). Specifically, a 67% increase (CEE versus placebo) and 59% increase (CEE+MPA versus placebo) among healthy postmenopausal women that reported either having had a hysterectomy (n = 8376) or not (n = 14203) prior to randomization, respectively. === Other factors === A prospective study in 1994 noted that body mass index remains the strongest predictor of symptomatic gallstones among young women. Other risk factors are having over four pregnancies, weight gain, and cigarette smoking. Alcohol was shown to have an inverse relationship between use and gallbladder disease. == Diseases of the gallbladder == Cholelithiasis (gallstones) are typically asymptomatic but can cause biliary pain episodically combined with other signs and symptoms of gallbladder disease such as nausea, vomiting, and pain radiating to the back. The curative treatment of symptomatic gallstones is a cholecystectomy. Abdominal pain can be confused with other gut disorders and will not relieve the pain in these instances. Cholecystitis, inflammation of the gallbladder can occur in both acute and chronic cases. Ultrasound is the diagnostic test of choice by showing an increased gallbladder wall thickness. Additionally, in acute cases, a leukocytosis, an increase in white blood cell count, is found. In chronic cases, a cholecystectomy is curative but is treated with medication as an alternative therapy for older patients. While in acute cases, patients take antibiotics for complications such as abscesses, pain control, and nothing to eat until a cholecystectomy. Gallbladder polyp is a growth in the gallbladder from various causes, with the most common being cholesterol polyp. Some can cause upper abdominal pain, while others remain asymptomatic. The size and symptoms determine the course of treatment, and those with smaller polyps may undergo routine monitoring for the growth of polyps. Larger polyps greater than 10mm will require cholecystectomy, gallbladder removal due to potential malignant qualities. Gallbladder cancer (Malignant neoplasm of the gallbladder) is rare, and most of the time is adenocarcinoma. As most early-stage cancers are asymptomatic, neoplasm of the gallbladder is found in late stages and has a poor prognosis. Multiple hypotheses have been formed about an individual's susceptibility to cancer with notations of increased susceptibility in patients with cholecystitis, gallstones, specific ethnicities, gallbladder polyps, and lifestyle diseases such as obesity. Symptoms include persistent right upper quadrant pain, jaundice, palpable mass. Biliary dyskinesia is a disease with the abnormal release of bile from the gallbladder leading to chronic biliary colic. Diagnosis is based on several studies examining the most common cause of gallstones and looking at the ejection fraction through a HIDA scan with cholecystokinin. This hormone causes bile release from the gallbladder. Postcholecystectomy syndrome (cholesterosis, hydrops, perforation, fistula) Xanthogranulomatous cholecystitis is a rare form of gallbladder disease which mimics gallbladder cancer although it is not cancerous. It was first discovered and reported in the medical literature in 1976 by J.J. McCoy, Jr., and colleagues. == Diagnosis == A diagnostic workup is based on the most likely diagnosis. In testing for gallbladder disease, specifically, liver panel tests and pancreatic enzymes such as lipase will be within normal limits. There can be a mild elevation in alkaline phosphatase and bilirubin in some instances, such as cholecystitis. If gallstones are blocking other biliary tract areas causing pancreatic gallstones or choledocholithiasis, elevated liver panel, pancreatic enzymes, and bilirubin will be noted. Ultrasound is the diagnostic imaging of choice to examine for thickening of the gallbladder walls, polyps, pericholecystic fluid, and gallstones. A positive Murphy's sign may also be noted using the ultrasound transducer. Another imaging modality is using cholescintigraphy to examine hepatic function. This scan assesses if the gallbladder is functioning as it is supposed to with a controlled amount of hormone. In regards to a suspected choledocholithiasis, a endoscopic retrograde cholangiopancreatography (ERCP) is used in both the diagnosis and treatment as it can remove the stones that are blocking the bile ducts causing choledocholithiasis. == Treatment == In patients with an asymptomatic disease where a gallstone or small polyp was found incidentally, no further treatment is undertaken until symptoms arise. When an individual has symptomatic gallbladder disease and early-stage cancer, a cholecystectomy is utilized. A cholecystectomy is controversial in advanced cancer due to the low 5-year survival rate, especially if regional lymph nodes are involved. Symptoms of gallbladder disease typically decrease after cholecystectomy unless the abdominal pain was caused by other digestive tract diseases such as irritable bowel syndrome. Nonsurgical treatment of gallstones and cholecystitis includes medication (for example chenodeoxycholic acid and ursodiol) to dissolve the stones. Because of side effects, ursodiol is more commonly chosen. It will take approximately two years to dissolve small stones with medications. Other avenues to reduce the modifiable risk factors that one may have for gallstones by reducing weight, dietary changes to lower cholesterol, and triglycerides. == See also == Gallbladder polyp == References == Yes == External links == Gallstones - Topic Overview Cholecystectomy: Surgical Removal of the Gallbladder Archived 2014-06-10 at the Wayback Machine Surgery Questions on gallbladder	Wikipedia/Gallbladder_disease
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietary choices, dietary supplements, and medical devices) and known interventions that warrant further study and comparison. Clinical trials generate data on dosage, safety and efficacy. They are conducted only after they have received health authority/ethics committee approval in the country where approval of the therapy is sought. These authorities are responsible for vetting the risk/benefit ratio of the trial—their approval does not mean the therapy is 'safe' or effective, only that the trial may be conducted. Depending on product type and development stage, investigators initially enroll volunteers or patients into small pilot studies, and subsequently conduct progressively larger scale comparative studies. Clinical trials can vary in size and cost, and they can involve a single research center or multiple centers, in one country or in multiple countries. Clinical study design aims to ensure the scientific validity and reproducibility of the results. Costs for clinical trials can range into the billions of dollars per approved drug, and the complete trial process to approval may require 7–15 years. The sponsor may be a governmental organization or a pharmaceutical, biotechnology or medical-device company. Certain functions necessary to the trial, such as monitoring and lab work, may be managed by an outsourced partner, such as a contract research organization or a central laboratory. Only 10 percent of all drugs started in human clinical trials become approved drugs. == Overview == === Trials of drugs === Some clinical trials involve healthy subjects with no pre-existing medical conditions. Other clinical trials pertain to people with specific health conditions who are willing to try an experimental treatment. Pilot experiments are conducted to gain insights for design of the clinical trial to follow. There are two goals to testing medical treatments: to learn whether they work well enough, called "efficacy", or "effectiveness"; and to learn whether they are safe enough, called "safety". Neither is an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is intended to be used, what other treatments are available, and the severity of the disease or condition. The benefits must outweigh the risks.: 8 For example, many drugs to treat cancer have severe side effects that would not be acceptable for an over-the-counter pain medication, yet the cancer drugs have been approved since they are used under a physician's care and are used for a life-threatening condition. In the US the elderly constitute 14% of the population, while they consume over one-third of drugs. People over 55 (or a similar cutoff age) are often excluded from trials because their greater health issues and drug use complicate data interpretation, and because they have different physiological capacity than younger people. Children and people with unrelated medical conditions are also frequently excluded. Pregnant women are often excluded due to potential risks to the fetus. The sponsor designs the trial in coordination with a panel of expert clinical investigators, including what alternative or existing treatments to compare to the new drug and what type(s) of patients might benefit. If the sponsor cannot obtain enough test subjects at one location investigators at other locations are recruited to join the study. During the trial, investigators recruit subjects with the predetermined characteristics, administer the treatment(s) and collect data on the subjects' health for a defined time period. Data include measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to symptoms, and whether improvement or worsening of the condition targeted by the study drug occurs. The researchers send the data to the trial sponsor, who then analyzes the pooled data using statistical tests. Examples of clinical trial goals include assessing the safety and relative effectiveness of a medication or device: On a specific kind of patient At varying dosages For a new indication Evaluation for improved efficacy in treating a condition as compared to the standard therapy for that condition Evaluation of the study drug or device relative to two or more already approved/common interventions for that condition While most clinical trials test one alternative to the novel intervention, some expand to three or four and may include a placebo. Except for small, single-location trials, the design and objectives are specified in a document called a clinical trial protocol. The protocol is the trial's "operating manual" and ensures all researchers perform the trial in the same way on similar subjects and that the data is comparable across all subjects. As a trial is designed to test hypotheses and rigorously monitor and assess outcomes, it can be seen as an application of the scientific method, specifically the experimental step. The most common clinical trials evaluate new pharmaceutical products, medical devices, biologics, diagnostic assays, psychological therapies, or other interventions. Clinical trials may be required before a national regulatory authority approves marketing of the innovation. === Trials of devices === Similarly to drugs, manufacturers of medical devices in the United States are required to conduct clinical trials for premarket approval. Device trials may compare a new device to an established therapy, or may compare similar devices to each other. An example of the former in the field of vascular surgery is the Open versus Endovascular Repair (OVER trial) for the treatment of abdominal aortic aneurysm, which compared the older open aortic repair technique to the newer endovascular aneurysm repair device. An example of the latter are clinical trials on mechanical devices used in the management of adult female urinary incontinence. === Trials of procedures === Similarly to drugs, medical or surgical procedures may be subjected to clinical trials, such as comparing different surgical approaches in treatment of fibroids for subfertility. However, when clinical trials are unethical or logistically impossible in the surgical setting, case-controlled studies will be replaced. === Patient and public involvement === Besides being participants in a clinical trial, members of the public can be actively collaborate with researchers in designing and conducting clinical research. This is known as patient and public involvement (PPI). Public involvement involves a working partnership between patients, caregivers, people with lived experience, and researchers to shape and influence what is researcher and how. PPI can improve the quality of research and make it more relevant and accessible. People with current or past experience of illness can provide a different perspective than professionals and compliment their knowledge. Through their personal knowledge they can identify research topics that are relevant and important to those living with an illness or using a service. They can also help to make the research more grounded in the needs of the specific communities they are part of. Public contributors can also ensure that the research is presented in plain language that is clear to the wider society and the specific groups it is most relevant for. == History == === Development === Although early medical experimentation was performed often, the use of a control group to provide an accurate comparison for the demonstration of the intervention's efficacy was generally lacking. For instance, Lady Mary Wortley Montagu, who campaigned for the introduction of inoculation (then called variolation) to prevent smallpox, arranged for seven prisoners who had been sentenced to death to undergo variolation in exchange for their life. Although they survived and did not contract smallpox, there was no control group to assess whether this result was due to the inoculation or some other factor. Similar experiments performed by Edward Jenner over his smallpox vaccine were equally conceptually flawed. The first proper clinical trial was conducted by the Scottish physician James Lind. The disease scurvy, now known to be caused by a Vitamin C deficiency, would often have terrible effects on the welfare of the crew of long-distance ocean voyages. In 1740, the catastrophic result of Anson's circumnavigation attracted much attention in Europe; out of 1900 men, 1400 had died, most of them allegedly from having contracted scurvy. John Woodall, an English military surgeon of the British East India Company, had recommended the consumption of citrus fruit from the 17th century, but their use did not become widespread. Lind conducted the first systematic clinical trial in 1747. He included a dietary supplement of an acidic quality in the experiment after two months at sea, when the ship was already afflicted with scurvy. He divided twelve scorbutic sailors into six groups of two. They all received the same diet but, in addition, group one was given a quart of cider daily, group two twenty-five drops of elixir of vitriol (sulfuric acid), group three six spoonfuls of vinegar, group four half a pint of seawater, group five received two oranges and one lemon, and the last group a spicy paste plus a drink of barley water. The treatment of group five stopped after six days when they ran out of fruit, but by then one sailor was fit for duty while the other had almost recovered. Apart from that, only group one also showed some effect of its treatment. Each year, May 20 is celebrated as Clinical Trials Day in honor of Lind's research. After 1750 the discipline began to take its modern shape. The English doctor John Haygarth demonstrated the importance of a control group for the correct identification of the placebo effect in his celebrated study of the ineffective remedy called Perkin's tractors. Further work in that direction was carried out by the eminent physician Sir William Gull, 1st Baronet in the 1860s. Frederick Akbar Mahomed (d. 1884), who worked at Guy's Hospital in London, made substantial contributions to the process of clinical trials, where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension. He also founded the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials." === Modern trials === Ideas of Sir Ronald A. Fisher still play a role in clinical trials. While working for the Rothamsted experimental station in the field of agriculture, Fisher developed his Principles of experimental design in the 1920s as an accurate methodology for the proper design of experiments. Among his major ideas include the importance of randomization—the random assignment of individual elements (eg crops or patients) to different groups for the experiment; replication—to reduce uncertainty, measurements should be repeated and experiments replicated to identify sources of variation; blocking—to arrange experimental units into groups of units that are similar to each other, and thus reducing irrelevant sources of variation; use of factorial experiments—efficient at evaluating the effects and possible interactions of several independent factors. Of these, blocking and factorial design are seldom applied in clinical trials, because the experimental units are human subjects and there is typically only one independent intervention: the treatment. The British Medical Research Council officially recognized the importance of clinical trials from the 1930s. The council established the Therapeutic Trials Committee to advise and assist in the arrangement of properly controlled clinical trials on new products that seem likely on experimental grounds to have value in the treatment of disease. The first randomised curative trial was carried out at the MRC Tuberculosis Research Unit by Sir Geoffrey Marshall (1887–1982). The trial, carried out between 1946 and 1947, aimed to test the efficacy of the chemical streptomycin for curing pulmonary tuberculosis. The trial was both double-blind and placebo-controlled. The methodology of clinical trials was further developed by Sir Austin Bradford Hill, who had been involved in the streptomycin trials. From the 1920s, Hill applied statistics to medicine, attending the lectures of renowned mathematician Karl Pearson, among others. He became famous for a landmark study carried out in collaboration with Richard Doll on the correlation between smoking and lung cancer. They carried out a case-control study in 1950, which compared lung cancer patients with matched control and also began a sustained long-term prospective study into the broader issue of smoking and health, which involved studying the smoking habits and health of more than 30,000 doctors over a period of several years. His certificate for election to the Royal Society called him "... the leader in the development in medicine of the precise experimental methods now used nationally and internationally in the evaluation of new therapeutic and prophylactic agents." International clinical trials day is celebrated on 20 May. The acronyms used in the titling of clinical trials are often contrived, and have been the subject of derision. == Types == Clinical trials are classified by the research objective created by the investigators. In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study. In an interventional study, the investigators give the research subjects an experimental drug, surgical procedure, use of a medical device, diagnostic or other intervention to compare the treated subjects with those receiving no treatment or the standard treatment. Then the researchers assess how the subjects' health changes. Trials are classified by their purpose. After approval for human research is granted to the trial sponsor, the U.S. Food and Drug Administration (FDA) organizes and monitors the results of trials according to type: Prevention trials look for ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include drugs, vitamins or other micronutrients, vaccines, or lifestyle changes. Screening trials test for ways to identify certain diseases or health conditions. Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. Treatment trials test experimental drugs, new combinations of drugs, or new approaches to surgery or radiation therapy. Quality of life trials (supportive care trials) evaluate how to improve comfort and quality of care for people with a chronic illness. Genetic trials are conducted to assess the prediction accuracy of genetic disorders making a person more or less likely to develop a disease. Epidemiological trials have the goal of identifying the general causes, patterns or control of diseases in large numbers of people. Compassionate use trials or expanded access trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. Usually, this involves a disease for which no effective therapy has been approved, or a patient who has already failed all standard treatments and whose health is too compromised to qualify for participation in randomized clinical trials. Usually, case-by-case approval must be granted by both the FDA and the pharmaceutical company for such exceptions. Fixed trials consider existing data only during the trial's design, do not modify the trial after it begins, and do not assess the results until the study is completed. Adaptive clinical trials use existing data to design the trial, and then use interim results to modify the trial as it proceeds. Modifications include dosage, sample size, drug undergoing trial, patient selection criteria and "cocktail" mix. Adaptive trials often employ a Bayesian experimental design to assess the trial's progress. In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. The aim is to more quickly identify drugs that have a therapeutic effect and to zero in on patient populations for whom the drug is appropriate. Clinical trials are conducted typically in four phases, with each phase using different numbers of subjects and having a different purpose to construct focus on identifying a specific effect. === Phases === Clinical trials involving new drugs are commonly classified into five phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug development process will normally proceed through phases I–IV over many years, frequently involving a decade or longer. If the drug successfully passes through phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are performed after the newly approved drug, diagnostic or device is marketed, providing assessment about risks, benefits, or best uses. == Trial design == A fundamental distinction in evidence-based practice is between observational studies and randomized controlled trials. Types of observational studies in epidemiology, such as the cohort study and the case-control study, provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators retrospectively assess associations between the treatments given to participants and their health status, with potential for considerable errors in design and interpretation. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health. Some Phase II and most Phase III drug trials are designed as randomized, double-blind, and placebo-controlled. Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment a subject receives. This intent is to prevent researchers from treating the two groups differently. A form of double-blind study called a "double-dummy" design allows additional insurance against bias. In this kind of study, all patients are given both placebo and active doses in alternating periods. Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect. Clinical studies having small numbers of subjects may be "sponsored" by single researchers or a small group of researchers, and are designed to test simple questions or feasibility to expand the research for a more comprehensive randomized controlled trial. Clinical studies can be "sponsored" (financed and organized) by academic institutions, pharmaceutical companies, government entities and even private groups. Trials are conducted for new drugs, biotechnology, diagnostic assays or medical devices to determine their safety and efficacy prior to being submitted for regulatory review that would determine market approval. === Active control studies === In cases where giving a placebo to a person suffering from a disease may be unethical, "active comparator" (also known as "active control") trials may be conducted instead. In trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness. In other cases, sponsors may conduct an active comparator trial to establish an efficacy claim relative to the active comparator instead of the placebo in labeling. === Master protocol === A master protocol includes multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure. Trials that could develop a master protocol include the umbrella trial (multiple medical products for a single disease), platform trial (multiple products for a single disease entering and leaving the platform), and basket trial (one medical product for multiple diseases or disease subtypes). Genetic testing enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. Multiple companies can participate, each bringing a different drug. The first such approach targets squamous cell cancer, which includes varying genetic disruptions from patient to patient. Amgen, AstraZeneca and Pfizer are involved, the first time they have worked together in a late-stage trial. Patients whose genomic profiles do not match any of the trial drugs receive a drug designed to stimulate the immune system to attack cancer. === Clinical trial protocol === A clinical trial protocol is a document used to define and manage the trial. It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol. The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organization of the planned trial. Details of the trial are provided in documents referenced in the protocol, such as an investigator's brochure. The protocol contains a precise study plan to assure safety and health of the trial subjects and to provide an exact template for trial conduct by investigators. This allows data to be combined across all investigators/sites. The protocol also informs the study administrators (often a contract research organization). The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan have been standardized to follow Good Clinical Practice guidance issued by the International Conference on Harmonisation (ICH). Regulatory authorities in Canada, China, South Korea, and the UK also follow ICH guidelines. Journals such as Trials, encourage investigators to publish their protocols. === Design features === ==== Informed consent ==== Clinical trials recruit study subjects to sign a document representing their "informed consent". The document includes details such as its purpose, duration, required procedures, risks, potential benefits, key contacts and institutional requirements. The participant then decides whether to sign the document. The document is not a contract, as the participant can withdraw at any time without penalty. Informed consent is a legal process in which a recruit is instructed about key facts before deciding whether to participate. Researchers explain the details of the study in terms the subject can understand. The information is presented in the subject's native language. Generally, children cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent. ==== Statistical power ==== In any clinical trial, the number of subjects, also called the sample size, has a large impact on the ability to reliably detect and measure the effects of the intervention. This ability is described as its "power", which must be calculated before initiating a study to figure out if the study is worth its costs. In general, a larger sample size increases the statistical power, also the cost. The statistical power estimates the ability of a trial to detect a difference of a particular size (or larger) between the treatment and control groups. For example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between placebo and trial groups receiving dosage of 10 mg/dL or more, but only 0.70 to detect a difference of 6 mg/dL. === Placebo groups === Merely giving a treatment can have nonspecific effects. These are controlled for by the inclusion of patients who receive only a placebo. Subjects are assigned randomly without informing them to which group they belonged. Many trials are doubled-blinded so that researchers do not know to which group a subject is assigned. Assigning a subject to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki provides guidelines on this issue. === Duration === Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. For example, a new cancer drug has, on average, six years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about eight years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. Drugs for other diseases have similar timelines. Some reasons a clinical trial might last several years: For chronic conditions such as cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient. For drugs that are not expected to have a strong effect (meaning a large number of patients must be recruited to observe 'any' effect), recruiting enough patients to test the drug's effectiveness (i.e., getting statistical power) can take several years. Only certain people who have the target disease condition are eligible to take part in each clinical trial. Researchers who treat these particular patients must participate in the trial. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial. A clinical trial might also include an extended post-study follow-up period from months to years for people who have participated in the trial, a so-called "extension phase", which aims to identify long-term impact of the treatment. The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low. For clinical trials involving potential for seasonal influences (such as airborne allergies, seasonal affective disorder, influenza, and skin diseases), the study may be done during a limited part of the year (such as spring for pollen allergies), when the drug can be tested. Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies, such as the Nurses' Health Study). == Administration == Clinical trials designed by a local investigator, and (in the US) federally funded clinical trials, are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is contracted to perform all the administrative work on a clinical trial. For Phases II–IV the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures the sponsor receives data from every site. Specialist site management organizations can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase I clinical trials of new medicines are often conducted in a specialist clinical trial clinic, with dedicated pharmacologists, where the subjects can be observed by full-time staff. These clinics are often run by a CRO which specialises in these studies. At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local institutional review board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO. === Quality === In the context of a clinical trial, quality typically refers to the absence of errors which can impact decision making, both during the conduct of the trial and in use of the trial results. === Marketing === An Interactional Justice Model may be used to test the effects of willingness to talk with a doctor about clinical trial enrollment. Results found that potential clinical trial candidates were less likely to enroll in clinical trials if the patient is more willing to talk with their doctor. The reasoning behind this discovery may be patients are happy with their current care. Another reason for the negative relationship between perceived fairness and clinical trial enrollment is the lack of independence from the care provider. Results found that there is a positive relationship between a lack of willingness to talk with their doctor and clinical trial enrollment. Lack of willingness to talk about clinical trials with current care providers may be due to patients' independence from the doctor. Patients who are less likely to talk about clinical trials are more willing to use other sources of information to gain a better insight of alternative treatments. Clinical trial enrollment should be motivated to utilize websites and television advertising to inform the public about clinical trial enrollment. === Information technology === The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Clinical trial management systems are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial, particularly with respect to investigational sites. Advanced analytics for identifying researchers and research sites with expertise in a given area utilize public and private information about ongoing research. Web-based electronic data capture (EDC) and clinical data management systems are used in a majority of clinical trials to collect case report data from sites, manage its quality and prepare it for analysis. Interactive voice response systems are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). While patient-reported outcome were often paper based in the past, measurements are increasingly being collected using web portals or hand-held ePRO (or eDiary) devices, sometimes wireless. Statistical software is used to analyze the collected data and prepare them for regulatory submission. Access to many of these applications are increasingly aggregated in web-based clinical trial portals. In 2011, the FDA approved a Phase I trial that used telemonitoring, also known as remote patient monitoring, to collect biometric data in patients' homes and transmit it electronically to the trial database. This technology provides many more data points and is far more convenient for patients, because they have fewer visits to trial sites. As noted below, decentralized clinical trials are those that do not require patients' physical presence at a site, and instead rely largely on digital health data collection, digital informed consent processes, and so on. == Analysis == A clinical trial produces data that could reveal quantitative differences between two or more interventions; statistical analyses are used to determine whether such differences are true, result from chance, or are the same as no treatment (placebo). Data from a clinical trial accumulate gradually over the trial duration, extending from months to years. Accordingly, results for participants recruited early in the study become available for analysis while subjects are still being assigned to treatment groups in the trial. Early analysis may allow the emerging evidence to assist decisions about whether to stop the study, or to reassign participants to the more successful segment of the trial. Investigators may also want to stop a trial when data analysis shows no treatment effect. == Ethical aspects == Clinical trials are closely supervised by appropriate regulatory authorities. All studies involving a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the US, this body is called the Institutional Review Board (IRB); in the EU, they are called Ethics committees. Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions. To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is to ensure potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In addition, the clinical trial participants must be made aware that they can withdraw from the clinical trial at any time without any adverse action taken against them. In California, the state has prioritized the individuals who can serve as the legally authorized representative. In some US locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. The International Conference of Harmonisation Guidelines for Good Clinical Practice is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure the "rights, safety and well being of trial subjects are protected". The notion of informed consent of participating human subjects exists in many countries but its precise definition may still vary. Informed consent is clearly a 'necessary' condition for ethical conduct but does not 'ensure' ethical conduct. In compassionate use trials the latter becomes a particularly difficult problem. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. See also Expanded access. However, it may be hard to turn this objective into a well-defined, quantified, objective function. In some cases this can be done, however, for instance, for questions of when to stop sequential treatments (see Odds algorithm), and then quantified methods may play an important role. Additional ethical concerns are present when conducting clinical trials on children (pediatrics), and in emergency or epidemic situations. Ethically balancing the rights of multiple stakeholders may be difficult. For example, when drug trials fail, the sponsors may have a duty to tell current and potential investors immediately, which means both the research staff and the enrolled participants may first hear about the end of a trial through public business news. === Conflicts of interest and unfavorable studies === In response to specific cases in which unfavorable data from pharmaceutical company-sponsored research were not published, the Pharmaceutical Research and Manufacturers of America published new guidelines urging companies to report all findings and limit the financial involvement in drug companies by researchers. The US Congress signed into law a bill which requires Phase II and Phase III clinical trials to be registered by the sponsor on the clinicaltrials.gov website compiled by the National Institutes of Health. Drug researchers not directly employed by pharmaceutical companies often seek grants from manufacturers, and manufacturers often look to academic researchers to conduct studies within networks of universities and their hospitals, e.g., for translational cancer research. Similarly, competition for tenured academic positions, government grants and prestige create conflicts of interest among academic scientists. According to one study, approximately 75% of articles retracted for misconduct-related reasons have no declared industry financial support. Seeding trials are particularly controversial. In the United States, all clinical trials submitted to the FDA as part of a drug approval process are independently assessed by clinical experts within the Food and Drug Administration, including inspections of primary data collection at selected clinical trial sites. In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that contract research organizations had, by 2000, received 60% of the grants from pharmaceutical companies in the US. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results. Despite explicit recommendations by stakeholders of measures to improve the standards of industry-sponsored medical research, in 2013, Tohen warned of the persistence of a gap in the credibility of conclusions arising from industry-funded clinical trials, and called for ensuring strict adherence to ethical standards in industrial collaborations with academia, in order to avoid further erosion of the public's trust. Issues referred for attention in this respect include potential observation bias, duration of the observation time for maintenance studies, the selection of the patient populations, factors that affect placebo response, and funding sources. === During public health crisis === Conducting clinical trials of vaccines during epidemics and pandemics is subject to ethical concerns. For diseases with high mortality rates like Ebola, assigning individuals to a placebo or control group can be viewed as a death sentence. In response to ethical concerns regarding clinical research during epidemics, the National Academy of Medicine authored a report identifying seven ethical and scientific considerations. These considerations are: === Pregnant women and children === Pregnant women and children are typically excluded from clinical trials as vulnerable populations, though the data to support excluding them is not robust. By excluding them from clinical trials, information about the safety and effectiveness of therapies for these populations is often lacking. During the early history of the HIV/AIDS epidemic, a scientist noted that by excluding these groups from potentially life-saving treatment, they were being "protected to death". Projects such as Research Ethics for Vaccines, Epidemics, and New Technologies (PREVENT) have advocated for the ethical inclusion of pregnant women in vaccine trials. Inclusion of children in clinical trials has additional moral considerations, as children lack decision-making autonomy. Trials in the past had been criticized for using hospitalized children or orphans; these ethical concerns effectively stopped future research. In efforts to maintain effective pediatric care, several European countries and the US have policies to entice or compel pharmaceutical companies to conduct pediatric trials. International guidance recommends ethical pediatric trials by limiting harm, considering varied risks, and taking into account the complexities of pediatric care. == Safety == Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device), the regulatory agency for the country where the drug or device will be sold. A systematic concurrent safety review is frequently employed to assure research participant safety. The conduct and on-going review is designed to be proportional to the risk of the trial. Typically this role is filled by a Data and Safety Committee, an externally appointed Medical Safety Monitor, an Independent Safety Officer, or for small or low-risk studies the principal investigator. For safety reasons, many clinical trials of drugs are designed to exclude women of childbearing age, pregnant women, or women who become pregnant during the study. In some cases, the male partners of these women are also excluded or required to take birth control measures. === Sponsor === Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not. The sponsor is also responsible for monitoring the results of the study as they come in from the various sites as the trial proceeds. In larger clinical trials, a sponsor will use the services of a data monitoring committee (DMC, known in the US as a data safety monitoring board). This independent group of clinicians and statisticians meets periodically to review the unblinded data the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious adverse events. The sponsor is responsible for collecting adverse event reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment. The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations state that participating in clinical trials is voluntary, with the subject having the right not to participate or to end participation at any time. === Local site investigators === The ethical principle of primum non-nocere ("first, do no harm") guides the trial, and if an investigator believes the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and could act unethically to obtain and maintain their participation. The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study. The local investigator or his/her study staff are also responsible for ensuring the potential subjects in the study understand the risks and potential benefits of participating in the study. In other words, they (or their legally authorized representatives) must give truly informed consent. Local investigators are responsible for reviewing all adverse event reports sent by the sponsor. These adverse event reports contain the opinions of both the investigator (at the site where the adverse event occurred) and the sponsor, regarding the relationship of the adverse event to the study treatments. Local investigators also are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study treatment-related adverse events. When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected. The local investigator is responsible for being truthful to the local IRB in all communications relating to the study. === Institutional review boards (IRBs) === Approval by an Institutional Review Board (IRB), or Independent Ethics Committee (IEC), is necessary before all but the most informal research can begin. In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs. The IRB scrutinizes the study both for medical safety and for protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study. === Regulatory agencies === In the US, the FDA can audit the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures. A 'covered clinical study' refers to a trial submitted to the FDA as part of a marketing application (for example, as part of an NDA or 510(k)), about which the FDA may require disclosure of financial interest of the clinical investigator in the outcome of the study. For example, the applicant must disclose whether an investigator owns equity in the sponsor, or owns proprietary interest in the product under investigation. The FDA defines a covered study as "... any study of a drug, biological product or device in humans submitted in a marketing application or reclassification petition that the applicant or FDA relies on to establish that the product is effective (including studies that show equivalence to an effective product) or any study in which a single investigator makes a significant contribution to the demonstration of safety." Alternatively, many American pharmaceutical companies have moved some clinical trials overseas. Benefits of conducting trials abroad include lower costs (in some countries) and the ability to run larger trials in shorter timeframes, whereas a potential disadvantage exists in lower-quality trial management. Different countries have different regulatory requirements and enforcement abilities. An estimated 40% of all clinical trials now take place in Asia, Eastern Europe, and Central and South America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries. Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness." === Aggregation of safety data during clinical development === Aggregating safety data across clinical trials during drug development is important because trials are generally designed to focus on determining how well the drug works. The safety data collected and aggregated across multiple trials as the drug is developed allows the sponsor, investigators and regulatory agencies to monitor the aggregate safety profile of experimental medicines as they are developed. The value of assessing aggregate safety data is: a) decisions based on aggregate safety assessment during development of the medicine can be made throughout the medicine's development and b) it sets up the sponsor and regulators well for assessing the medicine's safety after the drug is approved. == Economics == Clinical trial costs vary depending on trial phase, type of trial, and disease studied. A study of clinical trials conducted in the United States from 2004 to 2012 found the average cost of Phase I trials to be between $1.4 million and $6.6 million, depending on the type of disease. Phase II trials ranged from $7 million to $20 million, and Phase III trials from $11 million to $53 million. === Sponsor === The cost of a study depends on many factors, especially the number of sites conducting the study, the number of patients involved, and whether the study treatment is already approved for medical use. The expenses incurred by a pharmaceutical company in administering a Phase III or IV clinical trial may include, among others: production of the drug(s) or device(s) being evaluated staff salaries for the designers and administrators of the trial payments to the contract research organization, the site management organization (if used) and any outside consultants payments to local researchers and their staff for their time and effort in recruiting test subjects and collecting data for the sponsor the cost of study materials and the charges incurred to ship them communication with the local researchers, including on-site monitoring by the CRO before and (in some cases) multiple times during the study one or more investigator training meetings expense incurred by the local researchers, such as pharmacy fees, IRB fees and postage any payments to subjects enrolled in the trial the expense of treating a test subject who develops a medical condition caused by the study drug These expenses are incurred over several years. In the US, sponsors may receive a 50 percent tax credit for clinical trials conducted on drugs being developed for the treatment of orphan diseases. National health agencies, such as the US National Institutes of Health, offer grants to investigators who design clinical trials that attempt to answer research questions of interest to the agency. In these cases, the investigator who writes the grant and administers the study acts as the sponsor, and coordinates data collection from any other sites. These other sites may or may not be paid for participating in the study, depending on the amount of the grant and the amount of effort expected from them. Using internet resources can, in some cases, reduce the economic burden. === Investigators === Investigators are often compensated for their work in clinical trials. These amounts can be small, just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies), or be substantial and include "overhead" that allows the investigator to pay the research staff during times between clinical trials. === Subjects === Participants in Phase I drug trials do not gain any direct health benefit from taking part. They are generally paid a fee for their time, with payments regulated and not related to any risk involved. Motivations of healthy volunteers is not limited to financial reward and may include other motivations such as contributing to science and others. In later phase trials, subjects may not be paid to ensure their motivation for participating with potential for a health benefit or contributing to medical knowledge. Small payments may be made for study-related expenses such as travel or as compensation for their time in providing follow-up information about their health after the trial treatment ends. == Participant recruitment and participation == Phase 0 and Phase I drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. The diversity observed in society should be reflected in clinical trials through the appropriate inclusion of ethnic minority populations. Patient recruitment or participant recruitment plays a significant role in the activities and responsibilities of sites conducting clinical trials. All volunteers being considered for a trial are required to undertake a medical screening. Requirements differ according to the trial needs, but typically volunteers would be screened in a medical laboratory for: Measurement of the electrical activity of the heart (ECG) Measurement of blood pressure, heart rate, and body temperature Blood sampling Urine sampling Weight and height measurement Drug abuse testing Pregnancy testing It has been observed that participants in clinical trials are disproportionately white. Often, minorities are not informed about clinical trials. One recent systematic review of the literature found that race/ethnicity as well as sex were not well-represented nor at times even tracked as participants in a large number of clinical trials of hearing loss management in adults. This may reduce the validity of findings in respect of non-white patients by not adequately representing the larger populations. === Locating trials === Depending on the kind of participants required, sponsors of clinical trials, or contract research organizations working on their behalf, try to find sites with qualified personnel as well as access to patients who could participate in the trial. Working with those sites, they may use various recruitment strategies, including patient databases, newspaper and radio advertisements, flyers, posters in places the patients might go (such as doctor's offices), and personal recruitment of patients by investigators. Volunteers with specific conditions or diseases have additional online resources to help them locate clinical trials. For example, the Fox Trial Finder connects Parkinson's disease trials around the world to volunteers who have a specific set of criteria such as location, age, and symptoms. Other disease-specific services exist for volunteers to find trials related to their condition. Volunteers may search directly on ClinicalTrials.gov to locate trials using a registry run by the U.S. National Institutes of Health and National Library of Medicine. There also is software that allows clinicians to find trial options for an individual patient based on data such as genomic data. === Research === The risk information seeking and processing (RISP) model analyzes social implications that affect attitudes and decision making pertaining to clinical trials. People who hold a higher stake or interest in the treatment provided in a clinical trial showed a greater likelihood of seeking information about clinical trials. Cancer patients reported more optimistic attitudes towards clinical trials than the general population. Having a more optimistic outlook on clinical trials also leads to greater likelihood of enrolling. === Matching === Matching involves a systematic comparison of a patient's clinical and demographic information against the eligibility criteria of various trials. Methods include: Manual: Healthcare providers or clinical trial coordinators manually review patient records and available trial criteria to identify potential matches. This might also include manually searching in clinical trial databases. Electronic health records (EHR). Some systems integrate with EHRs to automatically flag patients that may be eligible for trials based on their medical data. These systems may leverage machine learning, artificial intelligence or precision medicine methods to more effectively match patients to trials. These methods are faced with the challenge of overcoming the limitations of EHR records such as omissions and logging errors. Direct-to-patient services: Resources are specialized to support patients in finding clinical trials through online platforms, hotlines, and personalized support. == Decentralized trials == Although trials are commonly conducted at major medical centers, some participants are excluded due to the distance and expenses required for travel, leading to hardship, disadvantage, and inequity for participants, especially those in rural and underserved communities. Therefore, the concept of a "decentralized clinical trial" that minimizes or eliminates the need for patients to travel to sites, is now more widespread, a capability improved by telehealth and wearable technologies. == See also == Outcome measure Odds algorithm Preregistration (science) Marketing authorisation == References == == External links == The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, a guideline for regulation of clinical trials ClinicalTrials.gov, a worldwide database of registered clinical trials; US National Library of Medicine Cochrane Central Register of Controlled Trials (CENTRAL); a concentrated source for bibliographic reports of randomized controlled trials ClinicalTrials.eu, European Clinical Trials Information Network; Clinical Trials easily understood. The Hidden World of Clinical Trials: A Journey into Medical Innovation - A blog providing insights into medical innovation in clinical trials.	Wikipedia/Controlled_trials
Intestine transplantation (intestinal transplantation, or small bowel transplantation) is the surgical replacement of the small intestine for chronic and acute cases of intestinal failure. While intestinal failure can oftentimes be treated with alternative therapies such as parenteral nutrition (PN), complications such as PN-associated liver disease and short bowel syndrome may make transplantation the only viable option. One of the rarest type of organ transplantation performed, intestine transplantation is becoming increasingly prevalent as a therapeutic option due to improvements in immunosuppressive regimens, surgical technique, PN, and the clinical management of pre and post-transplant patients. == History == Intestine transplantation dates back to 1959, when a team of surgeons at the University of Minnesota led by Richard C. Lillehei reported successful transplantation of the small intestine in dogs. Five years later in 1964, Ralph Deterling in Boston attempted the first human intestinal transplant, albeit unsuccessfully. For the next two decades, attempts at transplanting the small intestine in humans were met with universal failure, and patients died of technical complications, sepsis, or graft rejection. However, the discovery of the immunosuppressant ciclosporin in 1972 triggered a revolution in the field of transplant medicine. Due to this discovery, in 1988, the first successful intestinal transplant was performed in Germany by E. Deltz, followed shortly by teams in France and Canada. Intestinal transplantation was no longer an experimental procedure, but rather a life-saving therapy. In 1990, a newer immunosuppressant drug, tacrolimus, appeared on the market as a superior alternative to ciclosporin. In the two decades since, intestine transplant efforts have improved tremendously in both number and outcomes. == Pre-transplant diagnoses and short bowel syndrome == Failure of the small intestine is life-threatening due to the inability to absorb nutrients, fluids, and electrolytes from food. Without these essential substances and the ability to maintain energy balances, homeostasis cannot be maintained and one's prognosis will be dismal. Causes of intestinal failure may be clinically complex, and may result from a combination of nutritional, infectious, traumatic, and metabolic complications that affect ordinary anatomy and physiology. Many underlying conditions that serve as precursors to failure are genetic or congenital in nature. For example, severe inflammation, ulceration, bowel obstruction, fistulation, perforation, or other pathologies of Crohn's disease may severely compromise intestinal function. Despite the danger these conditions may pose in themselves, they may lead to even further, more serious complications that necessitate replacement of the diseased intestine. The single leading cause for an intestinal transplant is affliction with short bowel syndrome, oftentimes a secondary condition of some other form of intestinal disease. Short-bowel syndrome was the cause for 73% of American intestinal transplantations in 2008, followed by functional bowel problems for 15% and other causes representing 12% of cases. Natural SBS is mercifully rare, estimated to be 3 per 100,000 births. Surgical removal is the most common cause, performed as a treatment for various gastroenterological and congenital conditions such as Crohn's disease, necrotizing enterocolitis, mesenteric ischemia, motility disorder, omphalocele/gastroschisis, tumors, and volvulus. == Alternative treatments == Regardless of the underlying condition, the loss of intestinal function does not necessarily necessitate a transplant. Several conditions, such as necrotizing enterocolitis or volvulus, may be adequately resolved by other surgical and nonsurgical treatments, especially if SBS never develops. An individual can obtain nutrients intravenously through PN, bypassing food consumption entirely and its subsequent digestion. Long-term survival with SBS and without PN is possible with enteral nutrition, but this is inadequate for many patients as it depends on the remaining intestine's ability to adapt and increase its absorptive capacity. Although more complicated and expensive to perform, any person may receive PN. Although PN can meet all energy, fluid, and nutrient needs and can be performed at home, quality of life can be significantly decreased. On average, PN takes 10 to 16 hours to administer but can take up to 24. Over this time frame, daily life can be significantly hindered as a consequence of attachment to the IV pump. Over long periods of time, PN can lead to numerous health conditions, including severe dehydration, catheter-related infections, and liver disease. PN-associated liver disease strikes up to 50% of patients within 5–7 years, correlated with a mortality rate of 2–50%. Another alternative treatment to transplant for patients with SBS is surgical bowel lengthening via either serial transverse enteroplasty (STEP) or the older longitudinal intestinal lengthening and tailoring (LILT) technique. Although both procedures contribute to an approximate 70% increase in length, STEP appears somewhat more favorable in terms of lower mortality and progression to transplant. Nevertheless, a positive reception to either procedure may reduce the level of PN required, if not negate its required use altogether. == Indications == There are four Medicare and Medicaid-approved indications for intestine transplantation: a loss of two of the six major routes of venous access, multiple episodes of catheter-associated life-threatening sepsis, fluid and electrolyte abnormalities in the face of maximal medical therapy, and PN-associated liver disease. Transplants may also be performed if the growth and development of a pediatric patient fails to ensue, or in extreme circumstances for patients with an exceptionally low quality of life on PN. A multidisciplinary team consisting of transplant surgeons, gastroenterologists, dieticians, anesthesiologists, psychiatrists, financial representatives, and other specialists should be consulted to evaluate the treatment plan and ensure transplantation is the patient's best option. Psychological preparations should be made for the transplant team and patient as well. Early referral requires trust between all parties involved in the operation to ensure that a rush to judgment does not lead to a premature transplant. Other absolute contraindications to receiving an intestinal transplant include the presence of systemic and untreated local infections, malignant cancer, severe neurological impairment, and severe cardiac and/or pulmonary disease. These criteria are similar to established guidelines for transplants of other organ types. HIV infection is a relative contraindication for intestine transplantation; desperate terminal patients may accept a transplant from a HIV-positive donor if they are willing to expose themselves to HIV. == Transplant types == There are three major types of intestine transplants: an isolated intestinal graft, a combined intestinal-liver graft, and a multivisceral graft in which other abdominal organs may be transplanted as well. In the most basic and common graft, an isolated intestinal graft, only sections of the jejunum and ileum are transplanted. These are performed in the absence of liver failure. In the event of severe liver dysfunction due to PN, enzyme deficiencies, or other underlying factors, the liver may be transplanted along with the intestine. In a multivisceral graft, the stomach, duodenum, pancreas, and/or colon may be included in the graft. Multivisceral grafts are considered when the underlying condition significantly compromises other sections of the digestive system, such as intra-abdominal tumors that have not yet metastasized, extensive venous thrombosis or arterial ischemia of the mesentery, and motility syndromes. == Pre-operative period == Donated intestines, like all organs, should be matched to a recipient prior to recovery, as to prepare him or her and minimize the time the organ spends outside the body. Potential recipients are placed on the International Intestinal Transplant Registry (ITR), where they contribute to the world's growing understanding of intestine transplantation. Before a transplant may be performed, an organ must first be located. In the United States, the matching of all organs is coordinated by the United Network for Organ Sharing (UNOS). The standard intestinal donor is deceased with a diagnosis of brain death. In terms of transplant outcomes, brain-dead donors are highly preferable to donors who have suffered cardiopulmonary death. If respiration can be assisted by a ventilator, brain-dead donors may exhibit maintainable cardiac, endocrine, and excretory function. If appropriately managed, the continuation of blood flow and bodily metabolism allows for healthier organs for procurement and additional time to prepare recipients for transplant. Furthermore, terminal ileum recovery from living donors is possible., and a laparoscopic technique is being developed to harvest limited sections of small bowel from living donors. When determining potential donor-recipient matches, important characteristics include donor size, age, tissue quality, and ABO and histo-compatibility. If the intestine is too large, it may be not transplantable into young or small patients. Ideally, intestines should be selected from donors of lighter weight than the proposed recipients to ensure simple closure of the abdominal wound. If a patient is too young or too old, they may not be hardy enough to survive the operation and recovery period. If the donor and recipient organs do not meet compatibility requirements, the threat of organ rejection by the body is all but certain. Organ rejection is the unfortunate circumstance of the host immune system recognizing the transplanted organ as foreign. This is the most notable complication facing transplant recipients. Through T-cell receptors, T-lymphocytes are able to distinguish between self and non-self by recognizing human leukocyte antigens (HLA) bound to the major histocompatibility complex (MHC) protein located on the surface of organ cells. Once identified as foreign, the immune system proceeds to destroy the transplanted tissue. The panel-reactive antibody (PRA) test measures the proportion of the population to which a recipient will react via pre-existing antibodies to various HLA antigens; in other words, how likely a patient is to acutely reject their new transplant. Therefore, it is essential that HLA and PRA statuses are tested for and demonstrate low immunoreactivity of the patient to the graft. In some cases, a recipient may suffer from graft-versus-host disease, in which cells of the transplanted organ attack the recipient's cells. To ensure proper histocompatibility, tissue quality, and safety from infection, blood work should be collected and tested in the laboratory. In addition to HLA and PRA typing, the complete blood count (CBC), coagulation profile, complete metabolic panel, and ABO blood group determination tests should be performed for both the donor and recipient. ABO-incompatible grafts can sometimes be performed on very young pediatric patients, as their immune systems have not fully developed and for whom waiting list mortality remains high. Additionally, blood serum should be tested for the presence of viruses, including HIV, hepatitis B and C, cytomegalovirus (CMV), and Epstein–Barr virus (EBV) antibodies to prevent infection. Particularly in the immunocompromised system necessitated by the transplant, these viruses can wreak havoc on the body and become extremely dangerous, even fatal. Even with healthy physiological levels, ABO and HLA compatibilities, and no signs of bacterial, viral, and fungal infections, organ transplantation is not without extrasurgical risk. == Waitlist and donation outcomes == A major challenge facing the intestinal transplant enterprise is meeting the need for transplantable intestines, particularly in the United States where the majority of intestinal transplants take place. There exists a narrow timeslot between procurement and transplantation that any organ remains viable, and logistical challenges are faced regarding bringing organ and recipient together. During procurement, organs that are being recovered are cooled and perfused with preservation solution. This slows organ activity and increases the time they remain viable for transplant. Although chilling and perfusion may extend intestinal lifespans by several hours, failure is still imminent unless transplanted. This duration between the cooling of the organ during procurement and the restoration of physiological temperature during implantation is the cold ischemic time. Due to the sensitivity of the intestine to ischemic injury, many potential donor intestines are lost to the events following brain death and trauma. Furthermore, irreversible intestinal damage is seen after approximately only 5 hours of cold ischemia in the form of mucosal damage and bacterial translocation outside the gastrointestinal tract. Therefore, ensuring cardiac survival and nearby donor-recipient proximity before procurement are essential so organs do not wait too long outside the body and without blood flow. Not only is there a lack of transplantable intestines, but a deficiency in the number of centers possessing the capability to carry out the complicated transplant procedure as well. As of 2005, there were only 61 medical centers in the world capable of executing an intestinal transplant. Furthermore, many young, small children, particularly those weighing less than 5 kg, cannot find a transplant due to the lack of size-matched donors. Despite these challenges, obtaining an intestine for transplant is rather probable in the United States. In 2008, there were 212 people on the U.S. intestinal transplant waitlist, 94% of whom were U.S. citizens. Regardless of transplant type, over half of new registrants are 5 years of age or younger. Adults compromise the next largest cohort, followed by pediatric patients aged 6 and older. In 2008, the ethnic composition of the intestinal transplant waitlist was 65% White, 18% Black, 16% Hispanic, 1% Asian, and 0.5% other or mixed race, resembling the demographics of the American general population at the time aside from a below-average Asian cohort. ABO blood types also matched the general population, with 31% A, 14% B, 5% AB, and 50% O. In 2004, the average waiting period to receive a transplant was 220 days, with a median of 142 days in 2008. The rate of waitlist additions has shifted from year to year; gains increased until 2006 (with 317 added), but then decreased in 2012 (to 124 added). In 2007, only 9% of patients on the U.S. waitlist died while waiting for a transplant. Waitlist mortality peaked around 2002 and was highest for liver-intestine (pediatric) patients. Deaths among all pediatric groups awaiting intestine-liver transplants have decreased in the years leading up to 2014 whereas adult intestine-liver deaths have dropped less dramatically. The decrease in recent years is likely due to improved care of infants with intestinal failure and subsequently a decrease in referrals for transplant. Although many improvements have been made in the States, outcomes everywhere still demonstrate much room for improvement. Worldwide, 25% of pediatric patients on the waitlist for an intestinal transplant die before they can receive one. == Procurement protocol == Following matching of the organ, the complicated procurement of the small bowel can be performed by a team of abdominal transplant surgeons. Once a donor has been selected and approved for donation, several pretreatments may be initiated to destroy microorganisms and immune cells. The donor intestine must be decontaminated with several antibiotics, including neomycin, erythromycin, amphotericin B, and cephalosporin. They may also be treated with anti-lymphocyte antibodies (anti-thymocyte globulin, alemtuzumab), irradiation directed against excessive mesenteric lymphatic tissue, and have their bowel irrigated. Once donor preparation is accomplished, procurement can begin by utilizing the same standard techniques for all abdominal organ procurements. The team exposes the abdominal cavity and inserts two cannulae for the infusion of University of Wisconsin organ preservation solution into the aorta and inferior mesenteric vein. As the abdominal organs are cooled in situ, the surrounding tissue is dissected so that they may be quickly extracted. In the next step, the aorta is cross-clamped, cutting off blood supply to the organs. Once blood and oxygen supply to an organ is cut off, organ death will approach swiftly unless steps are taken to preserve them until transplant. Organs are therefore fully drained of blood, flushed with cool preservation solution, and removed from the body. In an isolated intestinal transplant, the colon will be detached from the small intestine. The cecum and ascending colon are devascularized, while care is taken to preserve major vasculature in the ileum. The jejunum will be separated from the duodenum while preserving the vasculature of the jejunum, ileum, mesentery, and the pancreas. If healthy, the pancreas can oftentimes be retrieved as an additional isolated procurement. The intestinal allograft, when ready to be extracted, is attached by the mesenteric pedicle, where the vessels converge out of the intestinal system. This pedicle will be stapled closed, and can be separated from the body via a transverse cut to create a vascular cuff. The complete intestinal allograft can then be removed and wrapped in a surgical towel. The protocols for combined liver and multivisceral procurements are far more complicated and meticulous than isolated intestine alone. == Transplantation protocol == First, any abdominal scar tissue from previous surgeries must be removed. The aorta and vena cava are dissected in preparation for vascular anastomosis, followed by dissection of the proximal and distal ends of the digestive tract. Anastomosis is then performed to revascularize the graft. Arterial vessels are connected to the abdominal aorta, below the kidneys. However, venous drainage, or the reattachment of the transplanted organ to the venous system, may be performed differently depending on the unique intra-abdominal vasculature of the recipient. The graft is usually drained systemically into the infrarenal vena cava, but may also be drained portally into the hepatic portal or superior mesenteric vein. The graft is then reperfused with blood and any bleeding is stopped before the proximal and distal ends of the transplant bowel are connected to the original digestive tract. A loop ileostomy is then created as to provide easy access for future endoscopic observation and biopsies. A gastronomy or jejunostomy feeding tube may be placed before the abdominal wall is closed. When a liver is being transplanted in conjunction with the intestine, the recipient must first have their own liver removed. Following this, the aorta, cava, and portal veins of the donor and recipient are anastomosed. The graft is then flushed before the caval clamps are removed. The intestine is then reconstructed as in an isolated intestinal transplant, before being connected to the bile duct servicing the new liver. Multivisceral transplants are especially difficult and susceptible to complications because all organs must survive a conjoined procurement, transport, and transplantation. All three of these measures are tailored to the individual needs of the recipient. Preservation of the native spleen, pancreas, and duodenum during a multivisceral transplant can reduce the risk of additional complications related to these structures. == Post-operative period == Following the procedure, the patient is actively monitored in an intensive care unit (ICU). Broad-spectrum antibiotics are administered, bleeding monitored, and serum pH and lactate levels measured for evidence of intestinal ischemia. The patient's immune system is strongly modulated immediately post-operation. The initial phase of treatment consists of the administration of tacrolimus with corticosteroids to suppress T-lymphocyte activation. Next, various assortments of interleukin-2 (IL-2) receptor antagonists (daclizumab, basiliximab), anti-proliferation agents (azathioprine, mycophenolate mofetil), and the drugs cyclophosphamide and sirolimus are administered on an individual patient basis to further suppress the immune system. The bioavailability of these drugs is dependent on intestinal surface area and transit time, and therefore the length of the allograft determines the immunosuppression regimen. Intravenous administration of prostaglandin E1 is occasionally performed for the first 5 to 10 days following transplant to improve intestinal circulation and a potential dispensing of immunosuppressive effects. The gut is selectively decontaminated against high-risk flora and preventative care is taken against CMV and fungal infections. It is ideal to commence enteral nutrition as early as possible following transplantation. Therefore, a feeding tube connecting to the stomach or jejunum is quickly placed to facilitate rehabilitation. If gastrointestinal function is restored, a diet can be reestablished and cautiously advanced as tolerated. Most patients are weaned from PN within 4 weeks of transplantation, and nearly all are free from additional enteral supplementation by one year. Evidence for the restoration of function includes decreasing gastrostomy tube returns and increasing gas and enteric contents in the ileostomy. Routine surveillance endoscopy and biopsies via the ileostomy should be performed with decreasing frequency over several months to observe signs of rejection, ideally before clinical symptoms present themselves. Should the patient continue to perform well through the first post-transplant year, the ileostomy would generally be closed. Should rejection be suspected in the future, endoscopies would be performed and an appropriate antirejection therapy will be tailored. The median time for hospital discharge varies between procedures. The median times for isolated intestine, intestine-liver, and multivisceral transplants are 30, 60, and 40 days post-operation respectively. Within the first several months, carbohydrate and amino acid absorptive capacity should normalize, followed by the absorptive capacity for fats. Once enteral nutrition is capable of providing all nutritional needs, PN can be discontinued. Nearly all patients with a successful transplant are free of PN within one year. == Biological complications == Intestinal transplantation is the least performed type of transplant due to a number of unique obstacles. The most major of these is the profound immunosuppression required due to the ability of the intestine to elicit strong immune responses. Because of exposure to a wide range of gut flora and material consumed by the body, the intestinal epithelium possesses a highly developed innate immune system and antigen-presenting abilities. Immunosuppression is the primary determinant of outcome in small bowel transplantation; the risk for graft rejection is increased by under-immunosuppression and for local and systemic infection with over-immunosuppression. Ensuring an appropriate dose of immunosuppressant can therefore be difficult, especially as both ciclosporin (14–36%) and tacrolimus (8.5–22%) have generally low bioavailabilities. A major problem due to immunosuppression in intestinal transplant patients is post-transplant lymphoproliferative disorder, in which B-lymphocytes excessively proliferate due to infection by EBV and result in infectious mononucleosis-like lesions. Intestinal transplant recipients are also at risk for chronic renal failure because calcineurin inhibitors are toxic to the kidneys. A transplant recipient must remain on immunosuppressants for the rest of his or her life. Intestinal transplants are highly susceptible to infection even more so than the standard immunocompromised recipient of other organs due to the great composition and variety of the gut flora. A complex assortment of microorganisms inhabits the human digestive tract, with concentrations of up to 104–107 CFU/mL in the jejunoileum and 1011–1012 CFU/mL in the colon. While suppression of the immune system may prevent immune attack on the new allograft, it may also prevent the immune system's ability to keep certain gut microbial populations in line. Despite pre and post-decontamination of the transplant, recipients are at risk of local and systemic infection by both natural and external flora. The common symptom of graft dysfunction, whether due to infection, rejection, or some other condition, is diarrhea. == Transplant outcomes and impact == Intestinal transplant outcomes have improved significantly in recent years. Despite mild incongruities in survival rate percentages between centers in North America, Europe, Australia, and elsewhere, intestinal transplantations mostly approach survivorship rates of lung transplantation. At one-year, graft survival rates for isolated intestine currently waver around 80%, and 70% for intestine-liver and multivisceral. Over the same time period, patient survival for isolated intestine patients may even exceed 90%, while the more complicated multiorgan transplants do not show any increase in patient survival when compared to patients surviving with the intestinal graft alone. The five-year survival rate for patients and transplants ranges from 50 to 80% (overall mean 60%), depending on underlying disease and presurgical morbidity. Very young (<1 year) and very old (>60 years) patients receiving a transplant have pronounced rates of mortality. After 4 years, pediatric survival significantly worsens compared to adults. Several factors relating to superior patient and graft prognosis have proven to be statistically significant. Patients who have been admitted for transplant directly from home rather than the hospital, younger patients over one year of age, those receiving their first transplant, those receiving transplants at experienced transplant centers, and who receive antibody or sirolimus-based induction therapies have increased rates of survival. Furthermore, underlying etiology, the presence of comorbidity, the frequency of previous surgery, nutritional status, and the level of liver function have been found to affect patient-graft survival . Patients with a pre-transplant diagnosis of volvulus were found to possess a lower risk of mortality. As of 2008, the longest recorded surviving transplant survived for 18 years. Between 1999 and 2008, 131 retransplant procedures were performed in the United States. The improvement to quality of life following an intestinal transplantation is significant. Of living patients 6 months after transplant, 70% are considered to have regained full intestinal function, 15% are at partial function, and 15% have had their grafts removed. For those with full function, enteral nutritional autonomy is high. The ability to resume regular activities such as the ability to consume food and exert control over digestive function is certainly a welcome return for patients. The low quality of life induced by intestinal failure is oftentimes further supplemented by significant psychosocial disability and narcotic dependence. Following transplantation, these have been found to generally decrease. According to surveys comparing patients who have undergone transplants and those that have not, there seems to be a remarkable improvement for transplant recipients in such areas as anxiety, depression, appearance, stress, parenting, impulsiveness, optimism, medical compliance, and the quality of relationships. == Financial considerations == Receiving an organ transplant of any kind is a highly significant investment financially, but a successful, well-functioning transplant can be very cost-efficient relative to alternate therapies. Total charges to maintain PN at home can reach upwards of $150,000 a year, even though the actual cost of nutrition is typically only $18 to $22 a day. This excludes the cost for additional home support, equipment, and the care of PN-related complications. The cost involved in undergoing intestinal transplantation, including the initial hospitalization for the transplant, can range from $150,000 to $400,000, and reoccurring hospitalizations are common up through the second year. Two to three years post-transplant, the financial cost of transplantation reaches parity with PN and is more cost-effective thereafter. == References == == External links == Transplant Living Partnering With Your Transplant Team Archived 3 June 2015 at the Wayback Machine by UNOS Intestinal Transplantation at eMedicine Intestinal Transplant for Crohn's Disease, WebMD	Wikipedia/Intestinal_transplant_surgery
Esophageal diseases can derive from congenital conditions, or they can be acquired later in life. Many people experience a burning sensation in their chest occasionally, caused by stomach acids refluxing into the esophagus, normally called heartburn. Extended exposure to heartburn may erode the lining of the esophagus, leading potentially to Barrett's esophagus which is associated with an increased risk of adenocarcinoma most commonly found in the distal one-third of the esophagus. Some people also experience a sensation known as globus esophagus, where it feels as if a ball is lodged in the lower part of the esophagus. The following are additional diseases and conditions that affect the esophagus: Achalasia Acute esophageal necrosis Barrett's esophagus Boerhaave syndrome Caustic injury to the esophagus Chagas disease Diffuse esophageal spasm Esophageal atresia and tracheoesophageal fistula Esophageal cancer Esophageal dysphagia Esophageal varices Esophageal web Esophagitis GERD Hiatus hernia Killian–Jamieson diverticulum Mallory–Weiss syndrome Neurogenic dysphagia Nutcracker esophagus Schatzki's ring Zenker's diverticulum == References == == External links == Esophageal and Swallowing Disorders, Merck & Company Inc.	Wikipedia/Esophageal_disease
Paratuberculosis is a contagious, chronic and sometimes fatal infection that primarily affects the small intestine of ruminants. It is caused by the bacterium Mycobacterium avium subspecies paratuberculosis. Infections normally affect ruminants (mammals that have four compartments of their stomachs, of which the rumen is one), but have also been seen in a variety of nonruminant species, including rabbits, foxes, and birds. Horses, dogs, and nonhuman primates have been infected experimentally. Paratuberculosis is found worldwide, with some states in Australia (where it is usually called bovine Johne's disease or BJD) being the only areas proven to be free of the disease. At least in Canada, the signs of BJD usually start when cattle are four to seven years of age, and then usually only are diagnosed in one animal at a time. Cattle "with signs of Johne’s disease shed billions of bacteria through their manure and serve as a major source of infection for future calves." Some sources define "paratuberculosis" by the lack of Mycobacterium tuberculosis, rather than the presence of any specific infectious agent, leaving ambiguous the appropriateness of the term to describe Buruli ulcer or Lady Windermere syndrome. == Bacterium == The disease, discovered by Heinrich A. Johne, a German bacteriologist and veterinarian, in 1905, is caused by a bacterium named Mycobacterium avium subspecies paratuberculosis, an acid-fast bacillus, often abbreviated MAP. MAP is akin to, but distinct from, Mycobacterium tuberculosis, the main cause of tuberculosis in humans, and Mycobacterium bovis, the main cause of tuberculosis in cattle and occasionally also in humans. MAP is 99% genetically related to Mycobacterium avium, but has different phenotypic characteristics, such as: slower growth requires the addition of an iron transport chemical known as mycobactin when grown in vitro forms a rough colony when grown on a solid agar medium Infects mammals instead of birds Also, the environmental distribution of MAP is markedly different from that of M. avium, which can produce mycobactin, so can grow and multiply outside the body. == Control == Pasteurization is used to kill the causal agent, M. paratuberculosis, by heating cow's milk for a short time and then immediately cooling it. == Signs and symptoms == In cattle, the main signs of paratuberculosis are diarrhea and wasting. Most cases are seen in 2- to 6-year-old animals. The initial signs can be subtle, and may be limited to weight loss, decreased milk production, or roughening of the hair coat. The diarrhea is usually thick, without blood, mucus, or epithelial debris, and may be intermittent. Several weeks after the onset of diarrhea, a soft swelling may occur under the jaw. Known as "bottle jaw" or intermandibular edema, this symptom is due to protein loss from the bloodstream into the digestive tract. Paratuberculosis is progressive; affected animals become increasingly emaciated and usually die as the result of dehydration and severe cachexia. Signs are rarely evident until two or more years after the initial infection, which usually occurs shortly after birth. Animals are most susceptible to the infection in the first year of life. Newborns most often become infected by swallowing small amounts of infected manure from the birthing environment or udder of the mother. In addition, newborns may become infected while in the uterus or by swallowing bacteria passed in milk and colostrum. Animals exposed at an older age, or exposed to a very small dose of bacteria at a young age, are not likely to develop clinical disease until they are much older than two years. The clinical signs are similar in other ruminants. In sheep and goats, the wool or hair is often damaged and easily shed, and diarrhea is uncommon. In deer, paratuberculosis can progress rapidly. Intestinal disease has also been reported in rabbits and nonhuman primates. Unlike cattle and sheep, infections in deer often present with clinical illness in animals under one year of age. == Pathophysiology == The primary site targeted by Johne's disease is the lower part of the intestine known as the ileum. The wall of the ileum contains a large number of pockets of lymphoid tissue known as Peyer's patches that lie just beneath the interior surface of the intestine. Peyer's patches are clusters of macrophages and lymphocytes organized much like lymph nodes. Covering Peyer's patches are a layer of cells called M cells. These cells function to sample the content of the lumen of the intestines and pass antigens (bacteria) through to the underlying cells of the Peyer's patch to "show" these antigens to the macrophages and lymphocytes. This is a means of "educating" the cells in a young animal about its environment, and is a protective mechanism designed to help the animal become immune to pathogens in its environment. Unfortunately, when M cells bring M. paratuberculosis to the Peyer's patch, the bacteria find an ideal place for growth. Macrophages in Peyer's patches engulf M. paratuberculosis for the purpose of destroying the foreign invader, but for reasons yet unclear, these macrophages fail to do this. Inside a macrophage, M. paratuberculosis multiplies until it eventually kills the cell, spreads, and infects other nearby cells. In time, other parts of the ileum and other regions of the body are teeming with millions of the mycobacteria. How M. paratuberculosis neutralizes or evades the normally efficient bacterial killing mechanisms of the macrophages is unknown, although the unusually resistant cell wall of mycobacteria likely plays an important role. The animal's immune system reacts to the M. paratuberculosis invasion by recruiting more macrophages and lymphocytes to the site of the infection. The lymphocytes release a variety of chemicals signals, called cytokines, in an attempt to increase the bacterial killing power of the macrophages. Macrophages fuse together, forming large cells, called multinucleated giant cells, in an apparent attempt to kill the mycobacteria. Infiltration of infected tissues with millions of lymphocytes and macrophages leads to visible thickening of the intestines. This prevents nutrient absorption, and diarrhea results. Late in the infection, antibody production by the animal occurs to M. paratuberculosis in serum of animals, and is an indicator that clinical signs of disease and death from the infection will soon follow. For goats infected with this disease, the most apparent sign of having it is their bodies wasting away, even with a sufficient diet. If a goat develops Johne's and it has diarrhea, it is most likely going to die. When it has diarrhea, the goat is at the last stages of the disease. Herds should be tested once or twice a year to maintain the health and keep out the disease. == Morbidity and mortality == In an endemic herd, only a minority of the animals develops clinical signs; most animals either eliminate the infection or become asymptomatic carriers. The mortality rate is about 1%, but up to 50% of the animals in the herd can be asymptomatically infected, resulting in losses in production. Once the symptoms appear, paratuberculosis is progressive and affected animals eventually die. The percentage of asymptomatic carriers that develop overt disease is unknown. == Human risks == MAP is capable of causing Johne's-like symptoms in humans, though difficulty in testing for MAP infection presents a diagnostic hurdle. As of October 2019, neither the World Health Organization nor any individual nation had declared Johne's disease to be zoonotic. Clinical similarities are seen between Johne's disease in ruminants and inflammatory bowel disease in humans, and because of this, some researchers contend the organism is causative factor in Crohn's disease. However, epidemiologic studies have provided variable results; in certain studies, the organism (or an immune response directed against it) has been much more frequently found in patients with Crohn's disease than asymptomatic people. == Action and regulations == Paratuberculosis is a reportable disease in some states of the US. US Federal regulations prohibit culture positive or DNA test-positive animals from being moved across state lines except for slaughter. == References == == External links == USDA Johne's resource page University of Wisconsin School of Veterinary Medicine Johne's Information Center International Association for Paratuberculosis, Inc.	Wikipedia/Johne's_disease
A vaccine-preventable disease is an infectious disease for which an effective preventive vaccine exists. If a person acquires a vaccine-preventable disease and dies from it, the death is considered a vaccine-preventable death. The most common and serious vaccine-preventable diseases tracked by the World Health Organization (WHO) are: diphtheria, Haemophilus influenzae serotype b infection, hepatitis B, measles, meningitis, mumps, pertussis, poliomyelitis, rubella, tetanus, tuberculosis, and yellow fever. The WHO reports licensed vaccines being available to prevent, or contribute to the prevention and control of, 31 vaccine-preventable infections. == Background == In 2012, the World Health Organization estimated that vaccination prevents 2.5 million deaths each year. With 100% immunization, and 100% efficacy of the vaccines, one out of seven deaths among young children could be prevented, mostly in developing countries, making this an important global health issue. Four diseases were responsible for 98% of vaccine-preventable deaths: measles, Haemophilus influenzae serotype b, pertussis, and neonatal tetanus. The Immunization Surveillance, Assessment and Monitoring program of the WHO monitors and assesses the safety and effectiveness of programs and vaccines at reducing illness and deaths from diseases that could be prevented by vaccines. Vaccine-preventable deaths are usually caused by a failure to obtain the vaccine in a timely manner. This may be due to financial constraints or to lack of access to the vaccine. A vaccine that is generally recommended may be medically inappropriate for a small number of people due to severe allergies or a damaged immune system. In addition, a vaccine against a given disease may not be recommended for general use in a given country, or may be recommended only to certain populations, such as young children or older adults. Every country makes its own immunization recommendations, based on the diseases that are common in its area and its healthcare priorities. If a vaccine-preventable disease is uncommon in a country, then residents of that country are unlikely to receive a vaccine against it. For example, residents of Canada and the United States do not routinely receive vaccines against yellow fever, which leaves them vulnerable to infection if travelling to areas where risk of yellow fever is highest (endemic or transitional regions). == List of vaccine-preventable diseases == The WHO lists 25 diseases for which vaccines are available: Cholera COVID-19 Dengue fever Diphtheria Haemophilus influenzae type b Hepatitis (A and B only) Human papillomavirus infection Influenza Japanese encephalitis Malaria Measles Meningococcal meningitis Mumps Pertussis Pneumococcal disease Poliomyelitis Rabies Rotavirus Rubella Tetanus Tick-borne encephalitis Tuberculosis Typhoid fever Varicella Yellow fever === Used in non humans === Bordetella Canine distemper Canine influenza Canine parvovirus Chlamydia Feline calicivirus Feline distemper Feline leukemia Feline viral rhinotracheitis Leptospirosis Lyme disease == Vaccine-preventable diseases demonstrated in the laboratory on other animals == Enterococcus gallinarum on mice (to prevent bacteria-triggered autoimmune disease) == See also == Vaccination policy World Immunization Week Measles resurgence in the United States == References == == External links == Media related to Vaccine-preventable diseases at Wikimedia Commons	Wikipedia/Vaccine-preventable_diseases
Human immunodeficiency virus salivary gland disease (abbreviated to HIV-SGD, and also termed HIV-associated salivary gland disease), is swelling of the salivary glands and/or xerostomia in individuals infected with human immunodeficiency virus. == Signs and symptoms == Gradual enlargement of the major salivary glands, particularly the parotid glands. This swelling may be on one side or both sides, may cause disfigurement and may be painful. Xerostomia (dry mouth) with no other cause such as a side effect of medications. HIV-SGD may be the presenting sign of HIV infection. There may also be xerophthalmia (dry eyes) and arthralgia (joint pain), similar to Sjögren syndrome. == Epidemiology == HIV-SGD is more prevalent in HIV positive children than HIV positive adults, at about 19% and 1% respectively. Unlike other oral manifestations of HIV/AIDS such as Kaposi sarcoma, oral hairy leukoplakia and oral candidiasis, which decreased following the introduction of highly active antiretroviral therapy (HAART), HIV-SGD has increased. == References ==	Wikipedia/HIV_salivary_gland_disease
GLUT1 deficiency syndrome, also known as GLUT1-DS, De Vivo disease or Glucose transporter type 1 deficiency syndrome, is an autosomal dominant genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier. Glucose Transporter Type 1 Deficiency Syndrome has an estimated birth incidence of 1 in 90,000 to 1 in 24,300. This birth incidence translates to an estimated prevalence of 3,000 to 7,000 in the U.S. == Presentation == GLUT1 deficiency is characterized by an array of signs and symptoms including mental and motor developmental delays, infantile seizures refractory to anticonvulsants, ataxia, dystonia, dysarthria, opsoclonus, spasticity, other paroxysmal neurologic phenomena and sometimes deceleration of head growth also known as microcephaly. The presence and severity of symptoms vary considerably between affected individuals. Individuals with the disorder generally have frequent seizures (epilepsy), often beginning in the first months of life. In newborns, the first sign of the disorder may be involuntary eye movements that are rapid and irregular. Patients typically begin to experience seizures between three and six months of age, but some occur much later. Other seizure types may occur, including generalized tonic clonic, focal, myoclonic, atypical absence, atonic or unclassified. Mothers of infants with this disorder usually have uneventful pregnancies and deliveries, with the child appearing normal and within typical birth weight and length ranges. Infants with GLUT1 deficiency syndrome have a normal head size at birth, but the growth of the brain and skull is slow, in severe cases resulting in an abnormally small head size (microcephaly). Typically, seizures start between one and four months in 90% of cases with abnormal eye movements and apneic episodes preceding the onset of seizures in some cases. Seizures usually are complex to begin with and later become more generalized. Seizure frequency is variable and a history of decreasing frequency during times of ketosis may prompt a diagnosis. It is estimated that 10% of individuals with Glut 1 Deficiency do not have seizures and symptoms are typically less severe in these cases. Most of these non-epileptic cases will still have developmental delay, intellectual delays and movement disorders such as ataxia, alternating hemiplegia or dystonia. Some symptoms may be present all the time (like walking difficulties), while other signs may come and go (like seizures or poor balance). These findings can be clustered under three major domains: cognition, behavior and movement. === Effects === The syndrome can cause infantile seizures refractory to anticonvulsive drugs, developmental delay, acquired microcephaly and neurologic manifestations including spasticity, hypotonia and ataxia. The frequency, severity and types of seizures may vary considerably among GLUT1 deficiency patients and do not necessarily correspond to the severity of other symptoms. Most seizures in GLUT1 deficiency patients are not easily treated with anti-seizure medications. A minority of GLUT1 deficiency patients (approximately 10%) do not experience seizures. Cognitive symptoms often become apparent as developmental milestones are delayed. Cognitive deficits range from subtle learning difficulties to severe intellectual disabilities. Often speech and language are impaired. Behavioral symptoms affect relations with other people and may include short attention span, intractability, and delays in achieving age-appropriate behaviors. Sociability with peers, however, is a strength in GLUT1 deficiency patients. Movement symptoms relate to the quality of motor functions. Walking may be delayed or difficult because legs are stiff (spasticity), balance is poor (ataxia) or posture is twisted (dystonia). Fine motor deficits may affect speech quality and manipulative skills, such as writing. These abnormalities may be constant or intermittent (paroxysmal). Paroxysmal exercise-induced dyskinesia (PED) may also be present. Other intermittent symptoms may include headaches, confusion, and loss of energy. Episodes of confusion, lack of energy/stamina, and/or muscle twitches may occur; particularly during periods without food. Some young patients experience occasional abnormal eye movements that may resemble opsoclonus or nystagmus. The rapid eye movements that some Glut 1 patients exhibit are rapid, multidirectional, and there is often a head movement in the same direction as the eye movement. These abnormal eye movements were recently named aberrant gaze saccades. Hemiplegia or alternating intermittent hemiplegia may occur in some patients and mimic stroke-like symptoms. Another characteristic of GLUT1 deficiency is that symptoms are sensitive to food (e.g. symptoms that can be temporarily improved by intake of carbohydrates), and symptoms may be worse in the morning upon and just after waking. All symptoms may be aggravated or triggered by factors such as hunger, fatigue, heat, anxiety, and sickness. The symptom picture for each patient may evolve and change over time as children with GLUT1 deficiency grow and develop through adolescence and into adulthood. Data on adult Glut1DS are just emerging. Changes in symptomatology over time include a shift from infantile-childhood onset epilepsy to adolescent-adult onset movement disorders including PED. == Genetics == The GLUT1 protein that transports glucose across the blood brain barrier is encoded by the SLC2A1 gene, located on chromosome 1. In GLUT1 deficiency syndrome, one of the two genes is damaged by a mutation and an insufficient amount protein is made. As a result, insufficient glucose is passing the blood brain barrier. Having less functional GLUT1 protein reduces the amount of glucose available to brain cells, which affects brain development and function. Because glucose is the primary source of fuel for the brain, patients with GLUT1 deficiency have insufficient cellular energy to permit normal brain growth and function. Around 90% of cases of GLUT1 deficiency syndrome are de novo mutations of the SLC2A1 gene (a mutation not present in the parents, but present in one of the two copies of the gene in the baby), although it can be inherited. Glut 1 Deficiency can be inherited in an autosomal dominant manner. A person with GLUT1 deficiency syndrome has a 50% chance of passing along the altered SLC2A1 gene to his or her offspring. In a study focusing on GLUT1 mice model brain slides, physiological glucose concentration was found to be a modulator of frequency oscillations and less frequent 30–50 Hz or gamma oscillations. == Diagnosis == Early diagnosis is crucial in order to initiate treatment during the important early stages of brain development. To make a proper diagnosis, it is important to know the various symptoms of GLUT1 deficiency and how those symptoms evolve with age. GLUT1 deficiency is diagnosed based on the clinical features in combination with determining the glucose concentration in the CSF and/or a genetic analysis through a lumbar puncture (spinal tap). A low glucose value in CSF (<2.2 mmol/L) or lowered CSF/plasma glucose ratio (<0.4)are indicatieve of GLUT1 deficiency. A genetic mutation in the SLC2A1 gene also confirms the diagnosis, although mutations have not been identified in approximately 15% of GLUT1 deficiency patients. A highly specialized lab test called the red blood cell uptake assay may confirm GLUT1 deficiency but is not commercially available. == Management == Anti-seizure medications are generally not effective, since they do not provide nourishment to the starved brain. Once diagnosed, a medically supervised ketogenic diet is usually recommended as it can help to control seizures. The ketogentic diet is the current standard of care treatment, with 80% of patients having >90% seizure reduction and improving some movement disorders in approximately two thirds of GLUT1 deficiency patients. There is also some evidence of some cognitive benefits for GLUT1 deficiency patients on a ketogenic diet, and most parents report improved energy, alertness, balance, coordination, and concentration, especially when the diet is started early in childhood. The ketogenic diet is a diet high in fat and low in protein and carbohydrates, with up to 90% of calories obtained from fat. Since the diet is low in carbohydrates, the body gets little glucose, normally the main energy source. The fat in the diet is converted by the liver in ketone bodies, which causes a build up of ketones in the blood stream, called ketosis. Ketone bodies are transported across the blood-brain barrier by other means than the GLUT1 protein and thus serve as an alternative fuel for the brain when glucose is not available. While ketogenic diets have been proven effective to control seizures and relieve some movement disorders in many GLUT1 deficiency patients, some patients do not respond as well as others. In addition, some critical symptoms, including cognitive deficits and certain movement difficulties, tend to persist in GLUT1 deficiency patients treated by a ketogenic diet, raising the question whether GLUT1 deficiency is caused simply by a lack of proper brain energy or if there are more complicated and widespread systems and processes affected. The ketogenic diet must be carefully crafted and tailored to meet the needs of each patient and reduce the risk of side effects. It should only be used under the care of medical professionals and dietitians, and it may take some time to establish the ideal ratio of fat versus proteins and carbohydrates and other diet variables for each individual patient to experience optimal tolerance and benefits. Variations on the ketogenic diet, including the Modified Atkins Diet, and diets based on MCT oil have also been shown to be beneficial for some GLUT1 deficiency patients. While the classic ketogenic diet is commonly used for younger children, compliance with the ketogenic diet can be difficult for older children and adults. In recent years, the Modified Atkins Diet, and MCT oil based diets, have gained increasing acceptance among doctors treating these groups and may be more feasible for quality of life and compliance. There is growing empirical evidence that these diets can provide at least some of the benefits of the classical ketogenic diet for some GLUT1 deficiency patients. Ketone esters are an area of dietary therapy currently under investigation for potential treatment of GLUT1 deficiency and other medical conditions. Ketone esters are synthetic ketones that break down into natural ketones when metabolized. Ketone esters have been shown in recent research to improve seizures and movement disorders in GLUT1 deficient mice, but human studies have not yet been conducted. Triheptanoin (C7 oil), a triglyceride oil synthesized from castor beans. is an investigational pharmaceutical-grade medical food that has shown potential as a treatment for a number of inherited metabolic diseases. When metabolized by the body, C7 oil produces ketones similar to those produced on a ketogenic diet in addition to other types of ketones that are thought to fulfill further metabolic requirements in the absence of sufficient glucose. A phase 3 clinical trial however failed to find an improvement in patients with GLUT1 DS with disabling movement disorders. The inhibition of insulin production to increase glucose in the blood with the medicine diazoxide, in combination with continuous glucose monitoring, has been successful in one adolescent. The increased blood glucose also increases the availability of glucose in the brain, through the increased transfer of more glucose through the GLUT1-protein. She became seizure-free, became more physically active and had improved cognition. Researchers are studying gene therapy as a possible effective treatment for Glut 1 Deficiency. Therapies and rehabilitative services are beneficial since most GLUT1 deficiency patients experience movement disturbances as well as speech and language disorders. Occupational, physical, and speech/language therapies are standard for most patients, especially in childhood. Many families greatly benefit from other therapies such as aquatic therapy, hippotherapy, specific learning strategies, and behavioral therapy. Glut 1 patients Weak Areas are lowered IQ and adaptive behavior scores, expressive-language deficits, weakness in fine motor skills, limited visual attention to details, weakness in abstract analytical skills, and weakness in transfer of learning to new contexts. == References == == External links == GeneReview/NIH/UW entry on Glucose Transporter Type 1 Deficiency Syndrome	Wikipedia/De_Vivo_disease
Stomach diseases include gastritis, gastroparesis, Crohn's disease and various cancers. The stomach is an important organ in the body. It plays a vital role in digestion of foods, releases various enzymes and also protects the lower intestine from harmful organisms. The stomach connects to the esophagus above and to the small intestine below. It is intricately related to the pancreas, spleen and liver. The stomach does vary in size but its J shape is constant. The stomach lies in the upper part of the abdomen just below the left rib cage. The term gastropathy means "stomach disease" and is included in the name of the diseases portal hypertensive gastropathy, hyperplastic hypersecretory gastropathy (Ménétrier's disease), and others. However, not all stomach diseases are labeled with the word "gastropathy"; examples include peptic ulcer disease, gastroparesis, and dyspepsia. Many stomach diseases are associated with infections. In the past it was widely but incorrectly believed that the highly acidic environment of the stomach would keep the stomach immune from infection. Many studies have indicated that most cases of stomach ulcers, gastritis, and stomach cancer are caused by Helicobacter pylori infection. One of the ways it is able to survive in the stomach involves its urease enzymes which metabolize urea (which is normally secreted into the stomach) to ammonia and carbon dioxide which neutralises gastric acid and thus prevents its digestion. In recent years, it has been discovered that other Helicobacter bacteria are also capable of colonising the stomach and have been associated with gastritis. Having too little or no gastric acid is known as hypochlorhydria or achlorhydria respectively and are conditions which can have negative health impacts. Having high levels of gastric acid is called hyperchlorhydria. Many people believe that hyperchlorhydria can cause stomach ulcers. However, recent research indicates that the gastric mucosa which secretes gastric acid is acid-resistant. There are many types of chronic disorders which affect the stomach. However, since the symptoms are localized to this organ, the typical symptoms of stomach problems include nausea, vomiting, bloating, cramps, diarrhea and pain. == Gastritis == In the stomach there is a slight balance between acid and the wall lining which is protected by mucus. When this mucus lining is disrupted for whatever reason, signs and symptoms of acidity result. This may result in upper abdominal pain, indigestion, loss of appetite, nausea, vomiting and heartburn. When the condition is allowed to progress, the pain may become continuous; blood may start to leak and be seen in the stools. If the bleeding is rapid and of adequate volume it may even result in vomiting of bright red blood (hematemesis). When the acidity is uncontrolled, it can even cause severe blood loss (anemia) or lead to perforation (hole) in the stomach which is a surgical emergency. In many individuals, the progressive bleeding from an ulcer mixes with the feces and presents as black stools. Presence of blood in stools is often the first sign that there is a problem in the stomach. == Gastroparesis == Another very common long-term problem which is now more appreciated is gastroparesis. Gastroparesis affects millions of individuals and is often never suspected and most patients have a delay in diagnosis. Basically in gastroparesis, the stomach motility disappears and food remains stagnant in the stomach. The most common cause of gastroparesis is diabetes but it can also occur from a blockage at the distal end of stomach, a cancer or a stroke. Symptoms of gastroparesis includes abdominal pain, fullness, bloating, nausea, vomiting after eating food, loss of appetite and feeling of fullness after eating small amounts of food. == Crohn's disease == Crohn's disease is an inflammatory bowel disease that can affect any part of the digestive tract, even the stomach, although it's a rare presentation. Its main feature is inflammatory ulcers that can affect the total thickness of the stomach wall and can bleed but rarely perforate. Symptoms include abdominal pain, loss of appetite, and weight loss. Diarrhea is also a symptom that can develop, so checking stools for the appearance of blood is important. It is possible for symptoms of Crohn's disease to remain with a person for weeks or go away on their own. Reporting the symptoms to a doctor is recommended to prevent further complications. == Cancers == Cancers of the stomach are rare and the incidence has been declining worldwide. Stomach cancers usually occur due to fluctuations in acidity level and may present with vague symptoms of abdominal fullness, weight loss and pain. The actual cause of stomach cancer is not known but has been linked to infection with Helicobacter pylori, pernicious anemia, Menetriere's disease, and nitrogenous preservatives in food. == Diagnosis == === Endoscopy === There are many tools for investigating stomach problems. The most common is endoscopy. This procedure is performed as an outpatient and utilizes a small flexible camera. The procedure does require intravenous sedation and takes about 30–45 minutes; the endoscope is inserted via the mouth and can visualize the entire swallowing tube, stomach and duodenum. The procedure also allows the physician to obtain biopsy samples. In many cases of bleeding, the surgeon can use the endoscope to treat the source of bleeding with laser, clips or other injectable drugs. === X rays === Other radiological studies frequently used to assess patients with chronic stomach problems include a barium swallow, where a dye is consumed and pictures of the esophagus and stomach are obtained every few minutes. Other tests include a 24-hour pH study, CT scans or MRI etc. == References == == External links == Digestive Diseases A-Z The National Institute of Diabetes and Digestive and Kidney Diseases	Wikipedia/Stomach_disease
Riga–Fede disease (RFD) is a rare and benign mucosal condition, characterized by a tongue ulcer that is frequently brought on by traumatizing injuries sustained from repeatedly moving the tongue back and forth over the mandibular anterior incisors. == Signs and symptoms == Clinically, it typically manifests as a tongue-localized ulcer (60 percent of lesions), though it can also affect the lip, palate, gingiva, vestibular mucosa, and floor of the mouth. RFD may not cause any symptoms or may occasionally be accompanied by pain. == Causes == RFD is most frequently linked to the emergence of the natal-neonatal teeth in newborns or the primary lower incisor in older infants. == Diagnosis == Histopathologically speaking, RFD is characterized by mucosal areas that are ulcerated, granulation tissue present, and a mixed inflammatory infiltrate that is abundant in mast cells, macrophages, lymphocytes, and eosinophils. == Treatment == The lesion can be removed, the sharp incisal edges can be smoothed, or the tooth's sharp edges can be rounded with composite increments. The latter is where mild to moderate ulceration can occur. Teeth extraction may be helpful if the ulceration is large and preventing the patient from eating. == References == == Further reading == Costacurta, M.; Maturo, P.; Docimo, R. (2012). "Riga-Fede disease and neonatal teeth". Oral & Implantology. 5 (1). CIC Edizioni Internazionali: 26–30. PMC 3533976. PMID 23285403. Volpato, Luiz Evaristo Ricci; Simões, Cintia Aparecida Damo; Simões, Flávio; Nespolo, Priscila Alves; Borges, Álvaro Henrique (2015). "Riga-Fede Disease Associated with Natal Teeth: Two Different Approaches in the Same Case". Case Reports in Dentistry. 2015. Hindawi Limited: 1–4. doi:10.1155/2015/234961. ISSN 2090-6447. PMC 4569785. PMID 26421196. == External links == Whonamedit? DermNet	Wikipedia/Riga–Fede_disease
Cognitive behavioral therapy (CBT) is a form of psychotherapy that aims to reduce symptoms of various mental health conditions, primarily depression, PTSD, and anxiety disorders. Cognitive behavioral therapy focuses on challenging and changing cognitive distortions (thoughts, beliefs, and attitudes) and their associated behaviors in order to improve emotional regulation and help the individual develop coping strategies to address problems. Though originally designed as an approach to treat depression, CBT is often prescribed for the evidence-informed treatment of many mental health and other conditions, including anxiety, substance use disorders, marital problems, ADHD, and eating disorders. CBT includes a number of cognitive or behavioral psychotherapies that treat defined psychopathologies using evidence-based techniques and strategies. CBT is a common form of talk therapy based on the combination of the basic principles from behavioral and cognitive psychology. It is different from other approaches to psychotherapy, such as the psychoanalytic approach, where the therapist looks for the unconscious meaning behind the behaviors and then formulates a diagnosis. Instead, CBT is a "problem-focused" and "action-oriented" form of therapy, meaning it is used to treat specific problems related to a diagnosed mental disorder. The therapist's role is to assist the client in finding and practicing effective strategies to address the identified goals and to alleviate symptoms of the disorder. CBT is based on the belief that thought distortions and maladaptive behaviors play a role in the development and maintenance of many psychological disorders and that symptoms and associated distress can be reduced by teaching new information-processing skills and coping mechanisms. When compared to psychoactive medications, review studies have found CBT alone to be as effective for treating less severe forms of depression, and borderline personality disorder. Some research suggests that CBT is most effective when combined with medication for treating mental disorders, such as major depressive disorder. CBT is recommended as the first line of treatment for the majority of psychological disorders in children and adolescents, including aggression and conduct disorder. Researchers have found that other bona fide therapeutic interventions were equally effective for treating certain conditions in adults. Along with interpersonal psychotherapy (IPT), CBT is recommended in treatment guidelines as a psychosocial treatment of choice. It is recommended by the American Psychiatric Association, the American Psychological Association, and the British National Health Service. == History == === Philosophy === Precursors of certain fundamental aspects of CBT have been identified in various ancient philosophical traditions, particularly Stoicism. Stoic philosophers, particularly Epictetus, believed logic could be used to identify and discard false beliefs that lead to destructive emotions, which has influenced the way modern cognitive-behavioral therapists identify cognitive distortions that contribute to depression and anxiety. Aaron T. Beck's original treatment manual for depression states, "The philosophical origins of cognitive therapy can be traced back to the Stoic philosophers". Another example of Stoic influence on cognitive theorists is Epictetus on Albert Ellis. A key philosophical figure who influenced the development of CBT was John Stuart Mill through his creation of Associationism, a predecessor of classical conditioning and behavioral theory. Principles originating from Buddhism have significantly impacted the evolution of various new forms of CBT, including dialectical behavior therapy, mindfulness-based cognitive therapy, spirituality-based CBT, and compassion-focused therapy. The modern roots of CBT can be traced to the development of behavior therapy in the early 20th century, the development of cognitive therapy in the 1960s, and the subsequent merging of the two. === Behavioral therapy === Groundbreaking work in behaviorism began with John B. Watson and Rosalie Rayner's studies of conditioning in 1920. Behaviorally-centered therapeutic approaches appeared as early as 1924 with Mary Cover Jones' work dedicated to the unlearning of fears in children. These were the antecedents of the development of Joseph Wolpe's behavioral therapy in the 1950s. It was the work of Wolpe and Watson, which was based on Ivan Pavlov's work on learning and conditioning, that influenced Hans Eysenck and Arnold Lazarus to develop new behavioral therapy techniques based on classical conditioning. During the 1950s and 1960s, behavioral therapy became widely used by researchers in the United States, the United Kingdom, and South Africa. Their inspiration was by the behaviorist learning theory of Ivan Pavlov, John B. Watson, and Clark L. Hull. In Britain, Joseph Wolpe, who applied the findings of animal experiments to his method of systematic desensitization, applied behavioral research to the treatment of neurotic disorders. Wolpe's therapeutic efforts were precursors to today's fear reduction techniques. British psychologist Hans Eysenck presented behavior therapy as a constructive alternative. At the same time as Eysenck's work, B. F. Skinner and his associates were beginning to have an impact with their work on operant conditioning. Skinner's work was referred to as radical behaviorism and avoided anything related to cognition. However, Julian Rotter in 1954 and Albert Bandura in 1969 contributed to behavior therapy with their works on social learning theory by demonstrating the effects of cognition on learning and behavior modification. The work of Claire Weekes in dealing with anxiety disorders in the 1960s is also seen as a prototype of behavior therapy. The emphasis on behavioral factors has been described as the "first wave" of CBT. === Cognitive therapy === One of the first therapists to address cognition in psychotherapy was Alfred Adler, notably with his idea of basic mistakes and how they contributed to creation of unhealthy behavioral and life goals.Abraham Low believed that someone's thoughts were best changed by changing their actions. Adler and Low influenced the work of Albert Ellis, who developed the earliest cognitive-based psychotherapy called rational emotive behavioral therapy, or REBT. The first version of REBT was announced to the public in 1956. In the late 1950s, Aaron T. Beck was conducting free association sessions in his psychoanalytic practice. During these sessions, Beck noticed that thoughts were not as unconscious as Freud had previously theorized, and that certain types of thinking may be the culprits of emotional distress. It was from this hypothesis that Beck developed cognitive therapy, and called these thoughts "automatic thoughts". He first published his new methodology in 1967, and his first treatment manual in 1979. Beck has been referred to as "the father of cognitive behavioral therapy". It was these two therapies, rational emotive therapy, and cognitive therapy, that started the "second wave" of CBT, which emphasized cognitive factors. === Merger of behavioral and cognitive therapies === Although the early behavioral approaches were successful in many so-called neurotic disorders, they had little success in treating depression. Behaviorism was also losing popularity due to the cognitive revolution. The therapeutic approaches of Albert Ellis and Aaron T. Beck gained popularity among behavior therapists, despite the earlier behaviorist rejection of mentalistic concepts like thoughts and cognitions. Both of these systems included behavioral elements and interventions, with the primary focus being on problems in the present. In initial studies, cognitive therapy was often contrasted with behavioral treatments to see which was most effective. During the 1980s and 1990s, cognitive and behavioral techniques were merged into cognitive behavioral therapy. Pivotal to this merging was the successful development of treatments for panic disorder by David M. Clark in the UK and David H. Barlow in the US. Over time, cognitive behavior therapy came to be known not only as a therapy, but as an umbrella term for all cognitive-based psychotherapies. These therapies include, but are not limited to, REBT, cognitive therapy, acceptance and commitment therapy, dialectical behavior therapy, metacognitive therapy, metacognitive training, reality therapy/choice theory, cognitive processing therapy, EMDR, and multimodal therapy. This blending of theoretical and technical foundations from both behavior and cognitive therapies constituted the "third wave" of CBT. The most prominent therapies of this third wave are dialectical behavior therapy and acceptance and commitment therapy. Despite the increasing popularity of third-wave treatment approaches, reviews of studies reveal there may be no difference in the effectiveness compared with non-third wave CBT for the treatment of depression. == Medical uses == In adults, CBT has been shown to be an effective part of treatment plans for anxiety disorders, body dysmorphic disorder, depression, eating disorders, chronic low back pain, personality disorders, psychosis, schizophrenia, substance use disorders, and bipolar disorder. It is also effective as part of treatment plans in the adjustment, depression, and anxiety associated with fibromyalgia, and as part of the treatment after spinal cord injuries. In children or adolescents, CBT is an effective part of treatment plans for anxiety disorders, body dysmorphic disorder, depression and suicidality, eating disorders and obesity, obsessive–compulsive disorder (OCD), and post-traumatic stress disorder (PTSD), tic disorders, trichotillomania, and other repetitive behavior disorders. CBT has also been used to help improve a variety of childhood disorders, including depressive disorders and various anxiety disorders. CBT has shown to be the most effective intervention for people exposed to adverse childhood experiences in the form of abuse or neglect. Criticism of CBT sometimes focuses on implementations (such as the UK IAPT) which may result initially in low quality therapy being offered by poorly trained practitioners. However, evidence supports the effectiveness of CBT for anxiety and depression. Evidence suggests that the addition of hypnotherapy as an adjunct to CBT improves treatment efficacy for a variety of clinical issues. The United Kingdom's National Institute for Health and Care Excellence (NICE) recommends CBT in the treatment plans for a number of mental health difficulties, including PTSD, OCD, bulimia nervosa, and clinical depression. === Depression and anxiety disorders === Cognitive behavioral therapy has been shown as an effective treatment for clinical depression. Among psychotherapeutic approaches for major depressive disorder, cognitive behavioral therapy and interpersonal psychotherapy are recommended by clinical practice guidelines including The American Psychiatric Association Practice (APA) Guidelines (April 2000), and the APA endorsed Veteran Affairs clinical practice guideline. CBT has been shown to be effective in the treatment of adults with anxiety disorders. There is also evidence that using CBT to treat children and adolescents with anxiety disorders was probably more effective (in the short term) than wait list or no treatment and more effective than attention control treatment approaches. Some meta-analyses find CBT more effective than psychodynamic therapy and equal to other therapies in treating anxiety and depression. A 2013 meta-analysis suggested that CBT, interpersonal therapy, and problem-solving therapy outperformed psychodynamic psychotherapy and behavioral activation in the treatment of depression. According to a 2004 review by INSERM of three methods, cognitive behavioral therapy was either proven or presumed to be an effective therapy on several mental disorders. This included depression, panic disorder, post-traumatic stress, and other anxiety disorders. A systematic review of CBT in depression and anxiety disorders concluded that "CBT delivered in primary care, especially including computer- or Internet-based self-help programs, is potentially more effective than usual care and could be delivered effectively by primary care therapists." A 2024 systematic review found that exposure and response prevention (ERP), a specific form of cognitive behavioral therapy, is considered a first-line treatment for pediatric obsessive–compulsive disorder (OCD). Research indicates that ERP is effective in both in-person and remote settings, providing flexibility in treatment delivery without compromising efficacy. In CBT you work on reducing fear by changing how you think and act. Instead of thinking of the fear object (for example, a spider) as an imminent threat or danger, you're taught to reevaluate the fear object as less threatening to your safety and well-being. Instead of avoiding or running from the fear, you're encouraged to face the fear. ==== Theoretical approaches ==== One etiological theory of depression is Aaron T. Beck's cognitive theory of depression. His theory states that depressed people think the way they do because their thinking is biased towards negative interpretations. Beck's theory rests on the aspect of cognitive behavioral therapy known as schemata. Schemata are the mental maps used to integrate new information into memories and to organize existing information in the mind. An example of a schema would be a person hearing the word "dog" and picturing different versions of the animal that they have grouped together in their mind. According to this theory, depressed people acquire a negative schema of the world in childhood and adolescence as an effect of stressful life events, and the negative schema is activated later in life when the person encounters similar situations. Beck also described a negative cognitive triad. The cognitive triad is made up of the depressed individual's negative evaluations of themselves, the world, and the future. Beck suggested that these negative evaluations derive from the negative schemata and cognitive biases of the person. According to this theory, depressed people have views such as "I never do a good job", "It is impossible to have a good day", and "things will never get better". A negative schema helps give rise to the cognitive bias, and the cognitive bias helps fuel the negative schema. Beck further proposed that depressed people often have the following cognitive biases: arbitrary inference, selective abstraction, overgeneralization, magnification, and minimization. These cognitive biases are quick to make negative, generalized, and personal inferences of the self, thus fueling the negative schema. On the other hand, a positive cognitive triad relates to a person's positive evaluations of themself, the world, and the future. More specifically, a positive cognitive triad requires self-esteem when viewing oneself and hope for the future. A person with a positive cognitive triad has a positive schema used for viewing themself in addition to a positive schema for the world and for the future. Cognitive behavioral research suggests a positive cognitive triad bolsters resilience, or the ability to cope with stressful events. Increased levels of resilience is associated with greater resistance to depression. Another major theoretical approach to cognitive behavioral therapy treatment is the concept of Locus of Control outlined in Julian Rotter's Social Learning Theory. Locus of control refers to the degree to which an individual's sense of control is either internal or external. An internal locus of control exists when an individual views an outcome of a particular action as being reliant on themselves and their personal attributes whereas an external locus of control exists when an individual views other's or some outside, intangible force such as luck or fate as being responsible for the outcome of a particular action. A basic concept in some CBT treatments used in anxiety disorders is in vivo exposure. CBT-exposure therapy refers to the direct confrontation of feared objects, activities, or situations by a patient. For example, a woman with PTSD who fears the location where she was assaulted may be assisted by her therapist in going to that location and directly confronting those fears. Likewise, a person with a social anxiety disorder who fears public speaking may be instructed to directly confront those fears by giving a speech. This "two-factor" model is often credited to O. Hobart Mowrer. Through exposure to the stimulus, this harmful conditioning can be "unlearned" (referred to as extinction and habituation). CBT for children with phobias is normally delivered over multiple sessions, but one-session treatment has been shown to be equally effective and is cheaper. ==== Specialized forms of CBT ==== CBT-SP, an adaptation of CBT for suicide prevention (SP), was specifically designed for treating youths who are severely depressed and who have recently attempted suicide within the past 90 days, and was found to be effective, feasible, and acceptable. Acceptance and commitment therapy (ACT) is a specialist branch of CBT (sometimes referred to as contextual CBT). ACT uses mindfulness and acceptance interventions and has been found to have a greater longevity in therapeutic outcomes. In a study with anxiety, CBT and ACT improved similarly across all outcomes from pre- to post-treatment. However, during a 12-month follow-up, ACT proved to be more effective, showing that it is a highly viable lasting treatment model for anxiety disorders. Computerized CBT (CCBT) has been proven to be effective by randomized controlled and other trials in treating depression and anxiety disorders, including children. Some research has found similar effectiveness to an intervention of informational websites and weekly telephone calls. CCBT was found to be equally effective as face-to-face CBT in adolescent anxiety. ==== Combined with other treatments ==== Studies have provided evidence that when examining animals and humans, that glucocorticoids may lead to a more successful extinction learning during exposure therapy for anxiety disorders. For instance, glucocorticoids can prevent aversive learning episodes from being retrieved and heighten reinforcement of memory traces creating a non-fearful reaction in feared situations. A combination of glucocorticoids and exposure therapy may be a better-improved treatment for treating people with anxiety disorders. ==== Prevention ==== For anxiety disorders, use of CBT with people at risk has significantly reduced the number of episodes of generalized anxiety disorder and other anxiety symptoms, and also given significant improvements in explanatory style, hopelessness, and dysfunctional attitudes. In another study, 3% of the group receiving the CBT intervention developed generalized anxiety disorder by 12 months postintervention compared with 14% in the control group. Individuals with subthreshold levels of panic disorder significantly benefitted from use of CBT. Use of CBT was found to significantly reduce social anxiety prevalence. For depressive disorders, a stepped-care intervention (watchful waiting, CBT and medication if appropriate) achieved a 50% lower incidence rate in a patient group aged 75 or older. Another depression study found a neutral effect compared to personal, social, and health education, and usual school provision, and included a comment on potential for increased depression scores from people who have received CBT due to greater self recognition and acknowledgement of existing symptoms of depression and negative thinking styles. A further study also saw a neutral result. A meta-study of the Coping with Depression course, a cognitive behavioral intervention delivered by a psychoeducational method, saw a 38% reduction in risk of major depression. === Bipolar disorder === Many studies show CBT, combined with pharmacotherapy, is effective in improving depressive symptoms, mania severity and psychosocial functioning with mild to moderate effects, and that it is better than medication alone. INSERM's 2004 review found that CBT is an effective therapy for several mental disorders, including bipolar disorder. This included schizophrenia, depression, bipolar disorder, panic disorder, post-traumatic stress, anxiety disorders, bulimia, anorexia, personality disorders and alcohol dependency. === Psychosis === In long-term psychoses, CBT is used to complement medication and is adapted to meet individual needs. Interventions particularly related to these conditions include exploring reality testing, changing delusions and hallucinations, examining factors which precipitate relapse, and managing relapses. Meta-analyses confirm the effectiveness of metacognitive training (MCT) for the improvement of positive symptoms (e.g., delusions). For people at risk of psychosis, in 2014 the UK National Institute for Health and Care Excellence (NICE) recommended preventive CBT. === Schizophrenia === INSERM's 2004 review found that CBT is an effective therapy for several mental disorders, including schizophrenia. A Cochrane review reported CBT had "no effect on long‐term risk of relapse" and no additional effect above standard care. A 2015 systematic review investigated the effects of CBT compared with other psychosocial therapies for people with schizophrenia and determined that there is no clear advantage over other, often less expensive, interventions but acknowledged that better quality evidence is needed before firm conclusions can be drawn. === Addiction and substance use disorders === ==== Pathological and problem gambling ==== CBT is also used for pathological and problem gambling. The percentage of people who problem gamble is 1–3% around the world. Cognitive behavioral therapy develops skills for relapse prevention and someone can learn to control their mind and manage high-risk cases. There is evidence of efficacy of CBT for treating pathological and problem gambling at immediate follow up, however the longer term efficacy of CBT for it is currently unknown. ==== Smoking cessation ==== CBT looks at the habit of smoking cigarettes as a learned behavior, which later evolves into a coping strategy to handle daily stressors. Since smoking is often easily accessible and quickly allows the user to feel good, it can take precedence over other coping strategies, and eventually work its way into everyday life during non-stressful events as well. CBT aims to target the function of the behavior, as it can vary between individuals, and works to inject other coping mechanisms in place of smoking. CBT also aims to support individuals with strong cravings, which are a major reported reason for relapse during treatment. A 2008 controlled study out of Stanford University School of Medicine suggested CBT may be an effective tool to help maintain abstinence. The results of 304 random adult participants were tracked over the course of one year. During this program, some participants were provided medication, CBT, 24-hour phone support, or some combination of the three methods. At 20 weeks, the participants who received CBT had a 45% abstinence rate, versus non-CBT participants, who had a 29% abstinence rate. Overall, the study concluded that emphasizing cognitive and behavioral strategies to support smoking cessation can help individuals build tools for long term smoking abstinence. Mental health history can affect the outcomes of treatment. Individuals with a history of depressive disorders had a lower rate of success when using CBT alone to combat smoking addiction. A 2019 Cochrane review was unable to find sufficient evidence to differentiate effects between CBT and hypnosis for smoking cessation and highlighted that a review of the current research showed variable results for both modalities. ==== Substance use disorders ==== Studies have shown CBT to be an effective treatment for substance use disorders. For individuals with substance use disorders, CBT aims to reframe maladaptive thoughts, such as denial, minimizing and catastrophizing thought patterns, with healthier narratives. Specific techniques include identifying potential triggers and developing coping mechanisms to manage high-risk situations. Research has shown CBT to be particularly effective when combined with other therapy-based treatments or medication. INSERM's 2004 review found that CBT is an effective therapy for several mental disorders, including alcohol dependency. ==== Internet addiction ==== Research has identified Internet addiction as a new clinical disorder that causes relational, occupational, and social problems. Cognitive behavioral therapy (CBT) has been suggested as the treatment of choice for Internet addiction, and addiction recovery in general has used CBT as part of treatment planning. === Eating disorders === Though many forms of treatment can support individuals with eating disorders, CBT is proven to be a more effective treatment than medications and interpersonal psychotherapy alone. CBT aims to combat major causes of distress such as negative cognitions surrounding body weight, shape and size. CBT therapists also work with individuals to regulate strong emotions and thoughts that lead to dangerous compensatory behaviors. CBT is the first line of treatment for bulimia nervosa, and non-specific eating disorders. While there is evidence to support the efficacy of CBT for bulimia nervosa and binging, the evidence is somewhat variable and limited by small study sizes. INSERM's 2004 review found that CBT is an effective therapy for several mental disorders, including bulimia and anorexia nervosa. === With autistic adults === Emerging evidence for cognitive behavioral interventions aimed at reducing symptoms of depression, anxiety, and obsessive-compulsive disorder in autistic adults without intellectual disability has been identified through a systematic review. While the research was focused on adults, cognitive behavioral interventions have also been beneficial to autistic children. A 2021 Cochrane review found limited evidence regarding the efficacy of CBT for obsessive-compulsive disorder in adults with Autism Spectrum Disorder stating a need for further study. === Dementia and mild cognitive impairment === A Cochrane review in 2022 found that adults with dementia and mild cognitive impairment (MCI) who experience symptoms of depression may benefit from CBT, whereas other counselling or supportive interventions might not improve symptoms significantly. Across 5 different psychometric scales, where higher scores indicate severity of depression, adults receiving CBT reported somewhat lower mood scores than those receiving usual care for dementia and MCI overall. In this review, a sub-group analysis found clinically significant benefits only among those diagnosed with dementia, rather than MCI. The likelihood of remission from depression also appeared to be 84% higher following CBT, though the evidence for this was less certain. Anxiety, cognition and other neuropsychiatric symptoms were not significantly improved following CBT, however this review did find moderate evidence of improved quality of life and daily living activity scores in those with dementia and MCI. === Post-traumatic stress === Cognitive behavioral therapy interventions may have some benefits for people who have post-traumatic stress related to surviving rape, sexual abuse, or sexual assault. There is strong evidence that CBT-exposure therapy can reduce PTSD symptoms and lead to the loss of a PTSD diagnosis. In addition, CBT has also been shown to be effective for post-traumatic stress disorder in very young children (3 to 6 years of age). There is lower quality evidence that CBT may be more effective than other psychotherapies in reducing symptoms of posttraumatic stress disorder in children and adolescents. === Other uses === Evidence suggests a possible role for CBT in the treatment of attention deficit hyperactivity disorder (ADHD), hypochondriasis, and bipolar disorder, but more study is needed and results should be interpreted with caution. Moderate evidence from a 2024 systematic review supports the effectiveness of CBT and neurofeedback as part of psychosocial interventions for improving ADHD symptoms in children and adolescents. CBT has been studied as an aid in the treatment of anxiety associated with stuttering. Initial studies have shown CBT to be effective in reducing social anxiety in adults who stutter, but not in reducing stuttering frequency. There is some evidence that CBT is superior in the long-term to benzodiazepines and the nonbenzodiazepines in the treatment and management of insomnia. Computerized CBT (CCBT) has been proven to be effective by randomized controlled and other trials in treating insomnia. Some research has found similar effectiveness to an intervention of informational websites and weekly telephone calls. CCBT was found to be equally effective as face-to-face CBT in insomnia. A Cochrane review of interventions aimed at preventing psychological stress in healthcare workers found that CBT was more effective than no intervention but no more effective than alternative stress-reduction interventions. Cochrane Reviews have found no convincing evidence that CBT training helps foster care providers manage difficult behaviors in the youths under their care, nor was it helpful in treating people who abuse their intimate partners. CBT has been applied in both clinical and non-clinical environments to treat disorders such as personality disorders and behavioral problems. INSERM's 2004 review found that CBT is an effective therapy for personality disorders. CBT has been used with other researchers as well to minimize chronic pain and help relieve symptoms from those suffering from irritable bowel syndrome (IBS). ==== Individuals with medical conditions ==== In the case of people with metastatic breast cancer, data is limited but CBT and other psychosocial interventions might help with psychological outcomes and pain management. There is also some evidence that CBT may help reduce insomnia in cancer patients. There is some evidence that using CBT for symptomatic management of non-specific chest pain is probably effective in the short term. However, the findings were limited by small trials and the evidence was considered of questionable quality. Cochrane reviews have found no evidence that CBT is effective for tinnitus, although there appears to be an effect on management of associated depression and quality of life in this condition. CBT combined with hypnosis and distraction reduces self-reported pain in children. There is limited evidence to support CBT's use in managing the impact of multiple sclerosis, sleep disturbances related to aging, and dysmenorrhea, but more study is needed and results should be interpreted with caution. Previously CBT has been considered as moderately effective for treating myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), however a National Institutes of Health Pathways to Prevention Workshop stated that in respect of improving treatment options for ME/CFS that the modest benefit from cognitive behavioral therapy should be studied as an adjunct to other methods. The Centres for Disease Control advice on the treatment of ME/CFS makes no reference to CBT while the National Institute for Health and Care Excellence states that cognitive behavioral therapy (CBT) has sometimes been assumed to be a cure for ME/CFS, however, it should only be offered to support people who live with ME/CFS to manage their symptoms, improve their functioning and reduce the distress associated with having a chronic illness. === Age === CBT is used to help people of all ages, but the therapy should be adjusted based on the age of the patient with whom the therapist is dealing. Older individuals in particular have certain characteristics that need to be acknowledged and the therapy altered to account for these differences thanks to age. Of the small number of studies examining CBT for the management of depression in older people, there is currently no strong support. == Description == Mainstream cognitive behavioral therapy assumes that changing maladaptive thinking leads to change in behavior and affect, but recent variants emphasize changes in one's relationship to maladaptive thinking rather than changes in thinking itself. === Cognitive distortions === Therapists use CBT techniques to help people challenge their patterns and beliefs and replace errors in thinking, known as cognitive distortions with "more realistic and effective thoughts, thus decreasing emotional distress and self-defeating behavior". Cognitive distortions can be either a pseudo-discrimination belief or an overgeneralization of something. CBT techniques may also be used to help individuals take a more open, mindful, and aware posture toward cognitive distortions so as to diminish their impact. Mainstream CBT helps individuals replace "maladaptive... coping skills, cognitions, emotions and behaviors with more adaptive ones", by challenging an individual's way of thinking and the way that they react to certain habits or behaviors, but there is still controversy about the degree to which these traditional cognitive elements account for the effects seen with CBT over and above the earlier behavioral elements such as exposure and skills training. === Assumptions === Chaloult, Ngo, Cousineau and Goulet have attempted to identify the main assumptions of cognitive therapy used in CBT based on the research literature (Beck; Walen and Wessler; Beck, Emery and Greenberg, and Auger). They describe fourteen assumptions: Human emotions are primarily caused by people's thoughts and perceptions rather than events. Events, thoughts, emotions, behaviors, and physiological reactions influence each other. Dysfunctional emotions are typically caused by unrealistic thoughts. Reducing dysfunctional emotions requires becoming aware of irrational thoughts and changing them. Human beings have an innate tendency to develop irrational thoughts. This tendency is reinforced by their environment. People are largely responsible for their own dysfunctional emotions, as they maintain and reinforce their own beliefs. Sustained effort is necessary to modify dysfunctional thoughts, emotions, and behaviors. Rational thinking usually causes a decrease in the frequency, intensity, and duration of dysfunctional emotions, rather than an absence of affect or feelings. A positive therapeutic relationship is essential to successful cognitive therapy. Cognitive therapy is based on a teacher-student relationship, where the therapist educates the client. Cognitive therapy uses Socratic questioning to challenge cognitive distortions. Homework is an essential aspect of cognitive therapy. It consolidates the skills learned in therapy. The cognitive approach is active, directed, and structured. Cognitive therapy is generally short. Cognitive therapy is based on predictable steps. These steps largely involve learning about the CBT model; making links between thoughts, emotions, behaviors, and physiological reactions; noticing when dysfunctional emotions occur; learning to question the thoughts associated with these emotions; replacing irrational thoughts with others more grounded in reality; modifying behaviors based on new interpretations of events; and, in some cases, learning to recognize and change the major beliefs and attitudes underlying cognitive distortions. Chaloult, Ngo, Cousineau and Goulet have also described the assumptions of behavioral therapy as used in CBT. They refer to the work of Agras, Prochaska and Norcross, and Kirk. The assumptions are: Behaviors play an essential role in the onset, perpetuation and exacerbation of psychopathology. Learning theory is key in understanding the treatment of mental illness, as behaviors can be learned and unlearned. A rigorous evaluation (applied behavior analysis) is essential at the start of treatment. It includes identifying behaviors; precipitating, moderating, and perpetuating factors; the consequences of the behaviors; avoidance, and personal resources. The effectiveness of the treatment is monitored throughout its duration. Behavior therapy is scientific and the different forms of treatment are evaluated with rigorous evidence. Behavior therapy is active, directed, and structured. Together, these sets of assumptions cover the cognitive and behavioral aspects of CBT. === Phases in therapy === CBT can be seen as having six phases: Assessment or psychological assessment; Reconceptualization; Skills acquisition; Skills consolidation and application training; Generalization and maintenance; Post-treatment assessment follow-up. These steps are based on a system created by Kanfer and Saslow. After identifying the behaviors that need changing, whether they be in excess or deficit, and treatment has occurred, the psychologist must identify whether or not the intervention succeeded. For example, "If the goal was to decrease the behavior, then there should be a decrease relative to the baseline. If the critical behavior remains at or above the baseline, then the intervention has failed." The steps in the assessment phase include: Identify critical behaviors; Determine whether critical behaviors are excesses or deficits; Evaluate critical behaviors for frequency, duration, or intensity (obtain a baseline); If excess, attempt to decrease frequency, duration, or intensity of behaviors; if deficits, attempt to increase behaviors. The re-conceptualization phase makes up much of the "cognitive" portion of CBT. === Delivery protocols === There are different protocols for delivering cognitive behavioral therapy, with important similarities among them. Use of the term CBT may refer to different interventions, including "self-instructions (e.g. distraction, imagery, motivational self-talk), relaxation and/or biofeedback, development of adaptive coping strategies (e.g. minimizing negative or self-defeating thoughts), changing maladaptive beliefs about pain, and goal setting". Treatment is sometimes manualized, with brief, direct, and time-limited treatments for individual psychological disorders that are specific technique-driven. CBT is used in both individual and group settings, and the techniques are often adapted for self-help applications. Some clinicians and researchers are cognitively oriented (e.g. cognitive restructuring), while others are more behaviorally oriented (e.g. in vivo exposure therapy). Interventions such as imaginal exposure therapy combine both approaches. === Related techniques === CBT may be delivered in conjunction with a variety of diverse but related techniques such as exposure therapy, stress inoculation, cognitive processing therapy, cognitive therapy, metacognitive therapy, metacognitive training, relaxation training, dialectical behavior therapy, and acceptance and commitment therapy. Some practitioners promote a form of mindful cognitive therapy which includes a greater emphasis on self-awareness as part of the therapeutic process. == Methods of access == === Therapist === A typical CBT program would consist of face-to-face sessions between patient and therapist, made up of 6–18 sessions of around an hour each with a gap of 1–3 weeks between sessions. This initial program might be followed by some booster sessions, for instance after one month and three months. CBT has also been found to be effective if patient and therapist type in real time to each other over computer links. Cognitive-behavioral therapy is most closely allied with the scientist–practitioner model in which clinical practice and research are informed by a scientific perspective, clear operationalization of the problem, and an emphasis on measurement, including measuring changes in cognition and behavior and the attainment of goals. These are often met through "homework" assignments in which the patient and the therapist work together to craft an assignment to complete before the next session. The completion of these assignments – which can be as simple as a person with depression attending some kind of social event – indicates a dedication to treatment compliance and a desire to change. The therapists can then logically gauge the next step of treatment based on how thoroughly the patient completes the assignment. Effective cognitive behavioral therapy is dependent on a therapeutic alliance between the healthcare practitioner and the person seeking assistance. Unlike many other forms of psychotherapy, the patient is very involved in CBT. For example, an anxious patient may be asked to talk to a stranger as a homework assignment, but if that is too difficult, he or she can work out an easier assignment first. The therapist needs to be flexible and willing to listen to the patient rather than acting as an authority figure. === Computerized or Internet-delivered (CCBT) === Computerized cognitive behavioral therapy (CCBT) has been described by NICE as a "generic term for delivering CBT via an interactive computer interface delivered by a personal computer, internet, or interactive voice response system", instead of face-to-face with a human therapist. It is also known as internet-delivered cognitive behavioral therapy or ICBT. CCBT has potential to improve access to evidence-based therapies, and to overcome the prohibitive costs and lack of availability sometimes associated with retaining a human therapist. In this context, it is important not to confuse CBT with 'computer-based training', which nowadays is more commonly referred to as e-Learning. Although improvements in both research quality and treatment adherence is required before advocating for the global dissemination of CCBT, it has been found in meta-studies to be cost-effective and often cheaper than usual care, including for anxiety and PTSD. Studies have shown that individuals with social anxiety and depression experienced improvement with online CBT-based methods. A study assessing an online version of CBT for people with mild-to-moderate PTSD found that the online approach was as effective as, and cheaper than, the same therapy given face-to-face. A review of current CCBT research in the treatment of OCD in children found this interface to hold great potential for future treatment of OCD in youths and adolescent populations. Additionally, most internet interventions for post-traumatic stress disorder use CCBT. CCBT is also predisposed to treating mood disorders amongst non-heterosexual populations, who may avoid face-to-face therapy from fear of stigma. However presently CCBT programs seldom cater to these populations. In February 2006 NICE recommended that CCBT be made available for use within the NHS across England and Wales for patients presenting with mild-to-moderate depression, rather than immediately opting for antidepressant medication, and CCBT is made available by some health systems. The 2009 NICE guideline recognized that there are likely to be a number of computerized CBT products that are useful to patients, but removed endorsement of any specific product. === Smartphone app-delivered === Another new method of access is the use of mobile app or smartphone applications to deliver self-help or guided CBT. Technology companies are developing mobile-based artificial intelligence chatbot applications in delivering CBT as an early intervention to support mental health, to build psychological resilience, and to promote emotional well-being. Artificial intelligence (AI) text-based conversational application delivered securely and privately over smartphone devices have the ability to scale globally and offer contextual and always-available support. Active research is underway including real-world data studies that measure effectiveness and engagement of text-based smartphone chatbot apps for delivery of CBT using a text-based conversational interface. Recent market research and analysis of over 500 online mental healthcare solutions identified 3 key challenges in this market: quality of the content, guidance of the user and personalisation. A study compared CBT alone with a mindfulness-based therapy combined with CBT, both delivered via an app. It found that mindfulness-based self-help reduced the severity of depression more than CBT self-help in the short-term. Overall, NHS costs for the mindfulness approach were £500 less per person than for CBT. === Reading self-help materials === Enabling patients to read self-help CBT guides has been shown to be effective by some studies. However one study found a negative effect in patients who tended to ruminate, and another meta-analysis found that the benefit was only significant when the self-help was guided (e.g. by a medical professional). === Group educational course === Patient participation in group courses has been shown to be effective. In a meta-analysis reviewing evidence-based treatment of OCD in children, individual CBT was found to be more efficacious than group CBT. == Types == === Brief cognitive behavioral therapy === Brief cognitive behavioral therapy (BCBT) is a form of CBT which has been developed for situations in which there are time constraints on the therapy sessions and specifically for those struggling with suicidal ideation and/or making suicide attempts. BCBT was based on Rudd's proposed "suicidal mode", an elaboration of Beck's modal theory. BCBT takes place over a couple of sessions that can last up to 12 accumulated hours by design. This technique was first implemented and developed with soldiers on active duty by Dr. M. David Rudd to prevent suicide. Breakdown of treatment Orientation Commitment to treatment Crisis response and safety planning Means restriction Survival kit Reasons for living card Model of suicidality Treatment journal Lessons learned Skill focus Skill development worksheets Coping cards Demonstration Practice Skill refinement Relapse prevention Skill generalization Skill refinement === Cognitive emotional behavioral therapy === Cognitive emotional behavioral therapy (CEBT) is a form of CBT developed initially for individuals with eating disorders but now used with a range of problems including anxiety, depression, obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and anger problems. It combines aspects of CBT and dialectical behavioral therapy and aims to improve understanding and tolerance of emotions in order to facilitate the therapeutic process. It is frequently used as a "pretreatment" to prepare and better equip individuals for longer-term therapy. === Structured cognitive behavioral training === Structured cognitive-behavioral training (SCBT) is a cognitive-based process with core philosophies that draw heavily from CBT. Like CBT, SCBT asserts that behavior is inextricably related to beliefs, thoughts, and emotions. SCBT also builds on core CBT philosophy by incorporating other well-known modalities in the fields of behavioral health and psychology: most notably, Albert Ellis's rational emotive behavior therapy. SCBT differs from CBT in two distinct ways. First, SCBT is delivered in a highly regimented format. Second, SCBT is a predetermined and finite training process that becomes personalized by the input of the participant. SCBT is designed to bring a participant to a specific result in a specific period of time. SCBT has been used to challenge addictive behavior, particularly with substances such as tobacco, alcohol and food, and to manage diabetes and subdue stress and anxiety. SCBT has also been used in the field of criminal psychology in the effort to reduce recidivism. === Moral reconation therapy === Moral reconation therapy, a type of CBT used to help felons overcome antisocial personality disorder (ASPD), slightly decreases the risk of further offending. It is generally implemented in a group format because of the risk of offenders with ASPD being given one-on-one therapy reinforces narcissistic behavioral characteristics, and can be used in correctional or outpatient settings. Groups usually meet weekly for two to six months. === Stress inoculation training === This type of therapy uses a blend of cognitive, behavioral, and certain humanistic training techniques to target the stressors of the client. This is usually used to help clients better cope with their stress or anxiety after stressful events. This is a three-phase process that trains the client to use skills that they already have to better adapt to their current stressors. The first phase is an interview phase that includes psychological testing, client self-monitoring, and a variety of reading materials. This allows the therapist to individually tailor the training process to the client. Clients learn how to categorize problems into emotion-focused or problem-focused so that they can better treat their negative situations. This phase ultimately prepares the client to eventually confront and reflect upon their current reactions to stressors, before looking at ways to change their reactions and emotions to their stressors. The focus is conceptualization. The second phase emphasizes the aspect of skills acquisition and rehearsal that continues from the earlier phase of conceptualization. The client is taught skills that help them cope with their stressors. These skills are then practiced in the space of therapy. These skills involve self-regulation, problem-solving, interpersonal communication skills, etc. The third and final phase is the application and following through of the skills learned in the training process. This gives the client opportunities to apply their learned skills to a wide range of stressors. Activities include role-playing, imagery, modeling, etc. In the end, the client will have been trained on a preventive basis to inoculate personal, chronic, and future stressors by breaking down their stressors into problems they will address in long-term, short-term, and intermediate coping goals. === Activity-guided CBT: Group-knitting === A recently developed group therapy model, based on CBT, integrates knitting into the therapeutic process and has been proven to yield reliable and promising results. The foundation for this novel approach to CBT is the frequently emphasized notion that therapy success depends on how embedded the therapy method is in the patients' natural routine. Similar to standard group-based CBT, patients meet once a week in a group of 10 to 15 patients and knit together under the instruction of a trained psychologist or mental health professional. Central for the therapy is the patient's imaginative ability to assign each part of the wool to a certain thought. During the therapy, the wool is carefully knitted, creating a knitted piece of any form. This therapeutic process teaches the patient to meaningfully align thought, by (physically) creating a coherent knitted piece. Moreover, since CBT emphasizes the behavior as a result of cognition, the knitting illustrates how thoughts (which are tried to be imaginary tight to the wool) materialize into the reality surrounding us. === Mindfulness-based cognitive behavioral hypnotherapy === Mindfulness-based cognitive behavioral hypnotherapy (MCBH) is a form of CBT that focuses on awareness in a reflective approach, addressing subconscious tendencies. It is more the process that contains three phases for achieving wanted goals and integrates the principles of mindfulness and cognitive-behavioral techniques with the transformative potential of hypnotherapy. === Unified Protocol === The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) is a form of CBT, developed by David H. Barlow and researchers at Boston University, that can be applied to a range of anxiety disorders. The rationale is that anxiety and depression disorders often occur together due to common underlying causes and can efficiently be treated together. The UP includes a common set of components: Psycho-education Cognitive reappraisal Emotion regulation Changing behaviour The UP has been shown to produce equivalent results to single-diagnosis protocols for specific disorders, such as OCD and social anxiety disorder. Several studies have shown that the UP is easier to disseminate as compared to single-diagnosis protocols. Culturally adapted CBT The study of psychotherapy across races, religions, and cultures, or "ethno-psycho-therapy", is a relatively new discipline == Criticisms == === Relative effectiveness === The research conducted for CBT has been a topic of sustained controversy. While some researchers write that CBT is more effective than other treatments, many other researchers and practitioners have questioned the validity of such claims. For example, one study determined CBT to be superior to other treatments in treating anxiety and depression. However, researchers responding directly to that study conducted a re-analysis and found no evidence of CBT being superior to other bona fide treatments and conducted an analysis of thirteen other CBT clinical trials and determined that they failed to provide evidence of CBT superiority. In cases where CBT has been reported to be statistically better than other psychological interventions in terms of primary outcome measures, effect sizes were small and suggested that those differences were clinically meaningless and insignificant. Moreover, on secondary outcomes (i.e., measures of general functioning) no significant differences have been typically found between CBT and other treatments. A major criticism has been that clinical studies of CBT efficacy (or any psychotherapy) are not double-blind (i.e., either the subjects or the therapists in psychotherapy studies are not blind to the type of treatment). They may be single-blinded, i.e. the rater may not know the treatment the patient received, but neither the patients nor the therapists are blinded to the type of therapy given (two out of three of the persons involved in the trial, i.e., all of the persons involved in the treatment, are unblinded). The patient is an active participant in correcting negative distorted thoughts, thus quite aware of the treatment group they are in. The importance of double-blinding was shown in a meta-analysis that examined the effectiveness of CBT when placebo control and blindness were factored in. Pooled data from published trials of CBT in schizophrenia, major depressive disorder (MDD), and bipolar disorder that used controls for non-specific effects of intervention were analyzed. This study concluded that CBT is no better than non-specific control interventions in the treatment of schizophrenia and does not reduce relapse rates; treatment effects are small in treatment studies of MDD, and it is not an effective treatment strategy for prevention of relapse in bipolar disorder. For MDD, the authors note that the pooled effect size was very low. === Declining effectiveness === Additionally, a 2015 meta-analysis revealed that the positive effects of CBT on depression have been declining since 1977. The overall results showed two different declines in effect sizes: 1) an overall decline between 1977 and 2014, and 2) a steeper decline between 1995 and 2014. Additional sub-analysis revealed that CBT studies where therapists in the test group were instructed to adhere to the Beck CBT manual had a steeper decline in effect sizes since 1977 than studies where therapists in the test group were instructed to use CBT without a manual. The authors reported that they were unsure why the effects were declining but did list inadequate therapist training, failure to adhere to a manual, lack of therapist experience, and patients' hope and faith in its efficacy waning as potential reasons. The authors did mention that the current study was limited to depressive disorders only. === High drop-out rates === Furthermore, other researchers write that CBT studies have high drop-out rates compared to other treatments. One meta-analysis found that CBT drop-out rates were 17% higher than those of other therapies. This high drop-out rate is also evident in the treatment of several disorders, particularly the eating disorder anorexia nervosa, which is commonly treated with CBT. Those treated with CBT have a high chance of dropping out of therapy before completion and reverting to their anorexia behaviors. Other researchers analyzing treatments for youths who self-injure found similar drop-out rates in CBT and DBT groups. In this study, the researchers analyzed several clinical trials that measured the efficacy of CBT administered to youths who self-injure. The researchers concluded that none of them were found to be efficacious. === Philosophical concerns with CBT methods === The methods employed in CBT research have not been the only criticisms; some individuals have called its theory and therapy into question. Slife and Williams write that one of the hidden assumptions in CBT is that of determinism, or the absence of free will. They argue that CBT holds that external stimuli from the environment enter the mind, causing different thoughts that cause emotional states: nowhere in CBT theory is agency, or free will, accounted for. Another criticism of CBT theory, especially as applied to major depressive disorder (MDD), is that it confounds the symptoms of the disorder with its causes. === Side effects === CBT is generally regarded as having very few if any side effects. Calls have been made by some for more appraisal of possible side effects of CBT. Many randomized trials of psychological interventions like CBT do not monitor potential harms to the patient. In contrast, randomized trials of pharmacological interventions are much more likely to take adverse effects into consideration. A 2017 meta-analysis revealed that adverse events are not common in children receiving CBT and, furthermore, that CBT is associated with fewer dropouts than either placebo or medications. Nevertheless, CBT therapists do sometimes report 'unwanted events' and side effects in their outpatients with "negative wellbeing/distress" being the most frequent. === Socio-political concerns === The writer and group analyst Farhad Dalal questions the socio-political assumptions behind the introduction of CBT. According to one reviewer, Dalal connects the rise of CBT with "the parallel rise of neoliberalism, with its focus on marketization, efficiency, quantification and managerialism", and he questions the scientific basis of CBT, suggesting that "the 'science' of psychological treatment is often less a scientific than a political contest". In his book, Dalal also questions the ethical basis of CBT. == Society and culture == The UK's National Health Service announced in 2008 that more therapists would be trained to provide CBT at government expense as part of an initiative called Improving Access to Psychological Therapies (IAPT). The NICE said that CBT would become the mainstay of treatment for non-severe depression, with medication used only in cases where CBT had failed. Therapists complained that the data does not fully support the attention and funding CBT receives. Psychotherapist and professor Andrew Samuels stated that this constitutes "a coup, a power play by a community that has suddenly found itself on the brink of corralling an enormous amount of money ... Everyone has been seduced by CBT's apparent cheapness." The UK Council for Psychotherapy issued a press release in 2012 saying that the IAPT's policies were undermining traditional psychotherapy and criticized proposals that would limit some approved therapies to CBT, claiming that they restricted patients to "a watered-down version of cognitive behavioural therapy (CBT), often delivered by very lightly trained staff". == References == == Further reading == == External links == Association for Behavioral and Cognitive Therapies (ABCT) British Association for Behavioural and Cognitive Psychotherapies National Association of Cognitive-Behavioral Therapists International Association of Cognitive Psychotherapy Information on Research-based CBT Treatments	Wikipedia/Cognitive_behavioural_therapy
Management of ulcerative colitis involves first treating the acute symptoms of the disease, then maintaining remission. Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset which often leads to anaemia. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine. == Medications == Standard treatment for ulcerative colitis depends on extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse of the disease. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing a remission which involves relief of symptoms and mucosal healing of the lining of the colon and then longer-term treatment to maintain the remission. Anaemia, caused by both chronic blood loss from the gastrointestinal tract and reduced absorption due to the up-regulation of hepcidin should also be treated, and this often requires the use of parenteral iron. The following sections are sorted first by drug type and, second, by the type of ulcerative colitis: === Aminosalicylates === Aminosalicylates are the main anti-inflammatory drugs used to treat ulcerative colitis. Sometimes remission can be achieved, or at least maintained, with these drugs alone. If not, they are usually used in combination with the drugs listed in the ensuing sections. The anti-inflammatory action in all these drugs is produced by 5-aminosalicylic acid (5-ASA), the active ingredient in Mesalazine. 5-ASA is produced from the other drugs in the intestine. The aminosalicylates used to treat ulcerative colitis include the following: Mesalazine, also known as 5-aminosalicylic acid, mesalamine, or 5-ASA. Brand names include: Asacol, Octasa, Pentasa, Salofalk, Lialda, Ipocol, Apriso, and Mezavant. Sulfasalazine, also known as Azulfidine. This drug is in a traditional class of antibiotics, but decomposes in the intestine, releasing 5-ASA. Balsalazide, also known as Colazal, intended to release 5-ASA only in the large intestine. Olsalazine, also known as Dipentum, intended to release 5-ASA only in the large intestine. 5-ASA is poorly-absorbed by the intestines, and hence provides topical relief within the intestine. It is therefore a non-systemic drug. 5-ASA is related to the systemic non-steroidal anti-inflammatory drugs (NSAIDs), such as Aspirin and Ibuprofen. The free radical induction theory, discussed below, proposes that 5-ASA is serving not just as an anti-inflammatory agent, but also as a free radical trap, destroying the hydroxyl and other radicals that may damage colonic epithelial barrier. 5-ASA may also be an inhibitor of TNF. ==== Sulfasalazine side-effects ==== Possible side effects of 5-ASA include, nausea and vomiting, reduced sperm count and damage to red or white blood cells, or to the liver, kidneys, pancreas, nerves or hearing. Allergic reactions to sulfasalazine characterized by dizziness, fever and skin rash have been reported in a small percentage of patients. In some cases, sulfasalazine can exacerbate ulcerative colitis resulting in diarrhea, abdominal cramps and discomfort. In the intestine sulfasalazine is converted to 5-ASA and sulfapyridine, which is responsible for some of its side-effects, and which should be monitored in patients taking sulfasalazine. Sulfapyridine levels above 50 μg/L are associated with the side-effects. Patients on high dose sulfasalazine require folic supplementation (1 mg/day) (1000 μg/day) to maintain normal cell division. This may, however, be counter-productive for patients who are also taking methotrexate, which is a folic acid inhibitor. Folic acid might also be counter-productive for patients taking 6-MP and related drugs that inhibit all cell division. === Corticosteroids === It is often necessary to use corticosteroids in conjunction with 5-ASA drugs to bring about remission of ulcerative colitis. Thereafter it may be possible to maintain remission with 5-ASAs alone, though many patients require other, stronger immunosuppressive medications. Corticosteroids should not be used for long-term therapy of UC, particularly without the concomitant use of an immunomodulator or anti-TNF. Corticosteroids reduce inflammation by blocking portions of the leukocyte adhesion cascade which results in inflammation. Side effects of corticosteroids include Cushing's syndrome, which most often exhibits itself as temporary facial puffiness, called "moon face". Cushing's syndrome can, however, involve psychosis, including manic behavior. These drugs have been known to trigger bipolar disorder. In prescribing these drugs it might be well to inquire as to any family history of bipolar disorder. Corticosteroids should not be confused with anabolic steroids, the controversial performance-building "steroids" that are banned in certain sports. The following corticosteroids are used as immune system suppressants in treatment of ulcerative colitis: Cortisone Prednisone Hydrocortisone Methylprednisolone Budesonide, also known as Entocort, available for oral use or as an enema. Budesonide is metabolized faster than traditional steroids and appears to produce fewer systemic side effects. === Immunosuppressive drugs === Immunosuppressive drugs inhibit the immune system generally. These include the cytostatic drugs that inhibit cell division, including the cloning of white blood cells that is a part of the immune response. Immunosuppressive drugs used with ulcerative colitis include: Mercaptopurine, also known as 6-Mercaptopurine, 6-MP and Purinethiol. Azathioprine, also known as Imuran (US) or Azasan, which metabolises to 6-MP. Methotrexate, which inhibits folic acid. Mercaptopurine is a cytostatic drug that is an antimetabolite. The mercaptopurine molecule mimics purine, which is necessary for the synthesis of DNA. With mercaptopurine present, cells are not able to make DNA, and cell division is inhibited. In administering mercaptopurine it is necessary to monitor the levels of mercaptopurine metabolites in the blood to establish the correct dosage for a patient. An initial concern is hepatotoxicity. Mercaptopurine inhibits the production of white blood cells generally. Because this makes the body more susceptible to infection, patients need to watch for infections. Vaccinations are critically important, particularly the yearly flu shot and periodic pneumonia immunizations. Vaccine response is best if given prior to initiation of immunosuppressive medications, and patients on immunosuppressives should use caution when receiving vaccines containing live virus. Frequent blood cell counts are also recommended during administration of mercaptopurine. The drug may be toxic to bone marrow, where many blood components are made. If there is an abnormally large drop in white blood cell count, or any blood cell count, administration of the drug should be halted at least temporarily. Methotrexate is another immunosuppressive drug. It works by inhibiting folic acid, which is necessary for DNA replication and, therefore, cell division. === TNF inhibitors === TNF is a protein that is released by activated white blood cells, triggering more inflammation, an immune system response and more damage to the mucosa of the colon because of the immune activation. Certain drugs inhibit TNF, hence reducing inflammation and immune system involvement. Infliximab was approved by the FDA for treating ulcerative colitis in March 2005. It is usually given as an intravenous infusions at weeks 0,2 and 6 and then every eight weeks thereafter. It is very useful for inducing and maintaining a remission of ulcerative colitis. Infliximab works better when used in combination with immunmodulators such as 6-mercaptopurine or azathioprine, but a corresponding increase in adverse events means that the decision to use one drug or two must be based on an individualized discussion between the patient and their doctor. Infliximab and its biosimilar agents Humira and its biosimilar agents == Treatment of complications == === Proctitis === Proctitis is an inflammation of the anus and the lining of the rectum, usually involving the distal, or lower, 10–15 cm (3.9–5.9 in) of the colon, including the rectum. Approximately 30% of ulcerative colitis patients initially present with proctitis. Standard treatment for active disease includes Mesalazine suppositories and cortisone foam (Cortifoam). Mesalazine 1 g SUPP QHS or Cortifoam QHS/BID is continued until remission, with response seen usually within three weeks. Maintenance therapy is with Mesalazine 1g QHS or Q3HS. Those with anal irritation or discomfort from the suppositories may switch to oral medications, such as sulfasalazine, Mesalazine, or Colazol, although they are not as effective as suppositories for proctitis. Maintenance therapy is not recommended for those with a first episode that responded to the Mesalazine. Steroid foam is not shown to prevent relapse. Systemic steroids such as prednisone are not used unless proctitis fails to respond to the above treatments. === Proctosigmoiditis and left-sided colitis === Proctosigmoiditis and left-sided colitis involves the lower colon, from the rectum up the left side of the patient. Patients often respond to topical agents alone, such as Mesalazine, or hydrocortisone enemas. Again, the Mesalazine is preferred for maintenance therapy. Initially a 4 g Mesalazine enema (Rowasa) is given nightly. If response is seen, the enemas can be tapered to every third night. If no response, a morning Mesalazine, or hydrocortisone enema (Cortenema) can be given. If still no response, oral anti-inflammatory drugs, with or without enemas, can be given, such as sulfasalazine, Mesalazine (Asacol, Pentasa), olsalazine (Dipentum), or balsalazide (Colazal). If still no response, dose should be increased to maximum: sulfasalazine maxes at 4-6 g/day, Mesalazine maxes at 4.8 g/day, and olsalazine at 3 g/day. They are usually divided tid or bid. Oral anti-inflammatory drugs require four to six weeks to work. Once remission is induced, maintenance levels can be used: sulfasalazine 2 g/day, mesalamine 1.2-2.4 g/day, or olsalazine 1 g/day. Patients on high dose sulfasalazine require folic supplementation (1 mg/day) because it inhibits folate absorption. If oral Mesalazine is still not working, prednisone is often given, starting at 40–60 mg/day. Prednisone often takes effect within 10–14 days. The dose should then be tapered by about 5 mg/week until it can be stopped altogether. === Extensive or pancolitis === Extensive or pancolitis. Patients usually require a combination of oral Mesalazine or sulfasalazine along with topical Mesalazine or steroid enemas. Oral prednisone (40–60 mg/day) should be given only in severe cases or if oral Mesalazine fails. Once remission is induced, maintenance therapy is with standard oral Mesalazine doses. Supplemental iron (ferrous sulfate or ferrous gluconate) may be given due to chronic blood loss. Loperamide may be given for symptomatic relief of chronic diarrhea, but should not be given in suspected toxic megacolon. === Severe or fulminant colitis === Severe or fulminant colitis. Patients need to be hospitalized immediately with subsequent bowel rest, nutrition, and IV steroids. Typical starting choices are hydrocortisone 100 mg IV q8h, prednisolone 30 mg IV q12h, or methylprednisolone 16–20 mg IV q8h. The last two are preferred due to less sodium retention and potassium wasting. 24-hour continuous infusion is preferred than the stated dosing. If the patient has not had any corticosteroids within the last 30 days, IV ACTH 120 units/day as continuous infusion is superior than the IV steroids mentioned above. In either case, if symptoms persist after 2–3 days, Mesalazine or hydrocortisone enemas daily or bid can be given. The use of antibiotics in those with severe colitis is not clear. However, there are those patients who have sub-optimal response to corticosteroids and continue to run a low grade fever with bandemia. Typically they can be treated with IV ciprofloxacin and metronidazole. However, in those with fulminant colitis or megacolon, with high fever, leukocytosis with high bandemia, and peritoneal signs, broad spectrum antibiotics should be given (i.e., ceftazidime, cefepime, imipeneum, meropenem, etc.). Abdominal x-ray should also be ordered. If intestinal dilation is seen, patients should be decompressed with NG tube and or rectal tube. === Refractory ulcerative colitis === Refractory ulcerative colitis. Patients with toxic megacolon (colonic dilation > 6 cm and toxic appearing) who do not respond to steroid therapy within 72 hours should be consulted for colectomy. Those with less severe disease but do not respond to IV steroids within 7–10 days should be considered for colectomy or IV cyclosporine. IV cyclosporine at a rate of 2 mg/kg/day and if no response in 7–10 days, colectomy should be considered. If response is seen, oral cyclosporine at 8 mg/kg/day should be continued for 3–4 months while 6-MP or azathioprine is introduced. Those already on 6-MP or azathioprine should continue with these medications. A cholesterol level should be checked in patients taking cyclosporine as low cholesterol may predispose to seizures. Also, prophylaxis against PCP (Pneumocystis carinii) pneumonia is advised. == Surgery == Unlike Crohn's disease, which cannot be cured/eliminated by surgically removing the diseased portions of the intestine and reconnecting the healthy ends, ulcerative colitis can generally be cured by surgical removal of the large intestine. Surgical removal of the large intestine will not get rid of extra-intestinal symptoms. This procedure is necessary in the event of exsanguinating hemorrhage, frank perforation, or documented or strongly suspected carcinoma. Surgery is also indicated for patients with severe colitis or toxic megacolon. Patients with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life. Depending on the type of surgery performed, the patient may still require periodic lower endoscopies to assess the pouch for dysplasia. Ulcerative colitis is a disease that affects many parts of the body outside the intestinal tract. In rare cases the extra-intestinal manifestations of the disease may require removal of the colon. == Microbiome modification == A Cochrane review of controlled trials using various probiotics found low-certainty evidence that probiotic supplements may increase the probability of clinical remission. People receiving probiotics were 73% more likely to experience disease remission and over 2x as likely to report improvement in symptoms compared to those receiving a placebo, with no clear difference in minor or serious adverse effects. Although there was no clear evidence of greater remission when probiotic supplements were compared with 5‐aminosalicylic acid treatment as a monotherapy, the likelihood of remission was 22% higher if probiotics were used in combination with 5-aminosalicylic acid therapy. It is currently unclear whether probiotics help to prevent future relapse in people with stable disease activity, either as a monotherapy or combination therapy. == Alternative treatments == === Dietary modification === There is no good evidence that dietary interventions have any impact on ulcerative colitis. === Fats and oils === Fish oil, eicosapentaenoic acid (EPA) is not conclusive. Slow release phosphatidylcholine has some evidence of benefit in ulcerative colitis. === Antioxidants === The free radical induction theory suggests that the initial cause of ulcerative colitis may be a metabolic defect that allows a buildup of chemicals related to hydrogen peroxide beneath the membrane that protects the cells of the intestinal wall from the bacteria inside the intestine, resulting in destruction of the membrane. During remission the membrane is reestablished, but may be subject to new damage, resulting in a flare up of the disease. To the extent this may be true, it would be appropriate to take antioxidants, dietary supplements that may support the body's defenses against oxidants like hydrogen peroxide. Antioxidants include: Vitamins A, C and E Coenzyme Q10 Selenium and manganese. Vitamin B6 and iron may be associated with increased hydrogen peroxide levels, and should not be taken in excess under this theory. S-Methylmethionine has been shown in animal models to reverse ulcers. === Helminthic therapy === Inflammatory bowel disease is less common in the developing world and it has been suggested that this may be because intestinal parasites are more common in underdeveloped countries. Some parasites are able to reduce the immune response of the intestine, an adaptation that helps the parasite colonize the intestine. A decrease in immune response could be helpful in inflammatory bowel disease. Helminthic therapy using the whipworm Trichuris suis was shown in a randomized control trial to produce benefit in patients with ulcerative colitis. This therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of patients in the western world may lead to inflammation. Both helminthic therapy and fecal bacteriotherapy induce a characteristic Th2 white cell response in the diseased areas, which is somewhat paradoxical given that ulcerative colitis immunology was thought to classically involve Th2 overproduction. == References ==	Wikipedia/Treatment_of_ulcerative_colitis
The Crohn's Disease Activity Index or CDAI is a research tool used to quantify the symptoms of patients with Crohn's disease. This is of useful importance in research studies done on medications used to treat Crohn's disease; most major studies on newer medications use the CDAI in order to define response or remission of disease. As Crohn's disease is a disease with a variety of symptoms that affect quality of life, the quantification of symptoms may be of secondary importance to a quantitative assessment of the effect on quality of life. This has been addressed by the Inflammatory Bowel Disease Questionnaire (IBDQ) and other indices of quality of life for patients with Crohn's disease. == Components of the index == The CDAI was developed by WR Best and colleagues from the Midwest Regional Health Center in Illinois, in 1976. It consists of eight factors, each summed after adjustment with a weighting factor. The components and weighting factors are the following: *One point each is added for each set of complications: the presence of joint pains (arthralgia) or frank arthritis inflammation of the iris or uveitis presence of erythema nodosum, pyoderma gangrenosum, or aphthous ulcers anal fissures, fistulae or abscesses other fistulae fever during the previous week. Remission of Crohn's disease is defined as CDAI below 150. Severe disease was defined as a value of greater than 450. Most major research studies on medications in Crohn's disease define response as a fall of the CDAI of greater than 70 points. == Harvey-Bradshaw index == The Harvey-Bradshaw index was devised in 1980 as a simpler version of the CDAI for data collection purposes. It consists of only clinical parameters: general well-being (0 = very well, 1 = slightly below average, 2 = poor, 3 = very poor, 4 = terrible) abdominal pain (0 = none, 1 = mild, 2 = moderate, 3 = severe) number of liquid stools per day abdominal mass (0 = none, 1 = dubious, 2 = definite, 3 = tender) complications, as above, with one point for each. A score of less than 5 is generally considered to represent clinical remission. A Simple Index of Crohn's disease activity has also been developed. == Validation of the CDAI == While the CDAI is considered to be the gold standard for assessing disease activity in Crohn's disease, validation of the index has been varied. A key criticism of the CDAI is that it does not incorporate a subjective assessment of quality of life, endoscopic factors, or systemic features, such as fatigue into its calculation. The CDAI correlated well with protein loss in the bowel in patients with protein losing enteropathy. == Inflammatory Bowel Disease Questionnaire == As most symptoms of Crohn's disease broadly affect quality of life, attempts have been made to incorporate physical, social, and emotional performance characteristics into tests for severity of Crohn's disease. The Inflammatory Bowel Disease Questionnaire (IBDQ) was developed to incorporate elements of social, systemic and emotional symptoms, as well as bowel related symptoms into an activity index. In a study of 305 patients in Ontario, the IBDQ was found to correlate well with the CDAI in assessing disease activity, but had the added benefit of being a more robust tool for determining the effect of symptoms on perceived quality of life. == References ==	Wikipedia/Crohn's_Disease_Activity_Index
Metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a type of chronic liver disease. This condition is diagnosed when there is excessive fat build-up in the liver (hepatic steatosis), and at least one metabolic risk factor. When there is also increased alcohol intake, the term MetALD, or metabolic dysfunction and alcohol associated/related liver disease is used, and differentiated from alcohol-related liver disease (ALD) where alcohol is the predominant cause of the steatotic liver disease. The terms non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH, now MASH) have been used to describe different severities, the latter indicating the presence of further liver inflammation. NAFL is less dangerous than NASH and usually does not progress to it, but this progression may eventually lead to complications, such as cirrhosis, liver cancer, liver failure, and cardiovascular disease. Obesity and type 2 diabetes are strong risk factors for MASLD. Other risks include being overweight, metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum HDL cholesterol), a diet high in fructose, and older age. Obtaining a sample of the liver after excluding other potential causes of fatty liver can confirm the diagnosis. Treatment for MASLD is weight loss by dietary changes and exercise; bariatric surgery can improve or resolve severe cases. There is some evidence for SGLT-2 inhibitors, GLP-1 agonists, pioglitazone, and vitamin E in the treatment of MASLD. In March 2024, resmetirom was the first drug approved by the FDA for MASH. Those with MASH have a 2.6% increased risk of dying per year. MASLD is the most common liver disorder in the world; about 25% of people have it. It is very common in developed nations, such as the United States, and affected about 75 to 100 million Americans in 2017. Over 90% of obese, 60% of diabetic, and up to 20% of normal-weight people develop MASLD. MASLD was the leading cause of chronic liver disease and the second most common reason for liver transplantation in the United States and Europe in 2017. MASLD affects about 20 to 25% of people in Europe. In the United States, estimates suggest that 30% to 40% of adults have MASLD, and about 3% to 12% of adults have MASH. The annual economic burden was about US$103 billion in the United States in 2016. == Definition == An abnormal accumulation of fat in the liver in the absence of secondary causes of fatty liver, such as significant alcohol use, viral hepatitis, or medications that can induce fatty liver, was the definition of NAFLD. However, the term MASLD accepts there may be other conditions present, but focuses on the metabolic abnormalities contributing to the disorder. MASLD encompasses a continuum of liver abnormalities, from metabolic dysfunction–associated steatotic liver (MASL, simple steatosis) to Metabolic dysfunction-associated steatohepatitis (MASH). These diseases begin with fatty accumulation in the liver (hepatic steatosis). A liver can remain fatty without disturbing liver function (MASL), but by various mechanisms and possible insults to the liver, it may also progress into steatohepatitis (MASH), a state in which steatosis is combined with inflammation and sometimes fibrosis. MASH can then lead to complications such as cirrhosis and hepatocellular carcinoma. The new name, metabolic dysfunction-associated steatotic liver disease (MASLD), was proposed after 70% of a panel of experts expressed support for this name. This new name was adopted in 2023. == Signs and symptoms == People with MASLD often have no noticeable symptoms, and it is often only detected during routine blood tests or unrelated abdominal imaging or liver biopsy. In some cases, it can cause symptoms related to liver dysfunction such as fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild yellow discoloration of the skin may occur, although this is rare. MASH can severely impair liver function, leading to cirrhosis, liver failure, and liver cancer. === Comorbidities === The condition is strongly associated with or caused by type 2 diabetes, insulin resistance, and metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein). It is also associated with hormonal disorders (panhypopituitarism, hypothyroidism, hypogonadism, polycystic ovary syndrome), persistently elevated transaminases, increasing age, and hypoxia caused by obstructive sleep apnea; some of these conditions predict disease progression. Most normal-weight people with MASLD ("lean MASLD") have impaired insulin sensitivity, are sedentary, and have increased cardiovascular disease risk and increased liver lipid levels. These are the consequences of a decreased capacity for storing fat and reduced mitochondrial function in fat and increased hepatic de novo lipogenesis. A recent systematic review reported an increased risk of severe COVID-19 infection in MASLD patients, but no difference in mortality was observed between MASLD and non-MASLD patients. == Risk factors == === Genetics === Two-thirds of families with a history of diabetes type 2 report more than one family member having MASLD. There is a higher risk of fibrosis for family members where someone was diagnosed with MASH. Asian populations are more susceptible to metabolic syndrome and MASLD than their western counterparts. Hispanic persons have a higher prevalence of MASLD than white individuals, whereas the lowest prevalence is observed in black individuals. MASLD is twice as prevalent in men as in women, which might be explained by lower levels of estrogen in men. Genetic variations in two genes are associated with MASLD: non-synonymous single-nucleotide polymorphisms (SNPs) in PNPLA3 and TM6SF2. Both correlate with MASLD presence and severity, but their roles for diagnosis remain unclear. Although NAFLD has a genetic component, the American Association for the Study of Liver Diseases (AASLD) does not recommend screening family members as there is not enough confirmation of heritability, although there is some evidence from familial aggregation and twin studies. === From diet === According to the Asia-Pacific Working Group (APWG) on MASLD, overnutrition is a major factor of MASLD and MASH, particularly for lean MASLD. Diet composition and quantity, in particular omega-6 fatty acid and fructose, have important roles in disease progression from MASL to MASH and fibrosis. Choline deficiency can lead to the development of MASLD. Higher consumption of processed, red, and organ meats have been associated with higher risk of developing MASLD. Some research also suggests eggs are also associated with developing MASLD. On the other hand, studies have found healthful plant foods such as legumes and nuts, to be associated with a lower risk of developing MASLD. Two different studies have found healthy plant-based diets rich in healthy plant foods and low in animal foods to be associated with a lower risk of developing MASLD, even after adjusting for BMI. === From lifestyle === Habitual snoring may be a risk factor for MASLD. Severe snoring often signals the presence of obstructive sleep apnea (OSAS), a much more serious breathing condition. Blockage or narrowing of the airways, even temporarily, can cause the body to experience lowered oxygen levels in the blood. This in turn may cause a variety of changes within the body such as tissue inflammation, increased insulin resistance, and liver injury. A prospective cohort study found the association between habitual snoring and MASLD development to be significant, and the trend was noted to be most prominent in lean individuals. == Pathophysiology == The primary characteristic of MASLD is the accumulation of lipids in the liver, largely in the form of triglycerides. However, the mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to liver dysfunction are complex and incompletely understood. MASLD can include steatosis along with varied signs of liver injury: either lobular or portal inflammation (a form of liver injury) or ballooning degeneration. Similarly, NASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, megamitochondria, and perisinusoidal fibrosis. Hepatocyte death via apoptosis or necroptosis is increased in MASH compared with simple steatosis, and inflammation is a hallmark of MASH. The degree of inflammation can be correlated to the number of inflammatory foci. Various definitions exist for an inflammatory focus, but one defines it as the presence of more than four mononuclear cells in close proximity inside the hepatic parenchyma. One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends the second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence NAFLD and NASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the NAFLD pathology. Many researchers describe NAFLD as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than the liver. The accumulation of senescent cells in the liver is seen in persons with NAFLD. In mice, liver senescent hepatocytes result in increased liver fat deposition. Treatment of NAFLD mice with senolytic agents has been shown to reduce hepatic steatosis. Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting the progression of NASH. === Fructose consumption === Non-alcoholic and alcoholic fatty liver disease share similar histological features, which suggests that they might share common pathogenic pathways. Fructose can cause liver inflammation and addiction similarly to ethanol by using similar metabolic pathways, unlike glucose. Therefore, some researchers argue that non-alcoholic and alcoholic fatty liver diseases are more alike than previously thought. Furthermore, high fructose consumption promotes fat accumulation in the liver by stimulating de novo lipogenesis in the liver and reducing the beta-oxidation of fat. Unlike the sugar glucose, the enzyme fructokinase rapidly metabolizes fructose. This leads to a decreased level of intracellular adenosine triphosphate (ATP). The decrease in ATP increases oxidative stress and impairments in proper protein synthesis and mitochondrial function in the liver. === Insulin resistance === Insulin resistance contributes to the accumulation of toxic fat in the liver in several ways. First, it promotes the release of free fatty acids (FFAs) from adipose tissue into the blood. Typically, adipose tissue stores lipids in the form of triglycerides, slowly releasing them into the bloodstream when insulin is low. In insulin-resistant adipose tissue, such as in people with obesity and type 2 diabetes, more triglycerides are broken down into FFAs and released into the bloodstream, promoting uptake by the liver. Second, insulin promotes the production of new FFAs in the liver via de novo lipogenesis; this production of liver fats continues to be stimulated by insulin, even when other tissues are insulin-resistant. These FFAs are combined back into triglycerides in the liver, forming the major constituent of the accumulated fat in the liver. The three sources of free fatty acids that contribute to liver triglyceride accumulation include FFAs circulating in the bloodstream (59%), FFAs derived from carbohydrates such as fructose and glucose (26%), and diet (14%). Despite the accumulation of triglycerides in the liver, they are not directly toxic to liver tissue. Instead, alteration of the profile of the other lipid subtypes present in the liver, such as diacylglycerols, phospholipids, ceramides, and free cholesterol, have a more significant role in the pathogenesis of MASLD. Once MASLD progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and liver, which results in a harmful cycle of insulin resistance, liver fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with NAFLD. Adiponectin has several properties that protect the liver. These properties include improved liver fat metabolism, decreased de novo lipogenesis, decreased glucose production in the liver, anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in MASLD. Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes the redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the liver. === Dysbiosis === Disruptions in the intestinal microbiota seem to influence NAFLD risk in several ways. People with NASH can have elevated levels of blood ethanol and Pseudomonadota (which produce alcohol), with dysbiosis proposed as a mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence NAFLD risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased liver exposure to harmful substances (e.g., translocated bacteria, bacterial toxins, and inflammatory chemical signals). The increased transport of these harmful substances to the liver promotes liver inflammation, enhances nutrient and calorie absorption, and alters choline metabolism. Higher levels of intestinal bacteria that produce butyrate may be protective. Excessive macronutrient intake contributes to gut inflammation and perturbation of homeostasis, and micronutrients may also be involved. In addition to reducing weight and risk factors, lifestyle changes may prompt positive changes in the gut microbiota. In particular, diet diversity may play a role that was overlooked in animal studies, since they often compare a Western high-fat, low-diversity diet against a low-fat but higher-diversity chow. The health benefits after bariatric surgery may also involve changes in the gut microbiota by increasing gut permeability. == Diagnosis == NAFLD was defined by the presence of excess fat in the liver that cannot be explained by another factor, such as excessive alcohol use (>21 standard drinks/week for men and >14 for women in the USA; >30 g daily for men and >20 g for women in UK and EU, >140 g/week for men and >70 g/week for women in Asia-Pacific), liver injury caused by drugs or toxins or viruses, nutritional deficiency, or endocrine conditions. In practice, diagnosis was often made simply based on the clinical presentation and a lack of high-volume alcohol consumption reported by the patient, but this is an unreliable method of diagnosis. NAFLD comprises two histological categories: NAFL, and the more aggressive form NASH. The presence of at least 5% fatty liver is common to both NAFL and NASH, but the features of substantial lobular inflammation and hepatocyte injuries such as ballooning or Mallory hyaline only occur in NASH. The majority of NAFL cases show minimal or no inflammation. Pericentral and perisinusoidal fibrosis occur more often in adult-onset NASH, whereas portal fibrosis is more common in children with the disorder. NASH represents a more advanced stage of NAFL and is associated with poor outcomes such as cardiovascular events, cirrhosis, or hepatocellular carcinoma. ICD-11 does not use the term NAFL as it was deemed confusing with the family of disorders NAFLD. The preferred descriptions are instead: NAFLD without NASH or simple steatosis and "NASH". Also, the modifier with or without fibrosis or cirrhosis completes the diagnostic description. Following the renaming of NAFLD to MASLD, these definitions are being updated. === Blood tests === Liver function tests may be abnormal, but they often remain within the normal range even in advanced disease. Other blood tests that may be useful to confirm the diagnosis include erythrocyte sedimentation rate, serum glucose, and albumin. Because the liver is important for making proteins used in blood clotting, coagulation-related studies are often carried out, especially the prothrombin time. In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out certain types of viral hepatitis and autoimmune diseases. Low thyroid activity is more prevalent in people with NASH, which would be detected by determining the thyroid-stimulating hormone. Some biomarker-based blood tests have been developed and may be useful for diagnosis. Although blood tests cannot diagnose MASLD, circulating serum biomarkers of liver fibrosis can give moderate estimates in the diagnosis of liver fibrosis and cirrhosis. The ratio of the transaminase liver enzyme aspartate aminotransferase (AST) to platelets in the blood, known as the AST/platelet ratio index (APRI score), and Fibrotest are recommended as the preferred noninvasive tests for cirrhosis by the Asian-Pacific Association for Study of the Liver (APASL). Several other scores such as FIB-4 score and NAFLD fibrosis score can also reflect the burden of the fibrosis in the liver, and previous studies have confirmed that these scores can predict future development of mortality and liver cancer. === Imaging === A liver ultrasound scan or magnetic resonance imaging (MRI) can diagnose steatosis, but not fibrosis, and confirmation of early cirrhosis detection by ultrasound by other diagnostic methods is recommended. The European Association for the Study of the Liver (EASL) recommends screening for steatosis whenever NAFLD is suspected as this is a strong predictor of the disease evolution and predicts future type 2 diabetes, cardiovascular events, and hypertension. These non-invasive methods can be used for NAFLD screening but are not accepted as a substitute for liver biopsy in NAFLD nor NASH clinical trials, as only a liver biopsy can define liver pathology. Ultrasound presented average sensitivity and specificity for diagnosing the disease in children, while in the adult population, sensitivity and specificity were significantly higher. Proton density fat fraction magnetic resonance imaging has been increasingly used for the diagnosis of steatosis in pediatric patients. Ultrasound elastography is an effective tool for staging liver fibrosis and discriminating NASH in children. Computerized tomography and magnetic resonance imaging are more accurate in detecting cirrhosis than conventional ultrasound. Transient elastography is recommended for the initial assessment of liver fibrosis and cirrhosis and helps to predict complications and prognosis, but the interpretation of results is carefully weighed in the presence of limiting factors such as steatosis, high BMI, low amount of hepatic fibrosis, narrow spaces between the ribs, and portal hypertension. Transient elastography is not a substitute for liver biopsy. Magnetic resonance elastography (MRE) is an established method that can accurately assess hepatic fibrosis and is recommended by the APASL, AGA, ACR and AASLD. MRE possesses excellent accuracy to detect fibrosis in NAFLD regardless of BMI and inflammation, and is suggested as a more reliable alternative to diagnose NAFLD and its progression to NASH compared to ultrasound and blood tests. === Liver biopsy === A liver biopsy (tissue examination) is the only test widely accepted (gold standard) as definitively diagnosing and distinguishing NAFLD (including NAFL and NASH) from other forms of liver disease and can be used to assess the severity of the inflammation and resultant fibrosis. However, since most people affected by NAFLD are likely to be asymptomatic, liver biopsy presents too high a risk for routine diagnosis, so other methods are preferred, such as liver ultrasonography or liver MRI. For young people, guidelines recommend liver ultrasonography, but biopsy remains the best evidence. Liver biopsy is also the gold standard to detect hepatic fibrosis and assess its progression. Routine liver function blood tests are not sensitive enough to detect MASLD, and biopsy is the only procedure that can reliably differentiate NAFL from NASH. There are several liver biopsy techniques available to obtain liver tissue. Percutaneous liver biopsy remains the most common practice. Biopsies can also be performed via the transvenous route, either during surgery or by laparoscopy, especially for people with contraindications to a percutaneous approach. The liver biopsy can also be image-guided, in real-time or not, which is recommended for some clinical situations such as people with known intra-hepatic lesions, previous intra-abdominal surgery who may have adhesions, a small liver that is difficult to percuss, obese people and people with evident ascites. Vital signs must be monitored frequently afterward (at least every 15 minutes in the hour following the biopsy). According to AASLD guidelines, a liver biopsy may be considered in people with NAFLD who are at increased risk of having steatohepatitis with or without advanced fibrosis, but only when all other competing chronic liver diseases are excluded (such as alcoholic liver disease). The presence of metabolic syndrome, NAFLD Fibrosis Score (FIB-4), or liver stiffness (as measured by Vibration-controlled transient elastography or MRE) can identify the individuals who are at higher risk of steatohepatitis or advanced fibrosis. The AASLD and ICD-11 consider that clinically useful pathology reporting distinguishes "between NAFL (steatosis), NAFL with inflammation and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning)" with the presence or absence of fibrosis being described and optionally comment on severity. The EASL recommends the Fatty Liver Inhibition of Progression (FLIP) algorithm to grade the ballooning and classify MASLD-associated liver injury, and the use of the NAFLD Activity Score (NAS) to grade the severity of NASH rather than for its diagnosis. They also consider the steatosis, activity, and fibrosis (SAF) score to be an accurate and reproducible scoring system. The AASLD recommends the use of the NAS scoring system with or without the SAF score if deemed appropriate. The Asia-Pacific Working Group disadvises the use of NAS, as it is considered uninformative for NAFLD and inappropriate to diagnose NASH. For liver fibrosis assessment, percutaneous liver biopsy, with or without image guidance, is contraindicated in uncooperative people. Transjugular liver biopsy is indicated for any person with diffuse liver disease who needs a biopsy but has a contraindication to percutaneous biopsy or needs a hemodynamic evaluation for diagnostic purposes. A transvenous liver biopsy is recommended instead of a percutaneous approach in people with clinically evident ascites, although percutaneous biopsy is an acceptable alternative approach after the removal of ascites. == Management == MASLD warrants treatment regardless of whether the affected person is overweight or not. MASLD is a preventable cause of death. Guidelines are available from the American Association for the Study of Liver Diseases (AASLD), American Association of Clinical Endocrinologists (AACE) National Institute for Health and Care Excellence (NICE), the European Association for the Study of the Liver (EASL), and the Asia-Pacific Working Party on NAFLD. === Lifestyle === Weight loss is the most effective treatment for MASLD and MASH. A loss of 5% to 10% body weight is recommended and has shown regression of liver damage, with 10% to 40% weight loss completely reversing MASH without cirrhosis. A weight loss of greater than 10% was associated with resolution of MASH in 90% of people in a biopsy based study. A structured weight loss program helps people with MASLD lose more weight compared with advice alone. This type of program also leads to improvements in NAFLD measured using blood tests, ultrasound, imaging, or liver biopsies. Although fibrosis improves with lifestyle interventions and weight loss, there is limited evidence for cirrhosis improvement. A combination of improved diet and exercise, rather than either alone, appears to best help manage NAFLD and reduce insulin resistance. Motivational support, such as with cognitive behavioral therapy, is helpful, as most people with MASLD do not perceive their condition as a disease, and thus have a low motivation to change. Higher-intensity behavioral weight loss therapies (diet and exercise combined) may produce more weight loss than lower-intensity ones. A 2019 systematic review suggested a change of guidelines to recommend these therapies for MASLD management. Weight loss is associated with improvements in biomarkers, MASLD grade, and reduced chances of NASH, but its effect on long-term health was not known. 2021 meta-analyses of trials over periods of 1 to 28 months found limited evidence to indicate that lifestyle modifications and nutritional supplementation have an effect on mortality, liver cirrhosis, liver decompensation, liver transplantation, and hepatocellular carcinoma in people with non-alcohol-related fatty liver disease; authors said that it was unlikely that differences in clinical outcomes would become apparent in trials with less than 5 years to 10 years of follow‐up, and that sample sizes needed to be much larger than had been used. === Diet === Treatment of NAFLD typically involves counseling to improve nutrition and calorie restriction. People with NAFLD can benefit from a moderate to low-carbohydrate diet and a low-fat diet. The Mediterranean diet also showed promising results in a 6-week study with a reduction of NASH induced inflammation and fibrosis, independently from weight loss. Tentative evidence supports dietary interventions in individuals with fatty liver who are not overweight. The EASL recommends energy restriction of 500–1000 kcal per week less than the normal daily diet, a target of 7–10% weight loss for obese/overweight MASLD, a low- to moderate-fat, and moderate- to high-carbohydrate diet, or a low-carbohydrate ketogenic or high-protein diet such as the Mediterranean diet, and avoiding all beverages and food containing fructose. Alcohol is an aggravating factor, and the AASLD recommends that people with NAFLD or NASH avoid alcohol consumption. The EASL allows alcohol consumption below 30g/day for men and 20g/day for women. The role of coffee consumption for NAFLD treatment is unclear though some studies indicate that regular coffee consumption may have protective effects. Herbal compounds such as silymarin (a milk thistle seed extract), curcumin, a turmeric extract, and green tea appear to improve NAFLD biomarkers and reduce the grade of NAFLD. Studies suggest an association between microscopic organisms that inhabit the gut (microbiota) and MASLD. Reviews reported the use of probiotics and synbiotics (combinations of probiotics and prebiotics) were associated with improvement in liver-specific markers of hepatic inflammation, measurements of liver stiffness, and steatosis in persons with MASLD. Vitamin E does not improve established liver fibrosis in those with MASLD but seems to improve certain markers of liver function and reduces inflammation and fattiness of the liver in some people with MASLD. The Asia-Pacific Work Group advises that Vitamin E may improve liver condition and aminotransferase levels, but only in adults without diabetes or cirrhosis who have NASH. The NICE guidelines recommend Vitamin E as an option for children and adults with NAFLD with advanced liver fibrosis, regardless of whether the person has diabetes mellitus. === Physical activity === Weight loss may improve MASLD and is recommended particularly for obese or overweight people; similar physical activities and diets are advisable for overweight people with MASLD as for other obese and overweight people. Although physical activity is less important for weight loss than dietary adaptations (to reduce caloric intake), the NICE advises physical activity to reduce liver fat even if there is no overall bodyweight reduction. Weight loss, through exercise or diet, is the most effective way to reduce liver fat and help NASH and fibrosis remission. Exercise alone can prevent or reduce hepatic steatosis, but it remains unknown whether it can improve all other aspects of the liver; hence a combined approach with diet and exercise is advised. Aerobic exercise may be more effective than resistance training, although there are contradictory results. Vigorous training is preferable to moderate training, as only the high-intensity exercise reduced the chances of MASLD developing into NASH or advanced fibrosis. The EASL recommends between 150 and 200 min/week in 3 to 5 sessions of moderate-intensity aerobic physical activity or resistance training. Since both effectively reduce liver fat, a pragmatic approach to the choice of physical activity that accounts for the individual's preferences for what they can maintain in the long-term is preferred. Any engagement in physical activity or increase over previous levels is better than remaining sedentary. === Medication === While many treatments appear to improve biochemical markers such as alanine transaminase levels, most do not reverse histological abnormalities or improve outcomes. Treatment with medications is primarily aimed at improving liver disease and is generally limited to those with biopsy-proven NASH and fibrosis. Insulin sensitizers (metformin and thiazolidinediones, such as pioglitazone) are not specifically recommended for MASLD as they do not directly improve the liver condition. They can be indicated for diabetic individuals, after a careful assessment of risks, to reduce insulin resistance and risks of complications. Indeed, the side effects associated with thiazolidinedione medications, which include osteopenia, increased fracture risk, fluid retention, congestive heart failure, bladder cancer, and long-term weight gain, have limited their adoption. Due to these side effects, the AASLD recommends the use of pioglitazone only for individuals with biopsy-proven NASH, and the Asia-Pacific Work Group recommends them only for individuals with MASLD with known diabetic issues. However, the AASLD advises against the use of metformin as studies were inconclusive about the improvement of the liver's histological condition. Although there was an improvement in insulin resistance and serum aminotransferases, this did not translate into NASH improvements. The NICE provides similar guidelines to the AASLD regarding pioglitazone and recommends it be administered in secondary care to adults with advanced liver fibrosis irrespective of whether or not they have diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1s) are at least as effective as pioglitazone and Vitamin E and significantly reduce steatosis, ballooning necrosis, lobular inflammation, and fibrosis according to a 2023 systematic review. Dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) agonists appear to be effective treatments; tirzepatide was more effective than placebo for resolution of MASH without worsening of fibrosis in patients with biopsy-confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis when given once-weekly for 52 weeks, while survodutide decreased liver fat content and improved fibrosis compared to placebo, although with more frequent adverse effects of nausea, diarrhea, and vomiting SGLT-2 inhibitors have also found success in some clinical trials, and proved more beneficial than GLP-1 agonists in the only head-to-head-trial completed as of 2024. Statin medications appear to improve liver histology and markers of liver biochemistry in people with MASLD. Since people with NAFLD are at a higher risk of cardiovascular disease, statin treatment is indicated. People with NAFLD are not at higher risk for serious liver injury from statins, according to AASLD and EASL. However, even if statins are safe to use in people with NASH cirrhosis, the AASLD suggests avoiding them in people with decompensated cirrhosis. Guidelines recommend statins to treat dyslipidemia for people with MASLD. According to NICE guidelines, statins can continue unless liver enzyme levels double within three months of starting statins. Treatment with pentoxifylline is not recommended. Omega-3 fatty acids may reduce liver fat and improve blood lipid profile but do not seem to improve liver histology (fibrosis, cirrhosis, cancer). The NICE does not recommend omega-3 fatty acid supplementation since randomized trials were inconclusive. Previous systematic reviews found that omega-3 fatty acid supplementation in those with NAFLD/NASH using doses of one gram daily or more (median dose four grams/day with median treatment duration six months) has been associated with improvements in liver fat. According to AASLD guidelines, "omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia for patients with NAFLD". Resmetirom (Rezdiffra) was approved for medical use in the United States in March 2024 for the treatment of noncirrhotic nonalcoholic steatohepatitis. Aspirin, 81 mg for 6 months, significantly reduced hepatic fat quantity compared with placebo among 40 randomized participants with MASLD in a 6-month, phase 2, randomized, double-blind clinical trial conducted at a single hospital in Boston, Massachusetts. In July 2024, two recent papers explore the metabolic effects of GLP-1 receptor agonists can be enhanced by combining them with other incretin hormones or molecules affecting complementary pathways. Two phase 2 trials reported by Loomba et al. and Sanyal et al. examined these enhanced treatments. Tirzepatide, which combines a GLP-1 receptor agonist and a glucose-dependent insulinotropic polypeptide receptor agonist, has synergistic effects on appetite, food intake, and metabolic function. Similarly, survodutide, a dual agonist of GLP-1 and glucagon receptors, promotes fat oxidation and reduces lipid synthesis in liver cells through its action on glucagon receptors. === Surgery === Bariatric surgery is an effective method for obese and diabetic individuals with MASLD to induce weight loss and reduce or resolve NASH inflammation, including fibrosis, and improve longevity. For the AASLD, bariatric surgery can be considered only for NASH on a case-by-case basis by an experienced bariatric surgery program. Indeed, some individuals might develop new or worsened features of MASLD. About 92% of people with MASLD saw an improvement in steatosis and 70% a complete resolution after bariatric surgery. A preoperative diet such as a low-calorie diet or a very-low-calorie diet is usually recommended to reduce liver volume by 16–20%. Preoperative weight loss is the only factor associated with postoperative weight loss. Preoperative weight loss can reduce operative time and hospital stay, although there is insufficient evidence whether preoperative weight loss reduces long-term morbidity or complications. Weight loss and decreases in liver size may be independent of the amount of calorie restriction. The APWG on MASLD recommends bariatric surgery as a treatment option for those with class II obesity (BMI >32.5 kg/m2 for Asians, 35 kg/m2 for Caucasians). They consider its effects on improving liver-related complications as unproven yet, but it effectively increases longevity by improving cardiovascular factors. Surgery carries more risks for individuals with NASH cirrhosis, with a review estimating overall morbidity to be 21%. For people with MASLD who have undifferentiated cirrhosis, the APWG recommends an investigation to determine the cause of the cirrhosis as well as the person's liver function and whether they have portal hypertension. === Screening === Cardiovascular system screening is considered mandatory by the EASL, as MASLD outcomes often result in cardiovascular complications, which can manifest as subclinical atherosclerosis, the cause of the majority of MASLD-related deaths. People with MASLD are at high risk for cardiovascular morbidity and mortality, and "aggressive modification of cardiovascular disease risk factors is warranted in all patients" according to AASLD. The AASLD further recommends for people with a cirrhotic NASH to be systematically screened for gastric and esophageal varices and liver cancer. They do not recommend routine liver biopsies and screening for liver cancer for non-cirrhotic people with NASH, but such screening sometimes occurs on a case-by-case basis. Also, people with MASLD may be considered for screening for hepatocellular carcinoma (liver cancer) and gastroesophageal varices. The NICE advises regular screening of NAFLD for advanced liver fibrosis every three years to adults and every two years for children using the enhanced liver fibrosis (ELF) blood test. Follow-up is recommended for people with obesity and insulin resistance using the homeostasis model assessment of insulin resistance (HOMA-IR). People with NASH with fibrosis and hypertension merit closer monitoring as there is a higher risk of disease progression. === Transplantation === MASLD is the second most common indication for liver transplantation in the US and Europe as of 2017. For people with NASH and end-stage liver disease, liver failure, or liver cancer, liver transplantation is an accepted procedure according to the EASL. People with NASH cirrhosis NASH who are being considered for a liver transplant warrant systematic evaluation for cardiovascular diseases (whether the symptoms are apparent or not). The overall survival is comparable to transplantation following other diseases. People with NASH cirrhosis who undergo liver transplantation are more likely to die post-transplant because of cardiovascular disease or chronic kidney disease. These people with NASH are often older and are thus more prone to these complications. For these reasons and others, individuals with morbid obesity (BMI ≥ 40 kg/m2) and NASH with cirrhosis may be considered unfit for liver transplantation until they follow lifestyle modifications to reduce bodyweight. Diabetic people with poor glycemic control are at similar risks, and optimal glycemic control is essential before attempting transplantation. The Asia Pacific Working Group guidelines recommend healthcare providers discuss lifestyle modifications before and after transplantation to reduce potential surgery risks and to assist with MASLD management after the transplant. Simultaneous bariatric surgery and liver transplantation were performed in exceptional circumstances. After transplantation, liver biopsy is the best method to monitor the evolution of post-transplant fibrosis, with significant fibrosis or portal hypertension one year after transplantation predicting rapid progression and graft loss and indicating the need for urgent intervention. == Prognosis == The average progression rate from one stage of liver fibrosis to the next in those with MASH is estimated to be seven years. The course of progression varies with different clinical manifestations among individuals. Fibrosis in those with MASH progressed more rapidly than in those with MASLD. The risk of cirrhosis, liver cancer, liver specific death and overall death is higher in those with MASH as compared to MASLD. All cause mortality in those with MASH is 25.5 deaths per 1000 person years, and liver specific mortality is 11.7 deaths per 1000 person years. In one study that examined people over 15 years, 11% of those with MASH developed cirrhosis as compared to less than 1% of people with MASLD. Other estimates have shown that MASLD and MASH were found to worsen with cirrhosis in respectively 2–3% and 15–20% of the people over a 10–20 year period. Obesity predicts a worse long-term outcome than for lean individuals. In the Asia-Pacific region, about 25% of MASLD cases progress to MASH under three years, but only a low proportion (3.7%) develop advanced liver fibrosis. An international study showed that people with MASLD with advanced fibrosis had a 10-year survival rate of 81.5%. MASLD is a risk factor for fibrosis, hypertension, chronic kidney disease, atrial fibrillation, myocardial infarction, ischemic stroke, and death from cardiovascular causes based on very-low to low-quality evidence from observational studies. Although MASLD can cause cirrhosis, liver failure and liver cancer, most deaths among people with MASLD are attributable to cardiovascular disease. According to a meta-analysis of 34,000 people with MASLD over seven years, these individuals have a 65% increased risk of developing fatal or nonfatal cardiovascular events when compared to those without MASLD. MASLD and MASH increase the risk of liver cancer. Cirrhosis and liver cancer induced by MASLD or MASH were the second cause of liver transplantation in the US in 2017, with MASLD or MASH expected to overtake alcohol related liver disease as the most common indication for a liver transplantation in the future. People with MASH cirrhosis have an increased risk of liver cancer. The rate of liver cancer associated with MASH increased fourfold between 2002 and 2012 in the US, which is more than any other cause of liver cancer. MASLD constitutes the third most common risk factor for liver cancer. Cirrhosis is found in only about 50% of people with MASLD and with liver cancer, so liver cancer may occur without cirrhosis being present. MASLD is a precursor of metabolic syndrome, although a bidirectional influence is possible. The presence and stage of fibrosis are the strongest prognostic factors for liver-related events and mortality, in particular for MASLD. == Epidemiology == MASLD incidence is rapidly rising, along with obesity and diabetes, and has become the most common cause of liver disease in developed countries, for adults, teenagers, and children. The percentage of people with MASLD ranges from 9 to 36.9% in different parts of the world. Approximately 20% of the United States and 25% of the Asia-Pacific populations have non-alcoholic fatty liver. Similar prevalence can be found in Europe, although less data is available. MASLD is the most common in the Middle East (32%) and South America (30%), while Africa has the lowest rates (13%). Compared to the 2000s, NAFL and NASH respectively increased 2-fold and 2.5-fold in the 2010s in the USA. MASLD and NASH are more prevalent in Hispanics - which can be attributed to high rates of obesity and type 2 diabetes in Hispanic populations, intermediate in Whites, and lowest in Blacks. NAFLD was observed to be twice as prevalent in men as women. For severely obese individuals, the prevalence of MASLD rises over 90%, and for those with diabetes, over 60%, and up to 20% for normal-weight people. MASLD is present in 65% to 90% of people who had bariatric surgery, and up to 75% of them have MASH. Ultrasonography and proton NMR spectroscopy studies suggest about 25% of the population seems to be affected by MASLD or MASH. Although the disease is commonly associated with obesity, a significant proportion of those affected are normal weight or lean. Lean MASLD affects between 10 and 20% of Americans and Europeans, and approximately 25% of Asians, although some countries have a higher incidence (e.g., India has a very high proportion of lean MASLD and almost no obese MASLD). PNPLA3 may be relevant for the progression of MASLD in lean people. Thus, people with MASLD deserve consideration for treatment regardless of the presence or absence of obesity. In children ages 1 to 19, the prevalence was found to be approximately 8% in the general population up to 34% in studies with data from child obesity clinics. The majority of cryptogenic cirrhosis is believed to be due to MASH. NAFLD prevalence is expected to increase steadily, from 25% in 2018 to a projected 33.5% of people with MASLD globally in 2030, and from 20% to a projected 27% of those with MASLD will progress to MASH. == History == The first acknowledged case of obesity-related non-alcoholic fatty liver was observed in 1952 by Samuel Zelman. Zelman started investigating after observing a fatty liver in a hospital employee who drank more than twenty bottles of Coca-Cola a day. He then went on to design a trial for a year and a half on 20 obese people who were not alcoholic, finding that about half of them had substantially fatty livers. Fatty liver was, however, linked to diabetes since at least 1784 — an observation picked up again in the 1930s. Studies in experimental animals implicated choline inadequacy in the 1920s and excess sugar consumption in 1949. The name "non-alcoholic steatohepatitis" (NASH) was later defined in 1980 by Jurgen Ludwig and his colleagues from the Mayo Clinic to raise awareness of the existence of this pathology, as similar reports previously were dismissed as "patients' lies". This paper was mostly ignored at the time but eventually came to be seen as a landmark paper, and starting in the mid-1990s, the condition began to be intensively studied, with a series of international meetings being held on the topic since 1998. The broader NAFLD term started to be used around 2002. Diagnostic criteria began to be worked out, and in 2005 the Pathology Committee of the NIH NASH Clinical Research Network proposed the NAS scoring system. == Society and culture == === Political recommendations === EASL recommends Europe's public health authorities to "restrict advertising and marketing of sugar-sweetened beverages and industrially processed foods high in saturated fat, sugar, and salt", as well as "fiscal measures to discourage the consumption of sugar-sweetened beverages and legislation to ensure that the food industry improves labeling and the composition of processed foods", as well as "public awareness campaigns on liver disease, highlighting that it is not only linked to excessive consumption of alcohol". === Media === In France, the French syndicate of non-alcoholic beverages "Boissons Rafraîchissantes de France" (that included soft drink producers such as Coca-Cola France, Orangina, PepsiCo France) was denounced by the French journal fr:Canard Enchainé for misleading consumers using a communication on their website titled "Better understanding the NASH pathology", explaining that "NASH pathology is sometimes called the soda illness by language abuse or an unfortunate semantic shortcut, as it is not directly linked to the consumption of non-alcoholic beverages". This page and others on the same website, such as one titled "Say no to disinformation," were since then removed. == Children == Pediatric MASLD was first reported in 1983. It is the most common chronic liver disease among children and adolescents since at least 2007, affecting 10 to 20% of them in the US in 2016. MASLD is associated with metabolic syndrome, which is a cluster of risk factors that contribute to the development of cardiovascular disease and type 2 diabetes mellitus. Studies have demonstrated that abdominal obesity and insulin resistance, in particular, are significant contributors to the development of NAFLD. Coexisting liver diseases, such as hepatitis C and cardiovascular diseases such as atherosclerosis, are also associated with an increased risk of NAFLD. Some children were diagnosed as early as two years old, with a mean age of diagnosis between 11 and 13 years old. The mean age is usually above 10 years, as children can also report non-specific symptoms and are thus difficult to diagnose for MASLD. Boys are more likely to be diagnosed with MASLD than girls. Overweight, or even weight gain, in childhood and adolescence, is associated with an increased risk of MASLD later in life, with adult MASLD predicted in a 31-year follow-up study by risk factors during childhood including BMI, plasma insulin levels, male sex, genetic background (PNPLA3 and TM6SF2 variants) and low birth weight, an emerging risk factor for adulthood MASLD. In a study, simple steatosis was present in up to 45% in children with a clinical suspicion of MASLD. Children with simple steatosis have a worse prognosis than adults, with significantly more of them progressing from NAFLD to NASH compared to adults. Indeed, 17-25% of children with MASLD develop MASH in general, and up to 83% for children with severe obesity (versus 29% for adults), further suggesting that hepatic fibrosis seems to follow a more aggressive clinical course in children compared to adults. Early diagnosis of MASLD in children may help prevent the development of liver disease during adulthood. This is challenging as most children with MASLD are asymptomatic, with only 42-59% showing abdominal pain. Other symptoms might be present, such as right upper quadrant pain or acanthosis nigricans, the latter of which is often present in children with NASH. An enlarged liver occurs in 30–40% of children with NAFLD. The AASLD recommends a diagnostic liver biopsy in children when the diagnosis is unclear or before starting a potentially hepatotoxic medical therapy. The EASL suggests using fibrosis tests such as elastography, acoustic radiation force impulse imaging, and serum biomarkers to reduce the number of biopsies. In follow up, NICE guidelines recommend that healthcare providers offer children regular MASLD screening for advanced liver fibrosis every two years using the enhanced liver fibrosis (ELF) blood test. Several studies also suggest magnetic resonance elastography as an alternative to the less reliable ultrasonography. Intensive lifestyle modifications, including physical activity and dietary changes, are the first line of treatment according to AASLD and EASL as it improves the liver histology and aminotransferase levels. In terms of pharmacological treatment, the AASLD and EASL do not recommend metformin, but vitamin E may improve liver health for some children. The NICE advises the use of vitamin E for children with advanced liver fibrosis, whether they have diabetes or not. The only treatment shown to be effective in childhood MASLD is weight loss. Some evidence indicates that maternal undernutrition or overnutrition increases a child's susceptibility to NASH and hastens its progression. == Research == === Diagnosis and biomarkers === Since a MASLD diagnosis based on a liver biopsy is invasive and makes it difficult to estimate epidemiology, it is a high research priority to find accurate, inexpensive, and noninvasive methods of diagnosing and monitoring MASLD disease and its progression. The search for these biomarkers of MASLD, NAFL, and NASH involves lipidomics, medical imaging, proteomics, blood tests, and scoring systems. According to a review, proton density fat fraction estimation by magnetic resonance imaging (MRI-PDFF) may be considered the most accurate and even gold standard test to quantify hepatic steatosis. They recommend ultrasound-based transient elastography to accurately diagnose both fibrosis and cirrhosis in a routine clinical setting, with more objectivity than ultrasonography but with lower accuracy than magnetic resonance elastography; and plasma cytokeratin 18 (CK18) fragment levels to be a moderately accurate biomarker of steatohepatitis. However, transient elastography can fail for people with pre-hepatic portal hypertension. === Medication development === A variety of medications with different mechanisms of action have been tested in clinical trials. Clinical trials can be separated into four main targets believed to reduce the progression of the disease or reverse it: Improving metabolism (improving insulin sensitivity, inhibiting de novo lipogenesis, or increasing fatty acid oxidation). Metabolic modulators tested in NASH include glucagon-like peptide-1 receptor agonists (GLP-1 agonists), GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) or glucagon co-agonists and thyromimetics. Some of these drugs may treat NAFLD by significantly reducing body weight. Reducing inflammation, for example reducing oxidative stress and hepatocyte death. These drugs, such as chemokine antagonists, anti-apoptotics, vascular adhesion protein-1 inhibitors, and c-Jun N-terminal kinase inhibitors, have not shown benefit. "Gut-liver axis targets" that either change a person's microbiome, or act on bile acids Anti-fibrotic drugs, such as fibroblast growth factor analogues, which have largely not met their endpoints Other treatments such as farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, and ASK1 (apoptosis signal-regulating kinase 1) inhibitors may improve NAFLD by multiple mechanisms simultaneously. Drugs in phase III trials as of 2024 are the thyromimetic resmetirom, lanifibranor (a pan-PPAR agonist), and the GLP-1 agonist semaglutide. == Notes == == References == == External links == Nonalcoholic Fatty Liver Disease (NAFLD) & NASH National Institutes of Health (NIH)	Wikipedia/Non-alcoholic_fatty_liver_disease
Milroy's disease (MD) is a familial disease characterized by lymphedema, commonly in the legs, caused by congenital abnormalities in the lymphatic system. Disruption of the normal drainage of lymph leads to fluid accumulation and hypertrophy of soft tissues. It was named by Sir William Osler for William Milroy, a Canadian physician, who described a case in 1892, though it was first described by Rudolf Virchow in 1863. == Presentation == The most common presentation of Milroy's disease is unilateral lower extremity lymphedema, and may also be accompanied by hydrocele. Males and females may have upslanting toenails, deep creases in the toes, wart-like growths (papillomas), and prominent leg veins. Some individuals develop non-contagious skin infections called cellulitis that can damage the thin tubes that carry lymph fluid (lymphatic vessels). Episodes of cellulitis can cause further swelling in the lower limbs. == Genetics == This disease is more common in women and an association with the gene FLT4 has been described. FLT4 codes for VEGFR-3, which is implicated in development of the lymphatic system. Milroy's disease is also known as primary or hereditary lymphedema type 1A or early onset lymphedema. It is a very rare disease with only about 200 cases reported in the medical literature. Milroy's disease is an autosomal dominant condition caused by a mutation in the FLT4 gene which encodes the vascular endothelial growth factor receptor 3 (VEGFR-3) gene located on the long arm (q) on chromosome 5 (5q35.3). In contrast to Milroy's disease (early onset lymphedema type 1A), which typically has its onset of swelling and edema at birth or during early infancy, hereditary lymphedema type II, known as Meige disease, has its onset around the time of puberty. Meige disease is also an autosomal dominant disease. It has been linked to a mutations in the 'forkhead' family transcription factor (FOXC2) gene located on the long arm of chromosome 16 (16q24.3). About 2000 cases have been identified. A third type of hereditary lymphedema, that has an onset after the age of 35 is known as lymphedema tarda. == Diagnosis == Only conservative measures can be taken. Certain treatments for lymphedema disorders may possibly alleviate specific symptoms; no cure and it is usually congenital. Genetic counseling can be done. May have similar health conditions, delays, disorders, and physical traits associated with other lymphatic genetic diseases and chromosome #5 abnormalities. == Prognosis == Milroy's disease does not normally affect life expectancy. Medscape states patients may have recurrent streptococcal cellulitis and lymphangitis, with subsequent hospitalizations for antibiotic therapy. A rare complication is the appearance of lymphangiosarcoma or angiosarcoma in patients with persistent lymphedema. Some patients may develop protein-losing enteropathy and visceral involvement. Chylous ascites and chylothorax rarely occur. == See also == List of cutaneous conditions == References == == Further reading == Brice, Glen W.; Mansour, Sahar; Ostergaard, Pia; Connell, Fiona; Jeffery, Steve; Mortimer, Peter (1993). "Milroy Disease". GeneReviews. University of Washington, Seattle. PMID 20301417. Retrieved 15 March 2019.	Wikipedia/Milroy_disease
Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the eye, and arthritis. The sores can last from a few days, up to a week or more. Less commonly there may be inflammation of the brain or spinal cord, blood clots, aneurysms, or blindness. Often, the symptoms come and go. The cause is unknown. It is believed to be partly genetic. Behçet's is not contagious. Diagnosis is based on at least three episodes of mouth sores in a year, together with at least two of the following: genital sores, eye inflammation, skin sores, a positive skin prick test. There is no cure. Treatments may include immunosuppressive medication such as corticosteroids and anti-TNFs as well as lifestyle changes. Lidocaine mouthwash may help with the pain. Colchicine may decrease the frequency of attacks. While rare in the United States and Europe, it is more common in the Middle East and Asia. In Turkey, for example, about 2 per 1,000 are affected. Onset is usually in a person's twenties or forties. The disease was initially described by Turkish dermatologist Hulusi Behçet in 1937. == Signs and symptoms == === Skin and mucosa === Nearly all people with Behçet's disease present with some form of painful ulcerations inside the mouth. They are a form of aphthous ulcers or non-scarring oral lesions. The oral lesions are similar to those found in inflammatory bowel disease and can be relapsing. Painful genital ulcerations usually develop around the anus, vulva, or scrotum and cause scarring in 75 percent of the patients. Additionally, patients may present with erythema nodosum, cutaneous pustular vasculitis, and lesions similar to pyoderma gangrenosum. === Eyes === Inflammatory eye disease can develop early in the disease course and lead to permanent vision loss in 20 percent of cases. Ocular involvement can be in the form of posterior uveitis, anterior uveitis, or retinal vasculitis. Anterior uveitis presents with painful eyes, conjuctival redness, hypopyon, and decreased visual acuity, while posterior uveitis presents with painless decreased visual acuity and visual field floaters. A rare form of ocular (eye) involvement in this syndrome is retinal vasculitis which presents with painless decrease of vision with the possibility of floaters or visual field defects. Optic nerve involvement in Behçet's disease is rare, typically presenting as progressive optic atrophy and visual loss. However, cases of acute optic neuropathy (specifically anterior ischemic optic neuropathy) have also been reported to occur. Optic nerve atrophy has been identified as the most common cause of visual impairment. Behçet's disease may result in primary or secondary optic nerve involvement. Papilledema as a result of dural sinus thrombosis and atrophy resulting from retinal disease, have been characterized as secondary causes of optic nerve atrophy in Behçet's disease. Signs and symptoms of acute optic neuropathy include painless loss of vision which may affect either one or both eyes, reduced visual acuity, reduced color vision, relative afferent pupillary defect, central scotoma, swollen optic disc, macular edema, or retrobulbar pain. When these symptoms occur with concurrent mucocutaneous ulcerations, they raise suspicion of acute optic neuropathy in Behçet's Disease. Progressive optic atrophy may result in decreased visual acuity or color vision. Intracranial hypertension with papilledema may be present. Episcleritis may occur, which causes eye redness and mild pain, without a significant impact on vision. === Bowels === Gastrointestinal (GI) manifestations include abdominal pain, nausea, and diarrhea with or without blood, and they often involve the terminal ileum and ileocecal valve. Some patients with BD experience abdominal tenderness, bloating, and general abdominal discomfort. When mild this can resemble irritable bowel syndrome; more severe cases bear similarities to inflammatory bowel diseases such as ulcerative colitis or Crohn's. Behçet's disease causes ulcers in the terminal ileum and ileocecal valve. The ulcers may be aphthous or have a classic punched out appearance with undermining. Linear and fissuring ulcers up to 5 cm may be present. Biopsies show vasculitis (phlebitis or venulitis) with a neutrophilic inflammatory infiltrate. Involvement of the oesophagus, stomach and large intestine is rare. === Lungs === Lung involvement is typically in the form of hemoptysis, pleuritis, cough, or fever, and in severe cases can be life-threatening if the outlet pulmonary artery develops an aneurysm which ruptures causing severe vascular collapse and death from bleeding in the lungs. Pulmonary artery thrombosis may occur. === Joints === Arthritis is seen in up to half of people, and is usually a non-erosive poly or oligoarthritis primarily of the large joints of the lower extremities. === Kidneys === Behçet's disease can rarely result in renal involvement. This can manifest in the following: Glomerulonephritis Renal amyloidosis IgA nephropathy Vascular disease Drug side effects, such as NSAIDs (non-steroidal anti-inflammatories), cyclophosphamide, cyclosporine and tacrolimus. Small vessel vascular disease results in renal vasculitis, whereas large vessel involvement causes aneurysms (bulging) and thrombosis (blockages). Serious kidney problems are more common in men typically with a history of large vessel involvement in other parts of the body. Bladder and urethral involvement is rare in Behçet's disease. === Brain === Central nervous system (CNS) involvement most often occurs as a chronic meningoencephalitis. Lesions tend to occur in the brainstem, the basal ganglia and deep hemispheric white matter and may resemble those of multiple sclerosis (MS). Brainstem atrophy is seen in chronic cases. Neurological involvements range from aseptic meningitis to vascular thrombosis such as dural sinus thrombosis and organic brain syndrome manifesting with confusion, seizures, and memory loss. Sudden hearing loss (sensorineural) is often associated with it. They often appear late in the progression of the disease but are associated with a poor prognosis. === Heart === Chronic aortic regurgitation due to aortic root disease may also be seen. Although infrequent, myocardial infarction (heart attack) with angiographically identified acute coronary artery thrombosis has been reported, including one case with a pathologically demonstrable lesion due to arteritis found at autopsy. === Blood vessels === Blood vessel problems are observed in 7–29% of people with arterial lesions representing 15% of vascular lesions. Arterial lesions pose a greater risk. Most common arterial lesions are occlusions or stenosis and aneurysms or pseudoaneurysms. == Cause == The cause is not well-defined, but it is primarily characterized by auto-inflammation of the blood vessels. Although sometimes erroneously referred to as a diagnosis of exclusion, the diagnosis can sometimes be reached by pathologic examination of the affected areas. The primary mechanism of the damage is autoimmune, which by definition is an overactive immune system that targets the patient's own body. The involvement of a subset of T cells (Th17) seems to be important. The primary cause is not well known. In fact, no one knows yet why the immune system starts to behave this way in Behçet's disease. There does however seem to be a genetic component involved, as first degree relatives of the affected patients are often affected in more than the expected proportion for the general population. Research suggests that previous infections may provoke the autoimmune responses present in Behçet's disease. Heat shock proteins (HSPs) are present in some bacteria and serve as a "danger signal" to the immune system. However, some HSPs share a similarity in bacteria and humans. The anti-HSP60 and anti-HSP65 antibodies that target HSPs produced by Streptococci (including S. sanguinis and S. pyogenes) and Mycobacterium tuberculosis can also target human HSPs, leading to immune responses linked to uveitis and various symptoms shown in parenchymal neuro-Behçet's disease. An association with the GIMAP ("GTPase of the immunity-associated protein") family of genes on the long arm of chromosome 7 (7q36.1) has been reported. Gene locations of single-nucleotide polymorphisms associated with Behçet's disease included GIMAP1, GIMAP2 and GIMAP4. == Pathophysiology == Behçet's disease is considered more prevalent in the areas surrounding the old silk trading routes in the Middle East and in Central Asia. Thus, it is sometimes known as Silk Road disease. However, this disease is not restricted to people from these regions. A large number of serological studies show a linkage between the disease and HLA-B51. HLA-B51 is more frequently found from the Middle East to South Eastern Siberia, but the incidence of B51 in some studies was 3 fold higher than the normal population. However, B51 tends not to be found in disease when a certain SUMO4 gene variant is involved, and symptoms appear to be milder when HLA-B27 is present. At the current time, a similar infectious origin has not yet been confirmed that leads to Behçet's disease, but certain strains of S. sanguinis has been found to have a homologous antigenicity. Vasculitis resulting in occlusion of the vessels supplying the optic nerve may be the cause of acute optic neuropathy and progressive optic atrophy in Behçet's disease. Histological evaluation in a reported case of acute optic neuropathy demonstrated substitution of the axonal portion of the optic nerve with fibrous astrocytes without retinal changes. CNS involvement in Behçet's disease may lead to intracranial hypertension most commonly due to dural venous sinus thrombosis and subsequent secondary optic atrophy. == Diagnosis == There is no specific pathological testing or technique available for the diagnosis of the disease, although the International Study Group criteria for the disease are highly sensitive and specific, involving clinical criteria and a pathergy test. Behçet's disease has a high degree of resemblance to diseases that cause mucocutaneous lesions such as Herpes simplex labialis, and therefore clinical suspicion should be maintained until all the common causes of oral lesions are ruled out from the differential diagnosis. Visual acuity, or color vision loss with concurrent mucocutaneous lesions or systemic Behçet's disease symptoms should raise suspicion of optic nerve involvement in Behçet's disease and prompt a work-up for Behçet's disease if not previously diagnosed in addition to an ocular work-up. Diagnosis of Behçet's disease is based on clinical findings including oral and genital ulcers, skin lesions such as erythema nodosum, acne, or folliculitis, ocular inflammatory findings and a pathergy reaction. Inflammatory markers such ESR, and CRP may be elevated. A complete ophthalmic examination may include a slit lamp examination, optical coherence tomography to detect nerve loss, visual field examinations, fundoscopic examination to assess optic disc atrophy and retinal disease, fundoscopic angiography, and visual evoked potentials, which may demonstrate increased latency. Optic nerve enhancement may be identified on Magnetic Resonance Imaging (MRI) in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid (CSF) analysis may demonstrate elevated protein level with or without pleocytosis. Imaging including angiography may be indicated to identify dural venous sinus thrombosis as a cause of intracranial hypertension and optic atrophy. === Diagnostic guidelines === According to the International Study Group guidelines, for a patient to be diagnosed with Behçet's disease, the patient must have oral (aphthous) ulcers (any shape, size, or number at least three times in any twelve-month period) along with two of the following four hallmark symptoms: eye inflammation (iritis, uveitis, retinal vasculitis, cells in the vitreous) genital ulcers (including anal ulcers and spots in the genital region and swollen testicles or epididymitis in men) pathergy reaction (papule >2 mm dia. 24–48 hrs or more after needle-prick). The pathergy test has a specificity of 95 percent to 100 percent, but the results are often negative in American and European patients skin lesions (papulo-pustules, folliculitis, erythema nodosum, acne in post-adolescents not on corticosteroids) Despite the inclusive criteria set forth by the International Study Group, there are cases where not all the criteria can be met and therefore a diagnosis cannot readily be made. There is, however, a set of clinical findings that a physician can rely upon in making a tentative diagnosis of the disease; essentially, Behçet's disease does not always follow the International Study Group guidelines and so a high degree of suspicion for a patient who presents having any number of the following findings is necessary: arthritis/arthralgia cardio-vascular problems of an inflammatory origin changes of personality, psychoses deep vein thrombosis epididymitis extreme exhaustion – chronic fatigue inflammatory problems in chest and lungs mouth ulcers nervous system symptoms problems with hearing or balance stomach or bowel inflammation superficial thrombophlebitis any other members of the family with a diagnosis of Behçet's disease. == Treatment == Current treatment is aimed at easing the symptoms, reducing inflammation, and controlling the immune system. The quality of the evidence for treating the oral ulcers associated with Behçet's disease, however, is poor. High-dose corticosteroid therapy is often used for severe disease manifestations. Anti-TNF therapy such as infliximab has shown promise in treating the uveitis associated with the disease. Infliximab as well as other anti-TNF therapies including etanercept and adalimumab may be useful in treating mucocutaneous disease according to several case reports and prospective studies, as well as one randomized trial for etanercept. Apremilast may also be used to treat oral ulcers associated with Behçet's disease. Interferon alpha-2a may also be an effective alternative treatment, particularly for the genital and oral ulcers as well as ocular lesions. Azathioprine, when used in combination with interferon alpha-2b also shows promise, and colchicine can be useful for treating some genital ulcers, erythema nodosum, and arthritis. Benzathine-penicillin may also reduce new arthritic attacks. Thalidomide has also been used due to its immune-modifying effect. Dapsone and rebamipide have been shown, in small studies, to have beneficial results for mucocutaneous lesions. Given its rarity, the optimal treatment for acute optic neuropathy in Behçet's disease has not been established. Early identification and treatment are essential. Response to ciclosporin, periocular triamcinolone, and IV methylprednisolone followed by oral prednisone has been reported although relapses leading to irreversible visual loss may occur even with treatment. Immunosuppressants such as interferon-alpha and tumour necrosis factor antagonists may improve though not completely reverse symptoms of ocular Behçet's disease, which may progress over time despite treatment. When symptoms are limited to the anterior chamber of the eye prognosis is improved. Posterior involvement, particularly optic nerve involvement, is a poor prognostic indicator. Secondary optic nerve atrophy is frequently irreversible. Lumbar puncture or surgical treatment may be required to prevent optic atrophy in cases of intracranial hypertension refractory to treatment with immunomodulators and steroids. Intravenous immunoglobulin therapy (IVIg) could be a treatment for severe or complicated cases. A recent 2024 reports that infliximab improved the likelihood of achieving a complete response at 22 weeks for patients with severe Behçet’s syndrome compared to cyclophosphamide, according to head-to-head trial data. Mild to moderate adverse events, primarily infections, were reported in 29.6% of patients on infliximab and 64% on cyclophosphamide. Serious adverse events occurred in 15% and 12% of patients, respectively. === Surgery === Surgical treatment of arterial manifestations of BD bears many pitfalls since the obliterative endarteritis of vasa vasorum causes thickening of the medial layer and splitting of elastin fibers. Therefore, anastomotic pseudoaneurysms are likely to form, as well as pseudoaneurysms at the site of the puncture in case of angiography or endovascular treatment; furthermore, early graft occlusion may occur. For these reasons, invasive treatment should not be performed in the acute and active phases of the disease when inflammation is at its peak. The evaluation of disease's activity is usually based on relapsing symptoms, ESR (erythrocyte sedimentation rate), and serum levels of CRP (C-reactive protein). Endovascular treatment can be an effective and safe alternative to open surgery, with less postoperative complications, faster recovery time, and reduced need for intensive care, while offering patency rates and procedural success rates comparable with those of surgery. This notwithstanding, long-term results of endovascular treatment in BD are still to be determined. == Epidemiology == The syndrome is rare in the United States, Africa and South America, but is common in Asia, suggesting a possible cause endemic to those areas. A theory suggested that past exposure to lethal infectious agents might have fixed the genetic susceptibility factors to Behçet's disease in those area. An estimated 15,000 to 20,000 Americans have been diagnosed with this disease. In the UK, it is estimated to have about 1 case for every 100,000 people. Globally, males are affected more frequently than females. In an epidemiologic study, 56 percent of patients with Behçet's disease developed ocular involvement at a mean age of 30. Ocular involvement was the first manifestation of Behçet's disease in 8.6 percent of patients. Ocular Behçet's disease with involvement of the optic nerve is rarely reported. Among patients with ocular Behçet's disease funduscopic findings of optic atrophy, and optic disc paleness have been identified with a frequency of 17.9 percent and 7.4 percent, respectively. Other fundoscopic findings include vascular sheathing (23.7%), retinal hemorrhage (9%), macular edema (11.3%), branch retinal vein occlusion (5.8%), and retinal edema (6.6%). However, optic atrophy was the most significant cause of visual impairment identified in 54 percent of patients with ocular Behçet's disease and permanent visual impairment. == Pregnancy == With Behçet's disease as a pre-existing disease in pregnancy or acquired, the pregnancy does not have an adverse effect on the course of Behçet's disease and may possibly ameliorate its course. Still, there is a substantial variability in clinical course between patients and even for different pregnancies in the same patient. Also, the other way around, Behçet's disease confers an increased risk of pregnancy complications, miscarriage and Cesarean section. Behçet's can cause male infertility, either as a result of the condition itself or of a side effect of concomitant medication such as colchicine, which is known to lower sperm count. == History == The first modern formal description of the symptoms was made by H. Planner and F. Remenovsky and published in 1922 in the Archiv für Dermatologie und Syphilis. Behçet's disease is named after Hulusi Behçet (1889–1948), the Turkish dermatologist and scientist who first recognized the three main symptoms of the syndrome in one of his patients in 1924 and reported his research on the disease in Journal of Skin and Venereal Diseases in 1936. The name (Morbus Behçet) was formally adopted at the International Congress of Dermatology in Geneva in September 1947. Symptoms of this disease may have been described by Hippocrates in the 5th century BC, in his Epidemion (book 3, case 7). Some sources use the term "Adamantiades's syndrome" or "Adamantiades–Behçet syndrome", for the work done by Benediktos Adamantiades. However, the current World Health Organization/ICD-10 standard is "Behçet's disease". In 1991, Saudi Arabian medical researchers described neuro-Behçet's disease, a neurological involvement in Behçet's disease, considered one of the most devastating manifestations of the disease. The mechanism can be immune-mediated or thrombotic. The term dates back to at least 1990. == References == == Further reading == == External links == Questions and answers about Behçet's disease – US National Institute of Arthritis and Musculoskeletal and Skin Diseases	Wikipedia/Behçet's_disease
Lysinuric protein intolerance (LPI) is an autosomal recessive metabolic disorder affecting amino acid transport. It is characterised by the body's inability to properly digest and use certain proteins. This condition leads to various metabolic complications and is typically diagnosed in infancy or early childhood. About 140 patients have been reported, almost half of them of Finnish origin. Individuals from Japan, Italy, Morocco and North Africa have also been reported plus one in Bixby, Oklahoma. == Signs and symptoms == Infants with LPI are usually symptom-free when breastfed because of the low protein concentration in human milk, but develop vomiting and diarrhea after weaning. The patients show failure to thrive, poor appetite, growth retardation, enlarged liver and spleen, prominent osteoporosis and osteopenia, delayed bone age and spontaneous protein aversion. Forced feeding of protein may lead to convulsions and coma. Mental development is normal if prolonged episode of hyperammonemia can be avoided. Some patients develop severe pulmonary and kidney complications. High levels of plasma glutamine and glycine are observed. == Genetic Basis == LPI has been associated with SLC7A7. LPI is caused by mutations in the SLC7A7 gene, which encodes for a protein involved in the transport of amino acids across cell membranes. Mutations in this gene impair the transport function, leading to the characteristic amino acid imbalances seen in LPI patients. == Mechanism == In LPI, urinary excretion of cationic amino acids (ornithine, arginine and lysine) is increased and these amino acids are poorly absorbed from the intestine. Therefore, their plasma concentrations are low and their body pools become depleted. Deficiency of arginine and ornithine restricts the function of the urea cycle and leads to hyperammonemia after protein-rich meals. Deficiency of lysine may play a major role in the skeletal and immunological abnormalities observed in LPI patients. == Clinical Features == The symptoms of LPI typically appear after weaning from breast milk to a protein-rich diet. Common symptoms include poor growth, muscle weakness, enlarged liver and spleen, and frequent infections. Neurological symptoms such as confusion and seizures can also occur. == Diagnosis == The diagnosis is based on the biochemical findings (increased concentrations of lysine, arginine and ornithine in urine and low concentrations of these amino acids in plasma, elevation of urinary orotic acid excretion after protein-rich meals, and inappropriately high concentrations of serum ferritin and lactate dehydrogenase isoenzymes) and the screening of known mutations of the causative gene from a DNA sample. == Treatment == Treatment of LPI consists of protein-restricted diet and supplementation with oral citrulline. Citrulline is a neutral amino acid that improves the function of the urea cycle and allows sufficient protein intake without hyperammonemia. == Prognosis == Under proper dietary control and supplementation, the majority of the LPI patients are able to have a nearly normal life. However, severe complications including pulmonary alveolar proteinosis and chronic kidney disease may develop even with proper treatment.Fertility appears to be normal in women, but mothers with LPI have an increased risk for complications during pregnancy and delivery. == References == == External links == GeneReview/NIH/UW entry on Lysinuric Protein Intolerance	Wikipedia/Lysinuric_protein_intolerance
A clinical biologist is a health professional such as a doctor of medicine, pharmacist, chemist or biologist that is specialized in clinical biology, a medical specialty derived from clinical pathology. The concept includes interventional biology, including assisted reproductive technology. These professionals follow a medical residency whose duration varies between countries (from 3 to 5 years). This term is frequently used in France, Switzerland, Belgium, and other countries in Western Europe, Africa or Asia. == Europe == === France === In France, a clinical biologist (biologiste médical) is a doctor in medicine or pharmacy who has completed a four-year specialization in medical biology. The profession is strictly regulated, and clinical biologists are responsible for overseeing and interpreting laboratory analyses. Their training includes a national competitive exam (internat de biologie médicale), followed by a structured residency program in clinical laboratories. They play a key role in laboratory diagnostics, clinical decision-making, and quality management of biological analyses. === Switzerland === In Switzerland, the equivalent profession to a clinical biologist is the FAMH Specialist in Laboratory Medicine. This title is awarded by the Foederatio Analyticorum Medicinalium Helveticorum (FAMH), the Swiss organization responsible for the postgraduate training and certification of specialists in medical laboratory diagnostics. To obtain this title, professionals must complete a four-year postgraduate training program, which is carried out alongside employment in an accredited medical laboratory. The program is open to individuals holding a medical degree (MD), a pharmacy degree, or a master’s/PhD in biomedical sciences, biology, or related disciplines. The training covers several specialties, including hematology, clinical chemistry, medical microbiology, immunology, and genetics. The FAMH Specialist in Laboratory Medicine plays a key role in medical diagnostics. They are responsible for the supervision and interpretation of laboratory analyses, validation of results, and communication with clinicians. They also ensure quality management and compliance with ISO 15189 standards, while contributing to the training and supervision of laboratory technical staff. The FAMH Specialist title is federally recognized and is a mandatory requirement to lead and validate medical diagnostic laboratories in Switzerland. === Belgium === In Belgium, a clinical biologist (biologiste clinique) is a medical doctor or pharmacist who has completed a five-year postgraduate specialization in clinical biology (biologie clinique). This specialization is regulated by the Belgian Ministry of Public Health, and clinical biologists work in both hospital and private laboratories. Their training includes rotations in different laboratory disciplines, including hematology, microbiology, and clinical chemistry. They are responsible for interpreting laboratory results, ensuring quality control, and advising clinicians on diagnostic strategies. == References == == See also == Biological pharmacist Medical laboratory Clinical laboratory scientist Clinical pathology	Wikipedia/Clinical_Biologist
Medical microbiology, the large subset of microbiology that is applied to medicine, is a branch of medical science concerned with the prevention, diagnosis and treatment of infectious diseases. In addition, this field of science studies various clinical applications of microbes for the improvement of health. There are four kinds of microorganisms that cause infectious disease: bacteria, fungi, parasites and viruses, and one type of infectious protein called prion. A medical microbiologist studies the characteristics of pathogens, their modes of transmission, mechanisms of infection and growth. The academic qualification as a clinical/Medical Microbiologist in a hospital or medical research centre generally requires a Bachelors degree while in some countries a Masters in Microbiology along with Ph.D. in any of the life-sciences (Biochem, Micro, Biotech, Genetics, etc.). Medical microbiologists often serve as consultants for physicians, providing identification of pathogens and suggesting treatment options. Using this information, a treatment can be devised. Other tasks may include the identification of potential health risks to the community or monitoring the evolution of potentially virulent or resistant strains of microbes, educating the community and assisting in the design of health practices. They may also assist in preventing or controlling epidemics and outbreaks of disease. Not all medical microbiologists study microbial pathology; some study common, non-pathogenic species to determine whether their properties can be used to develop antibiotics or other treatment methods. Epidemiology, the study of the patterns, causes, and effects of health and disease conditions in populations, is an important part of medical microbiology, although the clinical aspect of the field primarily focuses on the presence and growth of microbial infections in individuals, their effects on the human body, and the methods of treating those infections. In this respect the entire field, as an applied science, can be conceptually subdivided into academic and clinical sub-specialties, although in reality there is a fluid continuum between public health microbiology and clinical microbiology, just as the state of the art in clinical laboratories depends on continual improvements in academic medicine and research laboratories. == History == In 1676, Anton van Leeuwenhoek observed bacteria and other microorganisms, using a single-lens microscope of his own design. In 1796, Edward Jenner developed a method using cowpox to successfully immunize a child against smallpox. The same principles are used for developing vaccines today. Following on from this, in 1857 Louis Pasteur also designed vaccines against several diseases such as anthrax, fowl cholera and rabies as well as pasteurization for food preservation. In 1867 Joseph Lister is considered to be the father of antiseptic surgery. By sterilizing the instruments with diluted carbolic acid and using it to clean wounds, post-operative infections were reduced, making surgery safer for patients. In the years between 1876 and 1884 Robert Koch provided much insight into infectious diseases. He was one of the first scientists to focus on the isolation of bacteria in pure culture. This gave rise to the germ theory, a certain microorganism being responsible for a certain disease. He developed a series of criteria around this that have become known as the Koch's postulates. A major milestone in medical microbiology is the Gram stain. In 1884 Hans Christian Gram developed the method of staining bacteria to make them more visible and differentiated under a microscope. This technique is widely used today. In 1910 Paul Ehrlich tested multiple combinations of arsenic based chemicals on infected rabbits with syphilis. Ehrlich then found that arsphenamine was found effective against syphilis spirochetes. The arsphenamines was then made available in 1910, known as Salvarsan. In 1929 Alexander Fleming developed one of the most commonly used antibiotic substances both at the time and now: penicillin. In 1939 Gerhard Domagk found Prontosil red protected mice from pathogenic streptococci and staphylococci without toxicity. Domagk received the Nobel Prize in physiology, or medicine, for the discovery of the sulfa drug. DNA sequencing, a method developed by Walter Gilbert and Frederick Sanger in 1977, caused a rapid change the development of vaccines, medical treatments and diagnostic methods. Some of these include synthetic insulin which was produced in 1979 using recombinant DNA and the first genetically engineered vaccine was created in 1986 for hepatitis B. In 1995 a team at The Institute for Genomic Research sequenced the first bacterial genome; Haemophilus influenzae. A few months later, the first eukaryotic genome was completed. This would prove invaluable for diagnostic techniques. In 2007, a team at the Danish food company Danisco, were able to identify the purpose of the CRIPR-Cas systems as adaptive immunity to phages. The system was then quickly found to be able to help in genome editing through its ability to generate double strand breaks. A patient with sickle cell disease was the first person to be treated for a genetic disorder with CRISPR in July 2019. == Commonly treated infectious diseases == Bacterial Streptococcal pharyngitis Chlamydia Typhoid fever Tuberculosis Viral Rotavirus Hepatitis C Human papillomavirus (HPV) Parasitic Malaria Giardia lamblia Toxoplasma gondii Fungal Candida Histoplasmosis Dandruff Prion - Misfolded proteins that usually occur in the brain and trigger other normal proteins to misfold. They are extremely rare, and these built-up proteins lead to complications. Transmissible spongiform encephalopathies (TSE) Creutzfeldt-Jakob disease (CJD) Fatal familial insomnia == Causes and transmission of infectious diseases == Infections may be caused by bacteria, viruses, fungi, prions, and parasites. The pathogen that causes the disease may be exogenous (acquired from an external source; environmental, animal or other people, e.g. Influenza) or endogenous (from normal flora e.g. Candidiasis). The site at which a microbe enters the body is referred to as the portal of entry. These include the respiratory tract, gastrointestinal tract, genitourinary tract, skin, parenteral, blood transfusion, congenital, optic, and mucous membranes. The portal of entry for a specific microbe is normally dependent on how it travels from its natural habitat to the host. There are various ways in which disease can be transmitted between individuals. These include: Direct contact - Touching an infected host, including sexual contact Indirect contact - Touching a contaminated surface Droplet contact - Coughing or sneezing Fecal–oral route - Ingesting contaminated food or water sources Airborne transmission - Pathogen carrying spores Vector transmission - An organism that does not cause disease itself but transmits infection by conveying pathogens from one host to another Fomite transmission - An inanimate object or substance capable of carrying infectious germs or parasites Environmental - Hospital-acquired infection (Nosocomial infections) Like other pathogens, viruses use these methods of transmission to enter the body, but viruses differ in that they must also enter into the host's actual cells. Once the virus has gained access to the host's cells, the virus' genetic material (RNA or DNA) must be introduced to the cell. Replication between viruses is greatly varied and depends on the type of genes involved in them. Most DNA viruses assemble in the nucleus while most RNA viruses develop solely in cytoplasm. The mechanisms for infection, proliferation, and persistence of a virus in cells of the host are crucial for its survival. For example, some diseases such as measles employ a strategy whereby it must spread to a series of hosts. In these forms of viral infection, the illness is often treated by the body's own immune response, and therefore the virus is required to disperse to new hosts before it is destroyed by immunological resistance or host death. In contrast, some infectious agents such as the Feline leukemia virus, are able to withstand immune responses and are capable of achieving long-term residence within an individual host, whilst also retaining the ability to spread into successive hosts. Virulence refers to the ability of an organism to invade a host and cause disease. Virulence factors are molecules that enable bacteria to attach to and invade the host's cells. These factors can be secreted, featured on the membrane, or located inside the cell (cytosolic). Cytosolic factors help bacteria rapidly adapt their metabolic, physical, and structural characteristics. Membrane-bound factors help bacteria adhere to the host and avoid detection by the host's immune system. Secreted factors assist bacteria to overcome the body's innate and adaptive immune defenses. In extracellular threats, secreted factors work together to destroy host cells. == Diagnostic tests == Identification of an infectious agent for a minor illness can be as simple as clinical presentation; such as gastrointestinal disease and skin infections. In order to make an educated estimate as to which microbe could be causing the disease, epidemiological factors need to be considered; such as the patient's likelihood of exposure to the suspected organism and the presence and prevalence of a microbial strain in a community. Diagnosis of infectious disease is nearly always initiated by consulting the patient's medical history and conducting a physical examination. More detailed identification techniques involve microbial culture, microscopy, biochemical tests and genotyping. Other less common techniques (such as X-rays, CAT scans, PET scans or NMR) are used to produce images of internal abnormalities resulting from the growth of an infectious agent. === Microbial culture === Microbiological culture is the primary method used for isolating infectious disease for study in the laboratory. Tissue or fluid samples are tested for the presence of a specific pathogen, which is determined by growth in a selective or differential medium. The 3 main types of media used for testing are: Solid culture: A solid surface is created using a mixture of nutrients, salts and agar. A single microbe on an agar plate can then grow into colonies (clones where cells are identical to each other) containing thousands of cells. These are primarily used to culture bacteria and fungi. Liquid culture: Cells are grown inside a liquid media. Microbial growth is determined by the time taken for the liquid to form a colloidal suspension. This technique is used for diagnosing parasites and detecting mycobacteria. Cell culture: Human or animal cell cultures are infected with the microbe of interest. These cultures are then observed to determine the effect the microbe has on the cells. This technique is used for identifying viruses. === Microscopy === Culture techniques will often use a microscopic examination to help in the identification of the microbe. Instruments such as compound light microscopes can be used to assess critical aspects of the organism. This can be performed immediately after the sample is taken from the patient and is used in conjunction with biochemical staining techniques, allowing for resolution of cellular features. Electron microscopes and fluorescence microscopes are also used for observing microbes in greater detail for research. The two main types of electron microscopy are scanning electron microscopy and transmission electron microscopy. Transmission electron microscopy passes electrons through a thin cross-section of the cell of interest, and it then redirects the electrons onto a fluorescent screen. This method is useful for looking at the inside of cells, and the structures within, especially cell walls and membranes. Scanning electron microscopy reads the electrons that are reflected off the surface of the cells. A 3-dimensional image is then made which shows the size and exterior structure of the cells. Both techniques help give more detailed information about the structure of microbes. This makes it useful in many medical fields, such as diagnostics and biopsies of many body parts, hygiene, and virology. They provide critical information about the structure of pathogens, which allow physicians to treat them with more knowledge. === Biochemical tests === Fast and relatively simple biochemical tests can be used to identify infectious agents. For bacterial identification, the use of metabolic or enzymatic characteristics are common due to their ability to ferment carbohydrates in patterns characteristic of their genus and species. Acids, alcohols and gases are usually detected in these tests when bacteria are grown in selective liquid or solid media, as mentioned above. In order to perform these tests en masse, automated machines are used. These machines perform multiple biochemical tests simultaneously, using cards with several wells containing different dehydrated chemicals. The microbe of interest will react with each chemical in a specific way, aiding in its identification. Serological methods are highly sensitive, specific and often extremely rapid laboratory tests used to identify different types of microorganisms. The tests are based upon the ability of an antibody to bind specifically to an antigen. The antigen (usually a protein or carbohydrate made by an infectious agent) is bound by the antibody, allowing this type of test to be used for organisms other than bacteria. This binding then sets off a chain of events that can be easily and definitively observed, depending on the test. More complex serological techniques are known as immunoassays. Using a similar basis as described above, immunoassays can detect or measure antigens from either infectious agents or the proteins generated by an infected host in response to the infection. === Polymerase chain reaction === Polymerase chain reaction (PCR) assays are the most commonly used molecular technique to detect and study microbes. As compared to other methods, sequencing and analysis is definitive, reliable, accurate, and fast. Today, quantitative PCR is the primary technique used, as this method provides faster data compared to a standard PCR assay. For instance, traditional PCR techniques require the use of gel electrophoresis to visualize amplified DNA molecules after the reaction has finished. quantitative PCR does not require this, as the detection system uses fluorescence and probes to detect the DNA molecules as they are being amplified. In addition to this, quantitative PCR also removes the risk of contamination that can occur during standard PCR procedures (carrying over PCR product into subsequent PCRs). Another advantage of using PCR to detect and study microbes is that the DNA sequences of newly discovered infectious microbes or strains can be compared to those already listed in databases, which in turn helps to increase understanding of which organism is causing the infectious disease and thus what possible methods of treatment could be used. This technique is the current standard for detecting viral infections such as AIDS and hepatitis. == Treatments == Once an infection has been diagnosed and identified, suitable treatment options must be assessed by the physician and consulting medical microbiologists. Some infections can be dealt with by the body's own immune system, but more serious infections are treated with antimicrobial drugs. Bacterial infections are treated with antibacterials (often called antibiotics) whereas fungal and viral infections are treated with antifungals and antivirals respectively. A broad class of drugs known as antiparasitics are used to treat parasitic diseases. Medical microbiologists often make treatment recommendations to the patient's physician based on the strain of microbe and its antibiotic resistances, the site of infection, the potential toxicity of antimicrobial drugs and any drug allergies the patient has. In addition to drugs being specific to a certain kind of organism (bacteria, fungi, etc.), some drugs are specific to a certain genus or species of organism, and will not work on other organisms. Because of this specificity, medical microbiologists must consider the effectiveness of certain antimicrobial drugs when making recommendations. Additionally, strains of an organism may be resistant to a certain drug or class of drug, even when it is typically effective against the species. These strains, termed resistant strains, present a serious public health concern of growing importance to the medical industry as the spread of antibiotic resistance worsens. Antimicrobial resistance is an increasingly problematic issue that leads to millions of deaths every year. Adapting to the antibiotic medicine means it no longer can kill them or stop their growth. These bacterial infections can become extremely difficult to treat since the options to remove that bacterium are now slimmer. Antibiotic resistance can be caused by overuse, misuse, spontaneous resistance, and transmitted resistance. Taking antibiotics that are not prescribed to you allows naturally resistant bacteria to survive and become “superbugs.” Misuse of antibiotics includes forgetting to take one or more antibiotic doses, stopping treatment too soon, or using someone else’s medicine. Mutated bacteria become increasingly resistant to medicine. Whilst drug resistance typically involves microbes chemically inactivating an antimicrobial drug or a cell mechanically stopping the uptake of a drug, another form of drug resistance can arise from the formation of biofilms. Some bacteria are able to form biofilms by adhering to surfaces on implanted devices such as catheters and prostheses and creating an extracellular matrix for other cells to adhere to. This provides them with a stable environment from which the bacteria can disperse and infect other parts of the host. Additionally, the extracellular matrix and dense outer layer of bacterial cells can protect the inner bacteria cells from antimicrobial drugs. Phage therapy is a technique that was discovered before antibiotics, but fell to the wayside as antibiotics became predominate. It is now being considered as a potential solution to increasing antimicrobial resistance. Bacteriophages, viruses that only infect bacteria, can specifically target the bacteria of interest and inject their genome. This process makes the bacteria halt its own production to make more phages, and this continues until the bacteria lyses itself and releases the phages into the surrounding environment. Phage therapy does not kill microbiota since it is specific, and it can help those with antibiotic allergies. Some drawbacks are that it is a time-intensive process since the specific bacterium needs to be identified. It also does not currently have the body of research supporting its effects and safety that antibiotics do. Bacteria can also eventually become resistant, through systems like CRISPR/Cas9 system. Many clinical trials have been promising though, showing that it could potentially help with the antimicrobial resistance problem. It can also be used in conjunction with antibiotics for a cumulative effect. Medical microbiology is not only about diagnosing and treating disease, it also involves the study of beneficial microbes. Microbes have been shown to be helpful in combating infectious disease and promoting health. Treatments can be developed from microbes, as demonstrated by Alexander Fleming's discovery of penicillin as well as the development of new antibiotics from the bacterial genus Streptomyces among many others. Not only are microorganisms a source of antibiotics but some may also act as probiotics to provide health benefits to the host, such as providing better gastrointestinal health or inhibiting pathogens. == References == == External links ==	Wikipedia/Clinical_microbiology
Collapsin response mediator protein family or CRMP family consists of five intracellular phosphoproteins (CRMP-1, CRMP-2, CRMP-3, CRMP-4, CRMP-5) of similar molecular size (60–66 kDa) and high (50–70%) amino acid sequence identity. CRMPs are predominantly expressed in the nervous system during development and play important roles in axon formation from neurites and in growth cone guidance and collapse through their interactions with microtubules. Cleaved forms of CRMPs have also been linked to neuron degeneration after trauma induced injury. The modulation of CRMP-2 expression through various pharmaceuticals is a new and expanding area of research. By discovering chemicals that can either increase or decrease CRMP-2 expression, scientists can potentially reduce the effects of neurological diseases such as Alzheimer's disease and Parkinson's disease. == History == Members of the CRMP family were discovered independently in different species by several groups working in parallel. Among the five members of the family, CRMP-2 was first identified in 1995. Group of researchers led by Goshima found out that CRMP-2 played a role in the transduction of the extracellular Semaphorin 3A (Sema3A), an inhibitory protein for axonal guidance in chick dorsal root ganglion (DRG). The protein was first named as CRMP-62 having a relative molecular mass of 62 kDa and later referred as CRMP-2. Concurrently, a 64 kDa protein named as TOAD-64 for Turned On After Division, was shown to increase significantly during the development of the cortex of the brain. The cDNA sequence of TOAD-64 corresponded to that of rat CRMP-2. In 1996, mouse CRMP-4, often referred to as Ulip for Unc-33 like phosphoprotein, was discovered by Byk and colleagues, using a rabbit polyclonal antiserum which recognized a 64 kDa mouse brain specific phosphoprotein. In the same year, several other studies cloned CRMPs-1-4 in rat and dihydropyrimidinase (DHPase) homologous sequence of CRMPs-1, -2, and -4 in human fetal brain. Finally, in 2000, CRMP-5 was discovered using two-hybrid screenings of brain libraries or purification from a proteic complex. In following researches, CRMPs were studied as target antigens for autoantibodies in various autoimmune neurodegenerative disorders. == Structure == CRMP1-5 are between 564 and 572 amino acids and these proteins are found to be approximately 95% conserved between mouse and human. The protein sequence of CRMP1-4 is approximately 75% homologous with each other, while CRMP5 is only 50-51% homologous with each of the other CRMPs. Additionally, CRMPs are homologs of Unc-33 whose mutation causes impaired ability to form neural circuits and uncoordinated mobility in Caenorhabditis elegans. CRMP1-4 genes are roughly 60% homologous with the tetramer liver dihydropyrimidinase (DHPase), and also possess a similar structure to members of the metal-dependent amidohydrolases. However, the fact that CRMPs are not enzymatic reveals that they might lack the critical His residues that are present in amidohydrolase enzymes to allow them to bind metal atoms to their active site. Additionally, CRMPs can exist as homotetramers or as heterotetramers. The tetramers are positioned so that the active residues on the N-terminal are located on the outside of the complex. This allows CRMP to regulate various factors in the cytoplasm. Gel filtration analysis has shown that CRMP-5 and CRMP-1 form weaker homo-tetramers compared with CRMP-2, and that divalent cations, Ca2+ and Mg2+, destabilize oligomers of CRMP-5 and CRMP-1, but promote CRMP-2 oligomerization. The C-terminus consists of 80 amino acids and is the site of phosphorylation for various kinases. == Expression == The expression of CRMPs is regulated throughout development of the nervous system. In general, CRMPs are highly expressed in post-mitotic nerve cells since early embryonic life. In the developing nervous system, each CRMP displays a distinct expression pattern both in time and space. For example, in the external granular layer (EGL), where mitosis of cerebellar granular neuron occurs, CRMP-2 is highly expressed while CRMP-5 is never expressed. However, CRMP-2 and CRMP-5 are found to be co-expressed in post-mitotic granular neurons. CRMP expression is highest when neurons and synaptic connections mature actively during the first postnatal week, suggesting CRMPs’ role in neuronal migration, differentiation and axonal growth. Indeed, CRMP-2 expression is induced by neuronal differentiation promoting factors such as noggin, chordin, GDNF, and FGF. In the adult nervous system, CRMP expression is significantly downregulated and limited in areas associated with brain plasticity, neurogenesis, or regeneration. CRMP1 mRNA is mainly expressed in Purkinje cells of the cerebellum. Among the five members of the CRMP family, CRMP-2 is the most highly expressed in the adult brain, especially in post-mitotic neurons of the olfactory system, cerebellum, and hippocampus. CRMP-3 mRNA is only expressed in the granular layer of the cerebellum, inferior olive, and dentate gyrus of the hippocampus. CRMP-4 is the least expressed protein of CRMP family and its expression is restricted to the olfactory bulb, hippocampus, and the internal granule layer (IGL) of the cerebellum. Lastly, CRMP-5 is expressed not only in post-mitotic neurons of the olfactory bulb, olfactory epithelium, and dentate gyrus of the hippocampus, but also in peripheral nerve axons and sensory neurons. Other families of CRMP also appear in peripheral tissues. Expression of CRMPs-1, -4, and -5 in the adult testis is detected only in the cell spermatid stage and CRMP-2 mRNA is found in lung tissue of the fetal mouse and adult human. The expression of CRMPs also can be found in the death or survival signaling of postmitotic neurons. Although CRMP is a cytosolic protein, significant amount of CRMP expression is detected as membrane associated at the leading edge of the growth cone lamellipodium and filopodia. Also, injury-induced CRMPs expression is found in sprouting fibers in both the central and peripheral nervous system. CRMP-4 expression is promoted upon ischemic injury and is associated with neurons having intact morphology, suggesting that CRMP-4 provides a survival signal and may be involved in regeneration of neurons. Similarly, CRMP-2 has been suggested to participate in the survival and maintenance in postmitotic neurons as its over-expression accelerates nerve regeneration. However, CRMP-2 may also be involved in neuronal death as its expression is upregulated during the early stages of dopamine-induced neuronal apoptosis in cerebellar granule neurons. == Mechanism, Function and Regulation == === Axonal formation in developing neuron === CRMP-2 plays a role in neuronal polarity. Extensions of early neurons called lamellipodia form the early neurites. The neurites are indistinguishable between dendrites and the axon during this stage. One of these neurites eventually becomes the axon and grows longer than the dendritic neurites. CRMP-2 helps facilitate the rate of this axonal growth through its interactions with microtubules. CRMP-2 binds to and copolymerizes with tubulin heterodimers but does not bind as well to polymerized tubulin. This binding specificity promotes tubulin polymerization in vitro. CRMP-2/tubulin complexes are found in the distal part of the axon and modulate microtubule dynamics by controlling the rate of microtubule assembly. CRMP-2 also contributes to the establishment of neuronal polarity by regulating polarized Numb-mediated endocytosis at the axonal growth cones. In both cases, phosphorylation of CRMP-2 at Thr-555 by Rho kinase or at Thr-509, Thr-514 or Ser-518 by GSK-3β inactivates the protein by lowering binding affinity to tubulin and Numb. === Axonal growth cone guidance === In the developing nervous system, CRMPs’ involvement in axonal guidance has been proposed by localization of CRMPs in neurites and axonal growth cones. CRMPs participate in two distinct transduction pathways inducing axonal growth cone collapse. Both pathways involve Rho family GTPases, RhoA and Rac1, in their signaling cascade. Rho family GTPases regulate the cytoskeletal reorganization of the growth cone and affect the growth cone motility. In Sema3A signaling cascade, CRMP plays a role as intracellular messenger mediating repulsive signal. Sema3A initiates clustering of the receptor neuropilin 1 and plexin A1. While some of the other class of semaphorins directly bind to plexin receptors, Sema3A does not bind to plexin directly. Instead, it interacts with neuropilins as ligand-binding co-receptor for plexin and releases plexin-based signaling. The signal transduction pathway downstream of activated plexin receptor is mediated by CRMPs. In response to Sema3A signaling cascade, CRMPs which exist as a heterotetramer in the cytosol bind to the cytosolic domain of PlexA and its conformation changes. Further, CRMPs are phosphorylated by Cdk5, GSK3B, and Fes, a tyrosine protein kinase. Especially, phosphorylation of CRMP-1 and CRMP-2 are essential for Sema3A-regulated axonal guidance. In the presence of CRMP-2, the signal can induce alterations of Rac-dependent pathway, which modulates the actin filament assembly in the growth cone. In the absence of Sema3A, the interaction between CRMP tetramer and PlexA is blocked. Phospholipase D2 (PLD-2) which is localized in the growth cone and is involved in actin cytoskeleton rearrangement, can be inhibited by CRMP-2 and its inhibition results in actin depolymerization and possibly affects axonal growth cone collapse. In the presence of CRMP-2, the signal can induce alterations of Rac-dependent pathway, which modulates the actin filament assembly in the growth cone. CRMP-2 is also involved in another growth cone collapse signal induced by extracellular lysophosphatidic acid (LPA). A signal through seven-transmembrane receptor activates an intracellular pathway, RhoA and the downstream of RhoA, Rho-kinase subsequently phosphorylates CRMP-2 on Threonine-555 (Thr555). In DRG neurons, CRMP-2 is phosphorylated by Rho kinase in LPA signaling but not in Sema3A signaling, revealing the presence of both Rho kinase-dependent and Rho kinase-independent pathways for the growth cone collapse. In RhoA pathway, CRMP-1 interacts with Rho-kinase and modulates RhoA signaling. CRMP-2 can be regulated post-translationally by O-GluNAc (β-N-acetylglucosamine linked to hydroxyls of serine or threonine) as the modification blocks CRMP-2 from being phosphorylated. === Trauma induced degeneration === Cleaved CRMP products play a considerable role in the degeneration of axons as a result of trauma inflicted on the central nervous system (CNS). As a result of trauma induced on the CNS, glutamate activates NMDA receptors leading to an influx of calcium that activates the calcium-dependent protease calpain. It has been shown that activated calpain proteolytically cleaves CRMP-3, creating a cleavage product of CRMP that interacts with vital cytosolic and nuclear molecules to bring about neurodegeneration. The structure of this cleaved form of CRMP has not been determined yet, making it difficult to understand the protein-protein interactions that occur and why these forms are able to initiate neurodegeneration after CNS injury. Additionally, calpain inhibitors (ALLN) are shown to have prevented the CRMP‐3 cleavage and therefore no axonal degeneration or neuronal death, further suggesting that calpain targets CRMP-3 for cleavage during glutamate-induced neuronal death. Ca2+/calmodulin-dependent protein kinase II (CaMK II) is also activated by calcium influx through NMDA receptors, and is another possible activator of CRMP-3. CRMP-3 is not the only CRMP involved in neuronal degeneration brought upon by trauma and cerebral ischemia, as all CRMPs are in fact targeted for cleavage to help promote degeneration. === List of CRMPs (and associated knockout phenotypes and derived functions) === == Clinical significance == The expression of CRMPs is altered in neurodegenerative diseases and these proteins likely play an essential role in the pathogenesis of disorders in the nervous system, including Alzheimer's disease, Parkinson's disease, schizophrenia, and many others. One pharmaceutical that is relatively effective in targeting CRMP-2 to reduce the results of a neurodegenerative disease is lacosamide. Lacosamide is used in combination with other types of medications to control various types of seizures, especially epilepsy. One of the ways lacosamide does this is by modulating CRMP-2, thus inducing neuroprotective effects and decreasing the epileptic effects in people with epilepsy. CRMP-2 phosphorylated at Thr-509, Ser-518, and Ser-522 has been connected to the degenerating neuritis in Alzheimer's disease. Studies suggest that glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent protein kinase 5 (Cdk5) are highly expressed in Alzheimer's disease and are some of the protein kinases responsible for inactivating CRMP-2 in Alzheimer's disease. This inactivation of CRMP-2 in people with Alzheimer's disease promotes the expression of neurofibrillary tangles and plaque neurites which are consistent with people with this disease. CRMP-2 is also related to bipolar disorder and schizophrenia, likely as a result of the phosphorylation of CRMP-2 by GSK-3β. == References ==	Wikipedia/Collapsin_response_mediator_protein_family
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated that there are more than 80 recognized autoimmune diseases, with recent scientific evidence suggesting the existence of potentially more than 100 distinct conditions. Nearly any body part can be involved. Autoimmune diseases are a separate class from autoinflammatory diseases. Both are characterized by an immune system malfunction which may cause similar symptoms, such as rash, swelling, or fatigue, but the cardinal cause or mechanism of the diseases is different. A key difference is a malfunction of the innate immune system in autoinflammatory diseases, whereas in autoimmune diseases there is a malfunction of the adaptive immune system. Symptoms of autoimmune diseases can significantly vary, primarily based on the specific type of the disease and the body part that it affects. Symptoms are often diverse and can be fleeting, fluctuating from mild to severe, and typically comprise low-grade fever, fatigue, and general malaise. However, some autoimmune diseases may present with more specific symptoms such as joint pain, skin rashes (e.g., urticaria), or neurological symptoms. The exact causes of autoimmune diseases remain unclear and are likely multifactorial, involving both genetic and environmental influences. While some diseases like lupus exhibit familial aggregation, suggesting a genetic predisposition, other cases have been associated with infectious triggers or exposure to environmental factors, implying a complex interplay between genes and environment in their etiology. Some of the most common diseases that are generally categorized as autoimmune include coeliac disease, type 1 diabetes, Graves' disease, inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis), multiple sclerosis, alopecia areata, Addison's disease, pernicious anemia, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. Diagnosing autoimmune diseases can be challenging due to their diverse presentations and the transient nature of many symptoms. Treatment modalities for autoimmune diseases vary based on the type of disease and its severity. Therapeutic approaches primarily aim to manage symptoms, reduce immune system activity, and maintain the body's ability to fight diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressants are commonly used to reduce inflammation and control the overactive immune response. In certain cases, intravenous immunoglobulin may be administered to regulate the immune system. Despite these treatments often leading to symptom improvement, they usually do not offer a cure and long-term management is often required. In terms of prevalence, a UK study found that 10% of the population were affected by an autoimmune disease. Women are more commonly affected than men. Autoimmune diseases predominantly begin in adulthood, although they can start at any age. The initial recognition of autoimmune diseases dates back to the early 1900s, and since then, advancements in understanding and management of these conditions have been substantial, though much more is needed to fully unravel their complex etiology and pathophysiology. == Signs and symptoms == Autoimmune diseases represent a vast and diverse category of disorders that, despite their differences, share some common symptomatic threads. These shared symptoms occur as a result of the body's immune system mistakenly attacking its own cells and tissues, causing inflammation and damage. However, due to the broad range of autoimmune diseases, the specific presentation of symptoms can significantly vary based on the type of disease, the organ systems affected, and individual factors such as age, sex, hormonal status, and environmental influences. An individual may simultaneously have more than one autoimmune disease (known as polyautoimmunity), further complicating the symptomatology. === Common symptoms === Symptoms that are commonly associated with autoimmune diseases include: fatigue. This is the most common complaint of people with autoimmune disease. A 2015 US survey found that 98% of people with autoimmune diseases experienced fatigue, 89% said it was a "major issue", 68% said "fatigue is anything but normal. It is profound and prevents [them] from doing the simplest everyday tasks." and 59% said it was "probably the most debilitating symptom of having an [autoimmune disease]." low-grade fever malaise (a general feeling of discomfort or unease) muscle aches joint pain skin rashes Autoimmune diseases can present a diverse array of symptoms. For instance, some people may experience dry mouth or dry eyes, tingling or numbness in various body parts, unexpected changes in weight, and diarrhea. === Patterns of symptom occurrence === These symptoms often reflect the body's systemic inflammatory response. However, their occurrence and intensity can fluctuate over time, leading to periods of heightened disease activity, referred to as flare-ups, and periods of relative inactivity, known as remissions. The specific presentation of symptoms largely depends on the location and type of autoimmune response. For instance, in rheumatoid arthritis, an autoimmune disease primarily affecting the joints, symptoms typically include joint pain, swelling, and stiffness. On the other hand, type 1 diabetes, which results from an autoimmune attack on the insulin-producing cells of the pancreas, primarily presents with symptoms related to high blood sugar, such as increased thirst, frequent urination, and unexplained weight loss. === Commonly affected body areas === Commonly affected areas in autoimmune diseases include blood vessels, connective tissues, joints, muscles, red blood cells, skin, and endocrine glands such as the thyroid gland (in diseases like Hashimoto's thyroiditis and Graves' disease) and the pancreas (in type 1 diabetes). The impacts of these diseases can range from localized damage to certain tissues, alteration in organ growth and function, to more systemic effects when multiple tissues throughout the body are affected. === Value of tracking symptom occurrence === The appearance of these signs and symptoms can not only provide clues for the diagnosis of an autoimmune condition, often in conjunction with tests for specific biological markers, but also help monitor disease progression and response to treatment. Ultimately, due to the diverse nature of autoimmune diseases, a multidimensional approach is often needed for the management of these conditions, taking into consideration the variety of symptoms and their impacts on individuals' lives. == Types == While it is estimated that over 80 recognized types of autoimmune diseases exist, this section provides an overview of some of the most common and well-studied forms. === Coeliac disease === Coeliac disease is an immune reaction to eating gluten, a protein found in wheat, barley, and rye. For those with the disease, eating gluten triggers an immune response in the small intestine, leading to damage on the villi, small fingerlike projections that line the small intestine and promote nutrient absorption. This explains the increased risk of gastrointestinal cancers, as the gastrointestinal tract includes the esophagus, stomach, small intestine, large intestine, rectum, and anus, all areas that the ingested gluten would traverse in digestion. The incidence of gastrointestinal cancer can be partially reduced or eliminated if a patient removes gluten from their diet. Additionally, coeliac disease is correlated with lymphoproliferative disorders. === Graves' disease === Graves' disease is a condition characterized by development of autoantibodies to thyroid-stimulating hormone receptors. The binding of the autoantibodies to the receptors results in unregulated production and release of thyroid hormone, which can lead to stimulatory effects such as rapid heart rate, weight loss, nervousness, and irritability. Other symptoms more specific to Graves' disease include bulging eyes and swelling of the lower legs. === Inflammatory bowel disease === Inflammatory bowel disease encompasses conditions characterized by chronic inflammation of the digestive tract, including Crohn's disease and ulcerative colitis. In both cases, individuals lose immune tolerance for normal bacteria present in the gut microbiome. Symptoms include severe diarrhea, abdominal pain, fatigue, and weight loss. Inflammatory bowel disease is associated with cancers of the gastrointestinal tract and some lymphoproliferative cancers. === Multiple sclerosis === Multiple sclerosis (MS) is a neurodegenerative disease in which the immune system attacks myelin, a protective covering of nerve fibers in the central nervous system, causing communication problems between the brain and the rest of the body. Symptoms can include fatigue, difficulty walking, numbness or tingling, muscle weakness, and problems with coordination and balance. MS is associated with an increased risk of central nervous system cancer, primarily in the brain. === Rheumatoid arthritis === Rheumatoid arthritis (RA) primarily targets the joints, causing persistent inflammation that results in joint damage and pain. It is often symmetrical, meaning that if one hand or knee has it, the other one does too. RA can also affect the heart, lungs, and eyes. Additionally, the chronic inflammation and over-activation of the immune system creates an environment that favors further malignant transformation of other cells, perhaps explaining the associations with cancer of the lungs and skin as well as the increased risk of other hematologic cancers, none of which are directly affected by the inflammation of joints. === Psoriasis and psoriatic arthritis === Psoriasis is a skin condition characterized by the rapid buildup of skin cells, leading to scaling on the skin's surface. Inflammation and redness around the scales is common. Some individuals with psoriasis also develop psoriatic arthritis, which causes joint pain, stiffness, and swelling. === Sjögren's syndrome === Sjögren syndrome is a long-term autoimmune disease that affects the body's moisture-producing glands (lacrimal and salivary), and often seriously affects other organ systems, such as the lungs, kidneys, and nervous system. === Systemic lupus erythematosus === Systemic lupus erythematosus, referred to simply as lupus, is a systemic autoimmune disease that affects multiple organs, including the skin, joints, kidneys, and the nervous system. It is characterized by a widespread loss of immune tolerance. The disease is characterized by periods of flares and remissions, and symptoms range from mild to severe. Women, especially those of childbearing age, are disproportionately affected. === Type 1 diabetes === Type 1 diabetes is a condition resulting from the immune system attacking insulin-producing beta cells in the pancreas, leading to high blood sugar levels. Symptoms include increased thirst, frequent urination, and unexplained weight loss. It is most commonly diagnosed in children and young adults. === Undifferentiated connective tissue disease === Undifferentiated connective tissue disease occurs when people have features of connective tissue disease, such as blood test results and external characteristics, but do not fulfill the diagnostic criteria established for any one connective tissue disease. Some 30–40% transition to a specific connective tissue disease over time. == Causes == The exact causes of autoimmune diseases remain largely unknown; however, research has suggested that a combination of genetic, environmental, and hormonal factors, as well as certain infections, may contribute to the development of these disorders. The human immune system is equipped with several mechanisms to maintain a delicate balance between defending against foreign invaders and protecting its own cells. To achieve this, it generates both T cells and B cells, which are capable of reacting with self-proteins. However, in a healthy immune response, self-reactive cells are generally either eliminated before they become active, rendered inert via a process called anergy, or their activities are suppressed by regulatory cells. === Genetics === A familial tendency to develop autoimmune diseases suggests a genetic component. Some conditions, like lupus and multiple sclerosis, often occur in several members of the same family, indicating a potential hereditary link. Additionally, certain genes have been identified that increase the risk of developing specific autoimmune diseases. ==== Genetic predisposition ==== Evidence suggests a strong genetic component in the development of autoimmune diseases. For instance, conditions such as lupus and multiple sclerosis frequently appear in multiple members of the same family, signifying a potential hereditary link. Furthermore, certain genes have been identified that augment the risk of developing specific autoimmune diseases. Experimental methods like genome-wide association studies have proven instrumental in pinpointing genetic risk variants potentially responsible for autoimmune diseases. For example, these studies have been used to identify risk variants for diseases such as type 1 diabetes and rheumatoid arthritis. In twin studies, autoimmune diseases consistently demonstrate a higher concordance rate among identical twins compared with fraternal twins. For instance, the rate in multiple sclerosis is 35% in identical twins compared to 6% in fraternal twins. ==== Balancing infection and autoimmunity ==== There is increasing evidence that certain genes selected during evolution offer a balance between susceptibility to infection and the capacity to avoid autoimmune diseases. For example, variants in the ERAP2 gene provide some resistance to infection even though they increase the risk of autoimmunity (positive selection). In contrast, variants in the TYK2 gene protect against autoimmune diseases but increase the risk of infection (negative selection). This suggests the benefits of infection resistance may outweigh the risks of autoimmune diseases, particularly given the historically high risk of infection. Several experimental methods such as the genome-wide association studies have been used to identify genetic risk variants that may be responsible for diseases such as type 1 diabetes and rheumatoid arthritis. === Environmental factors === A significant number of environmental factors have been implicated in the development and progression of various autoimmune diseases, either directly or as catalysts. Current research suggests that up to seventy percent of autoimmune diseases could be attributed to environmental influences, which encompass an array of elements such as chemicals, infectious agents, dietary habits, and gut dysbiosis. However, a unifying theory that definitively explains the onset of autoimmune diseases remains elusive, emphasizing the complexity and multifaceted nature of these conditions. Various environmental triggers are identified, some of which include: Impaired oral tolerance Gut dysbiosis Increased gut permeability Heightened immune reactivity Chemicals, which are either a part of the immediate environment or found in drugs, are key players in this context. Examples of such chemicals include hydrazines, hair dyes, trichloroethylene, tartrazines, hazardous wastes, and industrial emissions. Ultraviolet radiation has been implicated as a potential causative factor in the development of autoimmune diseases, such as dermatomyositis. Furthermore, exposure to pesticides has been linked with an increased risk of developing rheumatoid arthritis. Vitamin D, on the other hand, appears to play a protective role, particularly in older populations, by preventing immune dysfunctions. Infectious agents are also being increasingly recognized for their role as T cell activators — a crucial step in triggering autoimmune diseases. The exact mechanisms by which they contribute to disease onset remain to be fully understood. For instance, certain autoimmune conditions like Guillain-Barre syndrome and rheumatic fever are thought to be triggered by infections. Furthermore, analysis of large-scale data has revealed a significant link between SARS-CoV-2 infection (the causative agent of COVID-19) and an increased risk of developing a wide range of new-onset autoimmune diseases. === Gender === Women typically make up some 80% of autoimmune disease patients. Whilst many proposals have been made for the cause of this high weighting, no clear explanation is available. A possible role for hormonal factors has been suggested. For example, some autoimmune diseases tend to flare during pregnancy (possibly as an evolutionary mechanism to increase health protection for the child), when hormone levels are high, and improve after menopause, when hormone levels decrease. Women may also naturally have autoimmune disease trigger events in puberty and pregnancy. Under-reporting by men may also be a factor, as men may interact less with the health system than women. === Infections === Certain viral and bacterial infections have been linked to autoimmune diseases. For instance, research suggests that the bacterium that causes strep throat, Streptococcus pyogenes, might trigger rheumatic fever, an autoimmune response affecting the heart. Similarly, some studies propose a link between the Epstein–Barr virus, responsible for mononucleosis, and the subsequent development of multiple sclerosis or lupus. === Dysregulated immune response === Another area of interest is the immune system's ability to distinguish between self and non-self, a function that is compromised in autoimmune diseases. In healthy individuals, immune tolerance prevents the immune system from attacking the body's own cells. When this process fails, the immune system may produce antibodies against its own tissues, leading to an autoimmune response. === Negative selection and the role of the thymus === The elimination of self-reactive T cells occurs primarily through a mechanism known as "negative selection" within the thymus, an organ responsible for the maturation of T cells. This process serves as a key line of defense against autoimmunity. If these protective mechanisms fail, a pool of self-reactive cells can become functional within the immune system, contributing to the development of autoimmune diseases. === Molecular mimicry === Some infectious agents, like Campylobacter jejuni, bear antigens that resemble, but are not identical to, the body's self-molecules. This phenomenon, known as molecular mimicry, can lead to cross-reactivity, where the immune response to such infections inadvertently results in the production of antibodies that also react with self-antigens. An example of this is Guillain–Barré syndrome, in which antibodies generated in response to a C. jejuni infection also react with the gangliosides in the myelin sheath of peripheral nerve axons. == Diagnosis == Diagnosing autoimmune disorders can be complex due to the wide range of diseases within this category and their often overlapping symptoms. Accurate diagnosis is crucial for determining appropriate treatment strategies. Generally, the diagnostic process involves a combination of medical history evaluation, physical examination, laboratory tests, and, in some cases, imaging or biopsies. === Medical history and examination === The first step in diagnosing autoimmune disorders typically involves a thorough evaluation of the patient's medical history and a comprehensive physical examination. Clinicians often pay close attention to the patient's symptoms, family history of autoimmune diseases, and any exposure to environmental factors that might trigger an autoimmune response. The physical examination can reveal signs of inflammation or organ damage, which are common features of autoimmune disorders. === Laboratory tests === Laboratory testing plays a pivotal role in the diagnosis of autoimmune diseases. These tests can identify the presence of certain autoantibodies or other immune markers that indicate a self-directed immune response. Autoantibody testing: Many autoimmune diseases are characterized by the presence of autoantibodies. Blood tests can identify these antibodies, which are directed against the body's own tissues. For example, antinuclear antibody (ANA) testing is commonly used in the diagnosis of systemic lupus erythematosus and other autoimmune diseases. Complete Blood Count: Blood counts can provide valuable information about the number and characteristics of different blood cells, which can be affected in some autoimmune diseases. C-Reactive Protein and Erythrocyte Sedimentation Rate: These tests measure the levels of inflammation in the body, which is often elevated in autoimmune disorders. Organ-specific tests: Certain autoimmune diseases target specific organs, so tests to evaluate the function of these organs can aid in diagnosis. For example, thyroid function tests are used in diagnosing autoimmune thyroid disorders, while a biopsy can diagnose coeliac disease by identifying damage to the small intestine. === Imaging studies === In some cases, imaging studies may be used to assess the extent of organ involvement and damage. For example, chest x-rays or CT scans can identify lung involvement in diseases like rheumatoid arthritis or systemic lupus erythematosus, while an MRI can reveal inflammation or damage in the brain and spinal cord in multiple sclerosis. === Differential diagnosis === Given the variety and nonspecific nature of symptoms that can be associated with autoimmune diseases, differential diagnosis—determining which of several diseases with similar symptoms is causing a patient's illness—is an important part of the diagnostic process. This often involves ruling out other potential causes of symptoms, such as infections, malignancies, or genetic disorders. === Multidisciplinary approach === Given the systemic nature of many autoimmune disorders, a multidisciplinary approach may be necessary for their diagnosis and management. This can involve rheumatologists, endocrinologists, gastroenterologists, neurologists, dermatologists, and other specialists, depending on the organs or systems affected by the disease. In summary, the diagnosis of autoimmune disorders is a complex process that requires a thorough evaluation of clinical, laboratory, and imaging data. Due to the diverse nature of these diseases, an individualized approach, often involving multiple specialists, is crucial for an accurate diagnosis. == Treatment == Treatment depends on the type and severity of the condition. The majority of the autoimmune diseases are chronic and there is no definitive cure, but symptoms can be alleviated and controlled with treatment. Standard treatment methods include: Vitamin or hormone supplements for what the body is lacking due to the disease (insulin, vitamin B12, thyroid hormone, etc.) Blood transfusions if the disease is blood related Physical therapy if the disease impacts bones, joints, or muscles Pharmaceutical treatment options include immunosuppressant drugs to reduce the immune response against the body's own tissues, such as: Non-steroidal anti-inflammatory drugs (NSAIDs) to reduce inflammation Glucocorticoids to reduce inflammation Disease-modifying anti-rheumatic drugs (DMARDs) to decrease the damaging tissue and organ effects of the inflammatory autoimmune response Because immunosuppressants weaken the overall immune response, relief of symptoms must be balanced with preserving the patient's ability to combat infections, which could potentially be life-threatening. Non-traditional treatments are being researched, developed, and used, especially when traditional treatments fail. These methods aim to either block the activation of pathogenic cells in the body, or alter the pathway that suppresses these cells naturally. These treatments aim to be less toxic to the patient and have more specific targets. Such options include: Monoclonal antibodies that can be used to block pro-inflammatory cytokines Antigen-specific immunotherapy which allows immune cells to specifically target the abnormal cells that cause autoimmune disease Co-stimulatory blockade that works to block the pathway that leads to the autoimmune response Regulatory T cell therapy that utilizes this special type of T cell to suppress the autoimmune response Thymoquinone, a compound found in the flower Nigella sativa, has been studied for potential in treating several autoimmune diseases due to its effects on inflammation. == Epidemiology == The first estimate of US prevalence for autoimmune diseases as a group was published in 1997 by Jacobson, et al. They reported US prevalence to be around 9 million, applying prevalence estimates for 24 diseases to a US population of 279 million. Jacobson's work was updated by Hayter & Cook in 2012. This study used Witebsky's postulates, as revised by Rose & Bona, to extend the list to 81 diseases and estimated overall cumulative US prevalence for the 81 autoimmune diseases at 5.0%, with 3.0% for males and 7.1% for females. The estimated community prevalence, which takes into account the observation that many people have more than one autoimmune disease, was 4.5% overall, with 2.7% for males and 6.4% for females. A 2024 estimate was that 1 in 15 people in the U.S. had at least one autoimmune disease. == Research == In both autoimmune and inflammatory diseases, the condition arises through aberrant reactions of the human adaptive or innate immune systems. In autoimmunity, the patient's immune system is activated against the body's own proteins. In chronic inflammatory diseases, neutrophils and other leukocytes are constitutively recruited by cytokines and chemokines, resulting in tissue damage. Mitigation of inflammation by activation of anti-inflammatory genes and the suppression of inflammatory genes in immune cells is a promising therapeutic approach. There is a body of evidence that once the production of autoantibodies has been initialized, autoantibodies have the capacity to maintain their own production. === Stem-cell therapy === Stem cell transplantation is being studied and has shown promising results in certain cases. Medical trials to replace the pancreatic β cells that are destroyed in type 1 diabetes are in progress. === Altered glycan theory === According to this theory, the effector function of the immune response is mediated by the glycans (polysaccharides) displayed by the cells and humoral components of the immune system. Individuals with autoimmunity have alterations in their glycosylation profile such that a proinflammatory immune response is favored. It is further hypothesized that individual autoimmune diseases will have unique glycan signatures. === Hygiene hypothesis === According to the hygiene hypothesis, high levels of cleanliness expose children to fewer antigens than in the past, causing their immune systems to become overactive and more likely to misidentify own tissues as foreign, resulting in autoimmune or allergic conditions such as asthma. === Vitamin D influence on immune response === Vitamin D is known as an immune regulator that assists in the adaptive and innate immune response. A deficiency in vitamin D, from hereditary or environmental influence, can lead to a more inefficient and weaker immune response and seen as a contributing factor to the development of autoimmune diseases. With vitamin D present, vitamin D response elements are encoded and expressed via pattern recognition receptors responses and the genes associated with those responses. The specific DNA target sequence expressed is known as 1,25-(OH)2D3. The expression of 1,25-(OH)2D3 can be induced by macrophages, dendritic cells, T-cells, and B-cells. In the presence of 1,25-(OH)2D3, the immune system's production of inflammatory cytokines are suppressed and more tolerogenic regulatory T-cells are expressed. This is due to vitamin D's influence on cell maturation, specifically T-cells, and their phenotype expression. Lack of 1,25-(OH)2D3 expression can lead to less tolerant regulatory T-cells, larger presentation of antigens to less tolerant T-cells, and increased inflammatory response. == See also == Epigenetics of autoimmune disorders List of autoimmune diseases Immune dysregulation == References == == Further reading == == External links == Media related to Autoimmune diseases and disorders at Wikimedia Commons	Wikipedia/Systemic_autoimmune_diseases
Antinuclear antibodies (ANAs, also known as antinuclear factor or ANF) are autoantibodies that bind to contents of the cell nucleus. In normal individuals, the immune system produces antibodies to foreign proteins (antigens) but not to human proteins (autoantigens). In some cases, antibodies to human antigens are produced; these are known as autoantibodies. There are many subtypes of ANAs such as anti-Ro antibodies, anti-La antibodies, anti-Sm antibodies, anti-nRNP antibodies, anti-Scl-70 antibodies, anti-dsDNA antibodies, anti-histone antibodies, antibodies to nuclear pore complexes, anti-centromere antibodies and anti-sp100 antibodies. Each of these antibody subtypes binds to different proteins or protein complexes within the nucleus. They are found in many disorders including autoimmunity, cancer and infection, with different prevalences of antibodies depending on the condition. This allows the use of ANAs in the diagnosis of some autoimmune disorders, including systemic lupus erythematosus, Sjögren syndrome, scleroderma, mixed connective tissue disease, polymyositis, dermatomyositis, autoimmune hepatitis and drug-induced lupus. The ANA test detects the autoantibodies present in an individual's blood serum. The common tests used for detecting and quantifying ANAs are indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). In immunofluorescence, the level of autoantibodies is reported as a titre. This is the highest dilution of the serum at which autoantibodies are still detectable. Positive autoantibody titres at a dilution equal to or greater than 1:160 are usually considered as clinically significant. Positive titres of less than 1:160 are present in up to 20% of the healthy population, especially the elderly. Although positive titres of 1:160 or higher are strongly associated with autoimmune disorders, they are also found in 5% of healthy individuals. Autoantibody screening is useful in the diagnosis of autoimmune disorders and monitoring levels helps to predict the progression of disease. A positive ANA test is seldom useful if other clinical or laboratory data supporting a diagnosis are not present. == Immunity and autoimmunity == The human body has many defense mechanisms against pathogens, one of which is humoral immunity. This defence mechanism produces antibodies (large glycoproteins) in response to an immune stimulus. Many cells of the immune system are required for this process, including lymphocytes (T-cells and B-cells) and antigen presenting cells. These cells coordinate an immune response upon the detection of foreign proteins (antigens), producing antibodies that bind to these antigens. In normal physiology, lymphocytes that recognise human proteins (autoantigens) either undergo programmed cell death (apoptosis) or become non-functional. This self-tolerance means that lymphocytes should not incite an immune response against human cellular antigens. Sometimes, however, this process malfunctions and antibodies are produced against human antigens, which may lead to autoimmune disease. == ANA subtypes == ANAs are found in many disorders, as well as some healthy individuals. These disorders include: systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren syndrome, scleroderma, polymyositis, dermatomyositis, primary biliary cirrhosis, drug induced lupus, autoimmune hepatitis, multiple sclerosis, discoid lupus, thyroid disease, antiphospholipid syndrome, juvenile idiopathic arthritis, psoriatic arthritis, juvenile dermatomyositis, idiopathic thrombocytopaenic purpura, infection and cancer. These antibodies can be subdivided according to their specificity, and each subset has different propensities for specific disorders. === Extractable nuclear antigens === Extractable nuclear antigens (ENA) are a group of autoantigens that were originally identified as antibody targets in people with autoimmune disorders. They are termed ENA because they can be extracted from the cell nucleus with saline. The ENAs consist of ribonucleoproteins and non-histone proteins, named by either the name of the donor who provided the prototype serum (Sm, Ro, La, Jo), or the name of the disease setting in which the antibodies were found (SS-A, SS-B, Scl-70). ==== Anti-Ro/SS-A and anti-La/SS-B ==== Anti-Ro and anti-La antibodies, also known as SS-A and SS-B, respectively, are commonly found in primary Sjögren's syndrome, an autoimmune disorder that affects the exocrine glands. The presence of both antibodies is found in 30–60% of Sjögren's syndrome, anti-Ro antibodies alone are found in 50–70% of Sjögren's syndrome and 30% of SLE with cutaneous involvement, and anti-La antibodies are rarely found in isolation. Anti-La antibodies are also found in SLE; however, Sjögren's syndrome is normally also present. Anti-Ro antibodies are also found less frequently in other disorders including autoimmune liver diseases, coeliac disease, autoimmune rheumatic diseases, cardiac neonatal lupus erythematosus and polymyositis. During pregnancy, anti-Ro antibodies can cross the placenta and cause heart block and neonatal lupus in babies. In Sjögren's syndrome, anti-Ro and anti-La antibodies correlate with early onset, increased disease duration, parotid gland enlargement, disease outside the glands and infiltration of glands by lymphocytes. Anti-Ro antibodies are specific to components of the Ro-RNP complex, comprising 45kDa, 52kDa, 54kDa and 60kDa proteins and RNA. The 60kDa DNA/RNA binding protein and 52kDa T-cell regulatory protein are the best characterised antigens of anti-Ro antibodies. Collectively, these proteins are part of a ribonucleoprotein (RNP) complex that associate with the human Y RNAs, hY1-hY5. The La antigen is a 48kDa transcription termination factor of RNA polymerase III, which associates with the Ro-RNP complex. The mechanism of antibody production in Sjögren's syndrome is not fully understood, but apoptosis (programmed cell death) and molecular mimicry may play a role. The Ro and La antigens are expressed on the surface of cells undergoing apoptosis and may cause the inflammation within the salivary gland by interaction with cells of the immune system. The antibodies may also be produced through molecular mimicry, where cross reactive antibodies bind to both virus and human proteins. This may occur with one of the antigens, Ro or La, and may subsequently produce antibodies to other proteins through a process known as epitope spreading. The retroviral gag protein shows similarity to the La protein and is proposed as a possible example for molecular mimicry in Sjögren's syndrome. ==== Anti-Sm ==== Anti-Smith (Anti-Sm) antibodies are a very specific marker for SLE. Approximately 99% of individuals without SLE lack anti-Sm antibodies, but only 20% of people with SLE have the antibodies. They are associated with central nervous system involvement, kidney disease, lung fibrosis and pericarditis in SLE, but they are not associated with disease activity. The antigens of the anti-Sm antibodies are the core units of the small nuclear ribonucleoproteins (snRNPs), termed A to G, and will bind to the U1, U2, U4, U5 and U6 snRNPs. Most commonly, the antibodies are specific for the B, B' and D units. Molecular and epidemiological studies suggest that anti-Sm antibodies may be induced by molecular mimicry because the protein shows some similarity to Epstein-Barr virus proteins. ==== Anti-nRNP/anti-U1-RNP ==== Anti-nuclear ribonucleoprotein (anti-nRNP) antibodies, also known as anti-U1-RNP antibodies, are found in 30–40% of SLE. They are often found with anti-Sm antibodies, but they may be associated with different clinical associations. In addition to SLE, these antibodies are highly associated with mixed connective tissue disease. Anti-nRNP antibodies recognise the A and C core units of the snRNPs and because of this they primarily bind to the U1-snRNP. The immune response to RNP may be caused by the presentation of the nuclear components on the cell membrane in apoptotic blebs. Molecular mimicry has also been suggested as a possible mechanism for the production of antibodies to these proteins because of similarity between U1-RNP polypeptides and Epstein-Barr virus polypeptides. ==== Anti-Scl-70/anti-topoisomerase I ==== Anti-Scl-70 antibodies are linked to scleroderma. The sensitivity of the antibodies for scleroderma is approximately 34%, but is higher for cases with diffuse cutaneous involvement (40%), and lower for limited cutaneous involvement (10%). The specificity of the antibodies is 98% and 99.6% in other rheumatic diseases and normal individuals, respectively. In addition to scleroderma, these antibodies are found in approximately 5% of individuals with SLE. The antigenic target of anti-Scl-70 antibodies is topoisomerase I. ==== Anti-Jo-1 ==== Although anti-Jo-1 antibodies are often included with ANAs, they are actually antibodies to the cytoplasmic protein, Histidyl-tRNA synthetase – an aminoacyl-tRNA synthetase essential for the synthesis of histidine loaded tRNA. They are highly associated with polymyositis and dermatomyositis, and are rarely found in other connective tissue diseases. Around 20–40% of polymyositis is positive for Jo-1 antibodies and most will have interstitial lung disease, HLA-DR3 and HLA-DRw52 human leukocyte antigen (HLA) markers; collectively known as Jo-1 syndrome. === Anti-dsDNA === Anti-double stranded DNA (anti-dsDNA) antibodies are highly associated with SLE. They are a very specific marker for the disease, with some studies quoting nearly 100%. Data on sensitivity ranges from 25 to 85%. Anti-dsDNA antibody levels, known as titres, correlate with disease activity in SLE; high levels indicate more active lupus. The presence of anti-dsDNA antibodies is also linked with lupus nephritis and there is evidence they are the cause. Some anti-dsDNA antibodies are cross reactive with other antigens found on the glomerular basement membrane (GBM) of the kidney, such as heparan sulphate, collagen IV, fibronectin and laminin. Binding to these antigens within the kidney could cause inflammation and complement fixation, resulting in kidney damage. Presence of high DNA-binding and low C3 levels have been shown to have extremely high predictive value (94%) for the diagnosis of SLE. It is also possible that the anti-dsDNA antibodies are internalised by cells when they bind membrane antigens and then are displayed on the cell surface. This could promote inflammatory responses by T-cells within the kidney. It is important to note that not all anti-dsDNA antibodies are associated with lupus nephritis and that other factors can cause this symptom in their absence. The antigen of anti-dsDNA antibodies is double stranded DNA. === Anti-histone antibodies === Anti-histone antibodies are found in the serum of up to 75–95% of people with drug-induced lupus and 75% of idiopathic SLE. Unlike anti-dsDNA antibodies in SLE, these antibodies do not fix complement. Although they are most commonly found in drug induced lupus, they are also found in some cases of SLE, scleroderma, rheumatoid arthritis and undifferentiated connective tissue disease. Many drugs are known to cause drug induced lupus and they produce various antigenic targets within the nucleosome that are often cross reactive with several histone proteins and DNA. Procainamide causes a form of drug-induced lupus that produces antibodies to the histone H2A and H2B complex. === Anti-gp210 and anti-p62 === Both anti-glycoprotein-210 (anti-gp210) and anti-nucleoporin 62 (anti-p62) antibodies are antibodies to components of the nuclear membrane and are found in primary biliary cirrhosis (PBC). Each antibody is present in approximately 25–30% of PBC. The antigens of both antibodies are constituents of the nuclear membrane. gp210 is a 200kDa protein involved in anchoring components of the nuclear pore to the nuclear membrane. The p62 antigen is a 60kDa nuclear pore complex. === Anti-centromere antibodies === Anti-centromere antibodies are associated with limited cutaneous systemic sclerosis, also known as CREST syndrome, primary biliary cirrhosis and proximal scleroderma. There are six known antigens, which are all associated with the centromere; CENP-A to CENP-F. CENP-A is a 17kDa histone H3-like protein. CENP-B is an 80kDa DNA binding protein involved in the folding of heterochromatin. CENP-C is a 140kDa protein involved in kinetochore assembly. CENP-D is a 50kDa protein of unknown function, but may be homologous to another protein involved in chromatin condensation, RCC1. CENP-E is a 312kDa protein from the kinesin motor protein family. CENP-F is a 367kDa protein from the nuclear matrix that associates with the kinetochore in late G2 phase during mitosis. CENP-A, B and C antibodies are most commonly found (16–42% of systemic sclerosis) and are associated with Raynaud's phenomenon, telangiectasias, lung involvement and early onset in systemic sclerosis. Anti-centromere antibodies are found in approximately 60% of patients with limited systemic scleroderma and in 15% of those with the diffuse form of scleroderma. The specificity of this test is >98%. Thus, a positive anti-centromere antibody finding is strongly suggestive of limited systemic scleroderma. Anti-centromere antibodies present early in the course of disease and are notably predictive of limited cutaneous involvement and a decreased likelihood of aggressive internal organ involvement, such as fibrosis in the lungs. When present in primary biliary cirrhosis, ACAs are prognostic of portal hypertension such that serum ACA levels correlate with the severity of portal hypertension. === Anti-sp100 === Anti-sp100 antibodies are found in approximately 20–30% of primary biliary cirrhosis (PBC). They are found in few individuals without PBC, and therefore are a very specific marker of the disease. The sp100 antigen is found within nuclear bodies; large protein complexes in the nucleus that may have a role in cell growth and differentiation. === Anti-PM-Scl === Anti-PM-Scl antibodies are found in up to 50% of polymyositis/systemic sclerosis (PM/SSc) overlap syndrome. Around 80% of individuals with antibodies present in their blood serum will have the disorder. The presence of the antibodies is linked to limited cutaneous involvement of PM/SSc overlap syndrome. The antigenic targets of the antibodies are components of the RNA-processing exosome complex in the nucleolus. There are ten proteins in this complex and antibodies to eight of them are found at varying frequencies; PM/Scl-100 (70–80%), PM/Scl-75 (46–80%), hRrp4 (50%), hRrp42 (21%), hRrp46 (18%), hCs14 (14%), hRrp41 (10%) and hRrp40 (7%). === Anti-DFS70 antibodies === Anti-DFS70 antibodies generate a dense fine speckled pattern in indirect immunofluorescence and are found in normals and in various conditions, but are not associated with a systemic autoimmune pathology. Therefore, they can be used to help to rule out such conditions in ANA positive individuals. A significant number of patients are diagnosed as systemic lupus erythematosus or undifferentiated connective tissue disease largely based on a positive ANA. In case no defined autoantibody can be detected (e.g. anti-ENA antibodies), the testing of anti-DFS70 antibodies is recommended to verify the diagnosis. Anti-DFS70 antibody tests are available as CE-marked tests. Until now, no FDA cleared assay is available. == ANA test == The presence of ANAs in blood can be confirmed by a screening test. Although there are many tests for the detection of ANAs, the most common tests used for screening are indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Following detection of ANAs, various subtypes are determined. === Indirect immunofluorescence === Indirect immunofluorescence is one of the most commonly used tests for ANAs. Typically, HEp-2 cells are used as a substrate to detect the antibodies in human serum. Microscope slides are coated with HEp-2 cells and the serum is incubated with the cells. If the said and targeted antibodies are present then they will bind to the antigens on the cells; in the case of ANAs, the antibodies will bind to the nucleus. These can be visualised by adding a fluorescent tagged (usually FITC or rhodopsin B) anti-human antibody that binds to the antibodies. The molecule will fluoresce when a specific wavelength of light shines on it, which can be seen under the microscope. Depending on the antibody present in the human serum and the localisation of the antigen in the cell, distinct patterns of fluorescence will be seen on the HEp-2 cells. Levels of antibodies are analysed by performing dilutions on blood serum. An ANA test is considered positive if fluorescence is seen at a titre of 1:40/1:80. Higher titres are more clinically significant as low positives (≤1:160) are found in up to 20% of healthy individuals, especially the elderly. Only around 5% of the healthy population have ANA titres of 1:160 or higher. ==== HEp-2 ==== Until around 1975, when HEp-2 cells were introduced, animal tissue was used as the standard substrate for immunofluorescence. HEp-2 cells are currently one of the most common substrates for ANA detection by immunofluorescence. Originally started a laryngeal carcinoma strain, the cell line was contaminated and displaced by HeLa cells, and has now been identified as actually HeLa cells. They are superior to the previously used animal tissues because of their large size and the high rate of mitosis (cell division) in the cell line. This allows the detection of antibodies to mitosis-specific antigens, such as centromere antibodies. They also allow identification of anti-Ro antibodies, because acetone is used for fixation of the cells (other fixatives can wash the antigen away). There are many nuclear staining patterns seen on HEp-2 cells: homogeneous, speckled, nucleolar, nuclear membranous, centromeric, nuclear dot and pleomorphic. The homogeneous pattern is seen when the condensed chromosomes and interphase chromatin stain. This pattern is associated with anti-dsDNA antibodies, antibodies to nucleosomal components, and anti-histone antibodies. There are two speckled patterns: fine and coarse. The fine speckled pattern has fine nuclear staining with unstained metaphase chromatin, which is associated with anti-Ro and anti-La antibodies. The coarse staining pattern has coarse granular nuclear staining, caused by anti-U1-RNP and anti-Sm antibodies. The nucleolar staining pattern is associated with many antibodies including anti-Scl-70, anti-PM-Scl, anti-fibrillarin and anti-Th/To. Nuclear membrane staining appears as a fluorescent ring around the cell nucleus and are produced by anti-gp210 and anti-p62 antibodies. The centromere pattern shows multiple nuclear dots in interphase and mitotic cells, corresponding to the number of chromosomes in the cell. Nuclear dot patterns show between 13 and 25 nuclear dots in interphase cells and are produced by anti-sp100 antibodies. Pleomorphic pattern is caused by antibodies to the proliferating cell nuclear antigen. Indirect immunofluorescence has been shown to be slightly superior compared to ELISA in detection of ANA from HEp-2 cells. ==== Crithidia luciliae ==== Crithidia luciliae are haemoflaggelate single celled protists. They are used as a substrate in immunofluorescence for the detection of anti-dsDNA antibodies. They possess an organelle known as the kinetoplast which is a large mitochondrion with a network of interlocking circular dsDNA molecules. After incubation with serum containing anti-dsDNA antibodies and fluorescent-labelled anti-human antibodies, the kinetoplast will fluoresce. The lack of other nuclear antigens in this organelle means that using C. luciliae as a substrate allows for the specific detection of anti-dsDNA antibodies. === ELISA === Enzyme-linked immunosorbent assay (ELISA) uses antigen-coated microtitre plates for the detection of ANAs. Each well of a microtitre plate is coated with either a single antigen or multiple antigens to detect specific antibodies or to screen for ANAs, respectively. The antigens are either from cell extracts or recombinant. Blood serum is incubated in the wells of the plate and is washed out. If antibodies that bind to antigen are present then they will remain after washing. A secondary anti-human antibody conjugated to an enzyme such as horseradish peroxidase is added. The enzyme reaction will produce a change in colour of the solution that is proportional to the amount of antibody bound to the antigen. There are significant differences in the detection of ANA by immunofluorescence and different ELISA kits and there is only a marginal agreement between these. A clinician must be familiar with the differences in order to evaluate the outcomes of the various assays. === Sensitivity === The following table lists the sensitivity of different types of ANAs for different diseases. Some ANAs appear in several types of disease, resulting in lower specificity of the test. For example, IgM-rheumatoid factor (IgM-RF) have been shown to cross-react with ANA giving falsely positive immunofluorescence. Positive ANA as well as anti-DNA antibodies have been reported in patients with autoimmune thyroid disease. ANA can have a positive test result in up to 45% of people with autoimmune thyroid conditions or rheumatoid arthritis and up to 15% of people with HIV or hepatitis C. As per Lupus Foundation of America, "about 5% of the general population will have a positive ANA. However, at least 95% of the people who have a positive ANA do not have lupus. A positive ANA test can sometimes run in families, even if family members have no evidence of lupus." On the other hand, they say, although 95% of the patients who actually have lupus test positive for ANA, "Only a small percentage have a negative ANA, and many of those have other antibodies (such as anti-phospholipid antibodies, anti-Ro, anti-SSA) or their ANA converted from positive to negative from steroids, cytotoxic medications, or uremia (kidney failure)." == History == The LE cell was discovered in bone marrow in 1948 by Hargraves et al. In 1957 Holborow et al. first demonstrated ANA using indirect immunofluorescence. This was the first indication that processes affecting the cell nucleus were responsible for SLE. In 1959 it was discovered that serum from individuals with SLE contained antibodies that precipitated with saline extracts of nuclei, known as extractable nuclear antigens (ENAs). This led to the characterisation of ENA antigens and their respective antibodies. Thus, anti-Sm and anti-RNP antibodies were discovered in 1966 and 1971, respectively. In the 1970s, the anti-Ro/anti-SS-A and anti-La/anti-SS-B antibodies were discovered. The Scl-70 antibody was known to be a specific antibody to scleroderma in 1979, however the antigen (topoisomerase-I) was not characterised until 1986. The Jo-1 antigen and antibody were characterised in 1980. == See also == Anti-neutrophil cytoplasmic antibody (ANCA) Rheumatoid factor == References == == External links == Autoimmunityblog – HEp-2 ANA summary Antinuclear+antibodies at the U.S. National Library of Medicine Medical Subject Headings (MeSH) Greidinger EL, Hoffman, DO, Robert W. (31 January 2003). "CE update [chemistry \| immunology]: Antinuclear Antibody Testing: Methods, Indications, and Interpretation". Laboratory Medicine. 34 (2): 113–117. doi:10.1309/VUB90VTPMEWV3W0F.	Wikipedia/Antinuclear_antibody
Anti-double stranded DNA (Anti-dsDNA) antibodies are a group of anti-nuclear antibodies (ANA) the target antigen of which is double stranded DNA. Blood tests such as enzyme-linked immunosorbent assay (ELISA) and immunofluorescence are routinely performed to detect anti-dsDNA antibodies in diagnostic laboratories. They are highly diagnostic of systemic lupus erythematosus (SLE) and are implicated in the pathogenesis of lupus nephritis. == Discovery == The first evidence for antinuclear antibodies arose in 1948 when Hargraves, Richmond and Morton discovered the LE cell. These abnormal cells, which are found in the bone marrow of persons who have SLE are categorised as polymorphonuclear leukocytes with phagocytosed whole nuclei. Subsequently, in 1957, antibodies to dsDNA were the first autoantibodies to be identified in patients with SLE. == Antibody production == Although the exact mechanism of the generation of dsDNA antibodies is still unknown, it is likely that extracellular DNA is one cause of an immune response against dsDNA. There is a great deal of evidence supporting the idea that dead or dying cells are one major source of this extracellular DNA. Apoptosis is the highly organised process of programmed cell death in which the cell degrades the nuclear DNA and signals for phagocytosis. In people with SLE and other autoimmune disorders this process is thought to be defective, causing either an increase in cell death and/or a decrease in the rate of dead cell clearance. There is a higher rate of apoptosis in people with SLE and various changes in genes and proteins have been implicated in the defects in apoptosis. These include increased levels of soluble Fas and bcl-2 and polymorphisms in the programmed cell death 1 and runt-related transcription factor X1. Blebs on apoptotic cells contain nearly all the autoantigens found in SLE, and phagocytes bind these apoptotic cells and phagocytose them. If this process is defective, these autoantigens can be released into the circulation allowing an immune response. Serum amyloid P component is a protein that is thought to aid in the clearance of chromatin produced by apoptotic cells and deficiencies in this protein have been shown (in mice) to cause spontaneous formation of ANA. Autoantigens present on the blebs of apoptotic cells are also prone to modification, which can increase their immunogenicity. Upon release of nuclear proteins and chromatin, antigen presenting cells, such as dendritic cells and macrophages, display these antigens to T helper cells. Although the details of this process are still controversial, evidence shows that to produce an immune response, DNA must activate an antigen presenting cell to produce type 1 interferons. This cytokine serves to induce maturation of plasmacytoid dendritic cells (PDCs) so that they can display their antigens to T helper cells. The mechanism in which eukaryotic DNA activates these cells is still as yet unclear; however, immunogenic CpG sequences have been found to either activate PDCs or act as adjuvant in the response to eukaryotic DNA. CpG motif DNA acts via the pattern recognition receptor, toll-like receptor 9, found highly expressed in PDCs and B cells. The T helper cells then activate B cells, which are also in the presence of these antigens, causing the production of autoantibodies. Anti-dsDNA antibodies can also be produced through infection via a mechanism known as molecular mimicry. Upon exposure to pneumococcal polysaccharides, cross reactive antibodies between dsDNA and pneumococcal polysaccharides are produced in lupus. Epstein–Barr virus is also known to induce dsDNA antibodies, as seen after immunisation of animals with EBNA-1 epitopes. Anti-dsDNA antibodies might also be created secondary to the production of antibodies to other proteins within the nucleosome. Mice that have T cells directed towards the nucleosome can elicit a response to other antigens such as dsDNA and histone via a mechanism known as antigen spreading. This effect can also occur after an infection causes the production of autoantibodies to other structures within the nucleus. == Role in disease == === SLE === Anti-dsDNA antibodies are incredibly specific for SLE, with studies quoting nearly 100%, and are therefore used in the diagnosis of SLE. Higher titres of anti-dsDNA antibodies are more suggestive of SLE and lower titres can be found in people without the disease. In contrast to the high specificity, estimates of 25–85% have been observed for the sensitivity of anti-dsDNA in SLE. Therefore, presence of anti-dsDNA antibodies are suggestive of SLE, however an absence of the antibodies does not rule out the disease. The levels of circulating anti-dsDNA antibodies fluctuate with disease activity in SLE. Increases in titres of the antibodies can coincide with, or even precede an increase of disease activity. For this reason titres are serially monitored by clinicians to assess disease progression. Titres are monitored more often in cases of more active lupus than that of less active lupus at intervals of 1–3 months and 6–12 months, respectively. Anti-dsDNA antibodies are highly associated with glomerulonephritis in SLE, although some patients with high titers of anti-dsDNA antibodies do not develop renal disease. This is most likely due to the fact that anti-dsDNA are a heterogeneous population, some of which have been found not to be pathogenic. Anti-dsDNA antibodies can be present in normal individuals, however these antibodies are usually low avidity IgM isotype. In contrast, pathogenic anti-dsDNA antibodies found in SLE are usually of IgG isotype and show high avidity for dsDNA. One possible mechanism for anti-dsDNA and their role in nephritis is the formation of immune complexes that arise by indirect binding to DNA or nucleosomes that are adhered to the glomerular basement membrane (GBM). Another mechanism is direct binding of antibodies to GBM antigens such as C1q, nucleosomal proteins, heparin sulphate or laminin, which can initiate an inflammatory response by activating complement. They can also be internalised by certain molecules on the GBM cells and cause inflammatory cascades, proliferation and alteration of cellular functions. === Rheumatoid arthritis === Patients with rheumatoid arthritis can develop anti-dsDNA antibodies, however they are usually treatment related. Anti-TNFα biological therapies, such as adalimumab, infliximab and etanercept, can often induce the production of anti-dsDNA antibodies. They are usually low avidity and are only detectable transiently after treatment. The presence of these antibodies can induce a lupus-like syndrome in some cases. === Viral infection === Infection with viral pathogens can induce anti-dsDNA antibodies transiently. Human immunodeficiency virus, parvovirus B19 and BK virus are known to induce these antibodies. === Other diseases === There is little evidence supporting the association between anti-dsDNA antibodies and other diseases. Occasionally the monoclonal proteins produced by myeloma patients can be anti-dsDNA. Also, some patients with type 1 autoimmune hepatitis produce anti-dsDNA antibodies. == Detection and quantitation == A variety of assay formats can be used to detect and quantify anti-dsDNA antibodies but there is no 'gold standard' for diagnostic purposes and the concordance between different assays/methods is low. === Farr assay === The Farr assay is used to quantify the amount of anti-dsDNA antibodies in serum. Ammonium sulphate is used to precipitate antigen-antibody complexes that form if the sera contains antibodies to dsDNA. The quantity of these antibodies is determined by using radioactively labelled dsDNA. Although this test is very specific, it is of little use in routine diagnostic laboratories due to its laboriousness and use of radioactive materials. The Farr assay is one of the only tests available that detects high avidity antibodies (along with Crithidia luciliae) and also has the ability to detect antibodies of any isotype. === PEG === The polyethylene glycol (PEG) assay precipitates DNA-antibody complexes, similar to the Farr Assay. However, unlike the Farr Assay it does not dissociate the low avidity antibody complexes, allowing for the detection of both high and low avidity anti-dsDNA antibodies. === Immunofluorescence === ==== Animal Tissue ==== Animal tissue was the first substrate for immunofluorescent detection of antinuclear antibodies and has been in use since the late 1950s. Liver and kidney tissue sections from animals such as rats are used to identify anti-dsDNA antibodies. This substrate has largely been superseded by the use of HEp-2 cells. ==== HEp-2 ==== Hep-2 cells, originally of laryngeal carcinoma origin, are actually a contamination of HeLa cells. They are routinely used in the diagnosis of ANA in diagnostic laboratories. HEp-2 cells provide a greater ability to differentiate patterns of ANA than animal sections, due to the large nuclei and high mitotic rate of the cell line. Upon incubation with serum containing anti-dsDNA antibodies and fluorescent labelled secondary antibodies, homogeneous staining of interphase nuclei and condensed chromosomal staining of mitotic cells can be seen. ==== Crithidia ==== Crithidia luciliae is a haemoflagellate protist with an organelle known as the kinetoplast. This organelle contains a high concentration of circular DNA with no recognisable nuclear antigens, allowing for the reliable detection of anti-dsDNA antibodies. The kinetoplast fluoresces if serum contains high avidity anti-dsDNA antibodies. This test has a higher specificity than EIA because it uses unprocessed DNA. Processed DNA can contain regions of ssDNA, allowing detection of anti-ssDNA antibodies, which can give false positive results. === EIA === EIA (enzyme immunoassay) detects antibodies using a DNA-coated polystyrene microtitre plate. The DNA used in these assays is often recombinant dsDNA or from calf thymus extract. Upon incubation with serum containing anti-dsDNA antibodies, the antibodies will bind to the DNA and can then be visualised using enzyme-linked secondary antibodies. This assay can be quantitative or semi-quantitative, allowing for estimations of the levels of anti-dsDNA antibodies. This test can produce false positives due to contamination of ssDNA from denatured dsDNA. EIA detects low and high avidity anti-dsDNA antibodies, increasing its sensitivity and reducing its specificity. === Flow cytometry === Flow cytometry for the detection of ANA uses multiplexed polystyrene beads coated with multiple autoantigens, such as SSA, SSB, Sm, RNP, Scl-70, Jo-1, dsDNA, centromere B and histone. Serum is incubated with the beads and in the presence of anti-dsDNA antibodies, or any other ANA, the antibodies will bind and fluorescent labelled secondary antibodies will be used for detection. The beads are run through a flow cell which uses a laser to detect fluorescence. === Multiplex immunoassay (MIA) === Similar to the flow cytometry method of ANA detection, the MIA uses wells containing autoantigens and HEp-2 extract coated beads. The bead sets are coated with specific autoantigens and can be detected individually to allow identification of the particular autoantibody. Automated analysis of the well fluorescence allows for rapid detection of autoantibodies. === Microarrays === Microarrays are a newly emerging method for the detection of ANA. Individual autoantigens are deposited in an array of dots onto a surface such as polystyrene. A single array could consist of hundreds of autoantigens for screening of multiple autoimmune diseases simultaneously. If anti-dsDNA antibodies are present, incubation of serum and the microarray allow for binding and the dots can then be visualised using a fluorescent labelled anti-IgG antibody. == Therapeutics == As a result of the highly specific nature of antibodies, they can be engineered to target and bind key motifs. These motifs can be key features within the pathogenesis of particular diseases, for example human papillomavirus. == References ==	Wikipedia/Anti-dsDNA_antibodies
Drug-induced lupus erythematosus is an autoimmune disorder caused by chronic use of certain drugs. These drugs cause an autoimmune response (the body attacks its own cells) producing symptoms similar to those of systemic lupus erythematosus (SLE). There are 38 known medications to cause DIL but there are three that report the highest number of cases: hydralazine, procainamide, and quinidine. While the criteria for diagnosing DIL has not been thoroughly established, symptoms of DIL typically present as muscle pain and joint pain. Generally, the symptoms recede after discontinuing use of the drugs. == Signs and symptoms == Signs and symptoms of drug-induced lupus erythematosus include the following: Joint pain (arthralgia) and muscle pain (myalgia) Fatigue Serositis—inflammation of the tissues lining the heart and lungs. Anti-histone antibodies in 95% of cases among those taking procainamide, hydralazine, chlorpromazine, and quinidine; however, these antibodies have been found in a smaller proportion of patients associated with other medications, including minocycline, propylthiouracil, and statins. These signs and symptoms are not side effects of the drugs taken which occur during short term use. DIL occurs over long-term and chronic use of the medications listed below. While these symptoms are similar to those of systemic lupus erythematosus, they are generally not as severe unless they are ignored which leads to more harsh symptoms, and in some reported cases, death. == Causes == The processes that lead to drug-induced lupus erythematosus are not entirely understood. The exact processes that occur are not known even after 50 years since its discovery, but many studies present theories on the mechanisms of DIL. A predisposing factor to developing DIL is N-acetylation speed, or the rate at which the body can metabolize the drug. This is greatly decreased in patients with a genetic deficiency of the enzyme N-acetyltransferase. A study showed that 29 of 30 patients with DIL were slow acetylators. In addition, these patients had more hydralazine metabolites in their urine than fast acetylators. These metabolites (byproducts of the interactions between the drug and constituents in the body) of hydralazine are said to have been created when white blood cells have been activated, meaning they are stimulated to produce a respiratory burst. Respiratory burst in white blood cells induces an increased production of free radicals and oxidants such as hydrogen peroxide. These oxidants have been found to react with hydralazine to produce a reactive species that is able to bond to protein. Monocytes, one type of white blood cell, detect the antigen and relay the recognition to T helper cells, creating antinuclear antibodies leading to an immune response. Further studies on the interactions between oxidants and hydralazine are necessary to understand the processes involved in DIL. Of the drugs that cause DIL, hydralazine has been found to cause a higher incidence. Hydralazine is a medication used to treat high blood pressure. Approximately 5% of the patients who have taken hydralazine over long periods of time and in high doses have shown DIL-like symptoms. Many of the other drugs have a low to very low risk to develop DIL. The following table shows the risk of development of DIL of some of these drugs on a high to very low scale. High risk: Procainamide (antiarrhythmic) Hydralazine (antihypertensive) Moderate risk: Quinidine (antiarrhythmic) Low to Very Low Risk: Infliximab anti (TNF-α) Etanercept anti (TNF-α) Isoniazid (antibiotic) Minocycline (antibiotic) Pyrazinamide (antibiotic) D-Penicillamine (anti-inflammatory) Carbamazepine (anticonvulsant) Oxcarbazepine (anticonvulsant) Phenytoin (anticonvulsant) Propafenone (antiarrhythmic) Chlorpromazine (antipsychotic) Minoxidil (antihypertensive vasodilator) == Diagnosis == Antinuclear antibodies are usually positive in drug-induced Lupus. Anti-Neutrophil Cytoplasmic antibodies (ANCA) can also be positive in association with certain drugs. Furthermore, anti-histone antibodies can also be positive in drug-induced lupus. Anti-Histone antibodies are positive in up to 95% of patients with drug induced lupus. The most common medications associated with drug induced lupus are hydralazine, procainamide, isoniazid, methyldopa, chlorpromazine, quinidine, and minocycline. == Treatment == It is important to recognize early that these drugs are causing DIL like symptoms and discontinue use of the drug. Symptoms of drug-induced lupus erythematosus generally disappear days to weeks after medication use is discontinued. Non-steroidal anti-inflammatory drugs (NSAIDs) will quicken the healing process. Corticosteroids may be used if more severe symptoms of DIL are present. == See also == Anti-histone antibody Lupus erythematosus Hydralazine Discoid lupus erythematosus List of cutaneous conditions == References == == External links == eMedicine	Wikipedia/Drug-induced_lupus_erythematosus
Mixed connective tissue disease (MCTD) is a systemic autoimmune disease that shares characteristics with at least two other systemic autoimmune diseases, including systemic sclerosis (Ssc), systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), and rheumatoid arthritis. The idea behind the "mixed" disease is that this specific autoantibody is also present in other autoimmune diseases such as systemic lupus erythematosus, polymyositis, scleroderma, etc. MCTD was characterized as an individual disease in 1972 by Sharp et al., and the term was introduced by Leroy in 1980. Some experts consider MCTD to be the same as undifferentiated connective tissue disease, but other experts specifically reject this idea because undifferentiated connective tissue disease is not necessarily associated with serum antibodies directed against the U1-RNP. Furthermore, MCTD is associated with a more clearly defined set of signs and symptoms. == Signs and symptoms == The early clinical features of MCTD are nonspecific and may include fatigue, low-grade fever, myalgias, Raynaud phenomenon, swelling of the fingers or hands, arthralgia, esophageal reflux or dysmotility, acrosclerosis (also known as sclerodactyly), mild myositis, and various forms of pulmonary involvement. MCTD can affect nearly any organ system. === Skin involvement === Skin involvement is common in most people with MCTD and is frequently a presenting characteristic. The most prevalent skin change is Raynaud's phenomenon, which usually appears early in the course of the disease. Swollen digits are a common sign, and on occasion, the complete hand swells. Acrosclerosis, also known as sclerodactyly, can develop with or without proximal scleroderma and is usually a later symptom of the condition. Rashes are found in 50–60% of patients. Common symptoms include photosensitivity and malar rashes, similar to those seen with SLE. Discoid lesions are also occasionally seen. Some patients with MCTD may have scleroderma-like symptoms such as squared telangiectasia on the hands and face, periungual telangiectasia, sclerodactyly, and calcinosis cutis. Like systemic sclerosis, aberrant nailfold capillaroscopy with enormous capillaries, atypical forms, and low capillary density is a common hallmark of MCTD, and this can accumulate over time. === Joint involvement === Approximately 60% of MCTD patients develop visible arthritis, frequently with rheumatoid arthritis (RA) deformities such as boutonniere deformities and swan neck alterations. Other features include tiny marginal erosions and destructive arthritis, such as arthritis mutilans. === Pulmonary involvement === The lungs are commonly affected in MCTD, with around 75% of patients having lung involvement. The most prevalent pulmonary complications of MCTD are interstitial lung disease (ILD) and pulmonary hypertension; however, a wide spectrum of other pulmonary problems have been recorded, including pleural effusions, pleuritic discomfort, alveolar hemorrhage, and thromboembolic illness. Early indications of pulmonary involvement include dyspnea, dry cough, and pleuritic chest pain. === Muscle involvement === Diagnosing MCTD involves identification of inflammatory myopathy that is histologically and clinically identical to polymyositis (PM). The majority of persons with MCTD do not experience clinical weakness. People with MCTD typically have mild myositis, with normal muscle enzymes and electromyographic results. In fact, some people may be completely asymptomatic. Myositis can be severe and difficult to differentiate from conventional dermatomyositis. Myalgia is a prevalent complaint among patients with MCTD. === Cardiac involvement === About 30% of MCTD patients have symptomatic heart disease, whereas up to 40% have subclinical cardiac illness. The most common ECG abnormalities are hemiblock, bundle branch block, and atrioventricular block. Pericarditis is the most common clinical indication of cardiac involvement, affecting up to 40% of patients. === Kidney involvement === Renal involvement is a key complication of MCTD. Some studies show that it affects around 25% of people and is generally asymptomatic. The most prevalent finding is membranous nephropathy; however, nephrotic range proteinuria may also occur. Tubulointerstitial nephritis, mesangioproliferative glomerulonephritis, and hypertensive episodes resembling scleroderma renal crisis have also been observed. === Gastrointestinal involvement === Gastrointestinal involvement is prevalent and overlaps with systemic sclerosis. Esophageal dysfunction is the most common gastrointestinal manifestation. The condition is initially asymptomatic, with difficulty swallowing (dysphagia) being the most prevalent symptom. === Nervous system involvement === The original clinical criteria of MCTD stressed the absence of central nervous system (CNS) involvement. For instance, people with MCTD do not suffer serious problems such as cerebritis, psychosis, or seizures. However, roughly 25% of individuals have a some form of CNS illness. The most common central nervous system manifestation is trigeminal (fifth cranial) nerve neuropathy, which may be a patient’s first symptom. Headaches are prevalent and are typically vascular in origin. Headaches can also be due to aseptic meningitis. Sensorineural hearing loss is frequently overlooked; however, it is estimated to occur in 50% of MCTD patients. === Hematologic involvement === Hematologic abnormalities are prevalent in MCTD. Mild lymphadenopathy affects 25–50% of patients, and it is frequently an early symptom of the disease. This usually subsides over time; however, it may reappear during flares. Between 50% and 75% of people with MCTD will experience anemia, lymphopenia, or leukopenia. Anemia of chronic disease is the most common type of anemia seen in MCTD. Thrombocytopenia can develop in MCTD but is less common than leukopenia or anemia. === Systemic involvement === Malaise and low-grade fever may develop with MCTD. The condition can cause elevated body temperatures without a clear cause. Sicca symptoms are frequent in MCTD, affecting 25-50% of individuals. == Causes == Genetic and environmental factors both influence susceptibility to MCTD. The condition is associated with aberrant immunological regulation and immune-effector pathways. === Triggers === Several environmental factors have been postulated to modify illness susceptibility or induce disease; the most persuasive of these is the role of female sex hormones, as evidenced by the disease's significant female-to-male ratio and other data. Furthermore, investigations indicate that Epstein–Barr virus, retroviruses, or other viruses may play a role in causing disease in some patients. Cytomegalovirus has also been proposed as capable of eliciting anti-RNP antibody responses in the absence of illness. Environmental exposure to vinyl chloride has been linked to the development of an MCTD-like condition. === Genetics === In MCTD, major histocompatibility complex (MHC) and non-MHC genes have been linked to disease vulnerability. HLA-DR4 in the MHC is linked to both anti-RNP antibody responses and MCTD. The HLA class II phenotype/genotype most closely connected with scleroderma, HLA-DR5, and its subgroups, has been demonstrated to have a negative connection with MCTD. Another genetic feature of MCTD is the presence of anti-RNP antibodies. However, these antibodies are not present in all patients. Genome-wide association studies have revealed that there are parts of a patient’s genetic material which cause production of these anti-RNP antibody. The mechanism is not yet thoroughly defined. == Mechanism == Several immunological variables have been linked to MCTD and may play a role in disease etiology. The 70-kD peptide of the U1-RNP antigen appears to be a dominant autoantigen in MCTD, consisting of a 437 residue polypeptide that noncovalently binds with U1-RNA via an RNA binding region on the polypeptide spanning residues 92-202. The U1 70-kD polypeptide and RNP undergo a range of potential and demonstrated structural alterations, each of which may influence the antigenicity of the RNP complex. Autoantibodies are generally recognized as a feature of several rheumatic illnesses, including MCTD. Two investigations have provided evidence that anti-RNP antibodies have a role in the development of MCTD by linking antibody emergence to clinical illness. Beyond antibody formation, B cells can serve in a variety of other important immunological pathways, including as antigen presentation, pathogenic cytokine secretion, and tissue harm via antibody-directed mechanisms. T cells appear to have a key role in the pathophysiology of MCTD. RNP-reactive CD4+ T cells have been detected in the peripheral blood of MCTD patients. Both anti-RNP and anti-U1-RNA antibodies identified in patients' serum have typically undergone isotope shift to immunoglobulin G (IgG) subtypes. In addition, there is intense lymphocyte infiltration, with many T cells detected in the locations of tissue injury at autopsy and in patient biopsy specimens. In vitro studies have also revealed that human RNP reactive T cells can aid in the generation of anti-RNP autoantibodies. Vascular changes cause some of the most severe clinical signs of MCTD. Adult MCTD patients had uncontrolled overexpression of endostatin and vascular endothelial growth factor (VEGF), two angiostatic and angiogenic factors. VEGF levels were higher in MCTD individuals who had pulmonary arterial hypertension and myositis, which may indicate a more severe course of disease. == Diagnosis == Because of the vast range of clinical symptoms in MCTD, diagnosis is not often straightforward. Different types of connective tissue disease, such as transitory illnesses and the early stages of characterized connective tissue diseases that will become completely defined in a few months or years, should be considered in the differential diagnosis. There are also uncompleted versions of recognized connective tissue diseases, in which clinical and serological symptoms allow for a diagnosis but classification criteria are not met. The most prevalent strategy to diagnosis in clinical practice combines serological criteria with at least three clinical criteria. === Classification === Four commonly accepted criteria for classifying patients with MCTD have been published, the Sharp criteria (1987), the Alarcón-Segovia criteria (1987), the Kasukawa criteria (1987), and the Kahn criteria (1991). The Alarcon-Segovia and Kahn criteria have equivalent sensitivity and specificity, and a comparison of the four diagnostic criteria suggests that the Kasukawa criteria provide the best sensitivity, while both Alarcon-Segovia and Kahn criteria have the maximum specificity. ==== Sharp criteria ==== The Sharp criteria require at least four major criteria, as well as anti-U1-RNP antibody titer of at least 1:4000, or two major criteria from criteria 1, 2, and 3, and two minor criteria, plus anti-U1-RNP antibody titer of at least 1:1000. The sharp criteria also excludes anyone with a positive anti-Sm antibody. It has a sensitivity of 42% and a specificity of 87.7%. Major criteria: Myositis Pulmonary involvement: Diffusion capacity < 70% of normal values Pulmonary hypertension Proliferative vascular lesions on lung biopsy Raynaud's phenomenon or esophageal hypomotility Swollen hands Anti-ENA antibody N 1:10,000 and anti-U1 RNP antibody positive and anti-Sm negative Minor criteria: Alopecia Leukopenia Anemia Pleuritis Pericarditis Arthritis Trigeminal neuropathy Malar rash Thrombocytopenia Mild myositis History of swollen hands ==== Alarcón-Segovia criteria ==== The Alarcón-Segovia criteria require serological criteria and at least three clinical criteria including either synovitis or myositis to qualify for a diagnosis of MCTD. It has a sensitivity of 62.5% and a specificity of 86.2%. Serological criteria: Anti-RNP antibody titer N 1:1000 Clinical criteria: Edema in hands Synovitis Myositis Raynaud's phenomenon Acrosclerosis ==== Kasukawa criteria ==== The Kasukawa criteria require a minimum of one of the common symptoms, a positive anti-RNP antibody, as well as one or more symptoms of the mixed symptoms in at least two of the three disease categories to qualify for a diagnosis of MCTD. It has a sensitivity of 75% and a specificity of 99.8%. Common symptoms: Raynaud's phenomenon Swollen fingers or hands anti-RNP antibody positive Mixed symptoms: SLE-like symptoms: Polyarthritis Lymphadenopathy Facial erythema Pericarditis or pleuritis Leukopenia or thrombocytopenia SSc-like findings: Sclerodactyly Pulmonary fibrosis, restrictive changes of lung, or reduced diffusion capacity Hypomotility or dilatation of esophagus PM-like findings: Muscle weakness Elevated serum levels of muscle enzymes (CPK) Myogenic pattern on EMG ==== Kahn criteria ==== The Kahn criteria require serological criteria in addition to Raynaud's phenomenon and two out of the three symptoms listed below (swelling of the fingers, myositis, and synovitis) to qualify for a diagnosis of MCTD. It has a sensitivity of 63% and a specificity of 86%. Serological criteria: Presence of high titer anti-RNP antibody corresponding to speckled ANA at titer ≥ 1 : 2000 Clinical criteria: Raynaud's phenomenon Synovitis Myositis Swollen fingers == Treatment == MCTD has no specific treatment. Management should address the individual's primary issues, such as arthritis, skin disease, or visceral involvement. Low-dose glucocorticoids, nonsteroidal anti-inflammatory medications, hydroxychloroquine, or a combination of these therapies can effectively treat many patients. Fever, tiredness, unspecific arthralgias, or myalgias are commonly treated with nonsteroidal anti-inflammatory medications (NSAIDs), hydroxychloroquine, or a low dose of prednisone, depending on the severity. Mild joint involvement can be effectively treated with NSAIDs, hydroxychloroquine, and oral prednisone. Methotrexate has been observed to be useful in more severe cases. If methotrexate is contraindicated, alternative disease-modifying medications for RA, such as leflunomide or azathioprine, may be used. High dosages of corticosteroids are typically effective in treating acute severe myositis. Topical steroids, prednisone, and/or hydroxychloroquine are useful in treating SLE-like skin rash, oral ulcers, and photosensitivity. Steroid treatment is often effective in treating sclerodermatous skin symptoms. Raynaud's phenomenon in MCTD typically responds to vasodilator therapy such as calcium channel blockers, as well as preventive measures including avoiding cold temperatures, smoking, and sympathomimetic drugs. Warming and protecting the fingers are also important. Recent breakthroughs have increased the therapy choices available to people with pulmonary hypertension. To ensure early detection, all individuals with MCTD must have screening echocardiography and high-resolution computed tomography upon diagnosis. Mild cases require regular testing to monitor for progression. Traditional therapies such as calcium channel blockers, ACE inhibitors, immunosuppression, and heart failure medications can be used. Pericarditis is typically treated with NSAIDs and/or corticosteroids based on severity. For moderate to severe myocarditis, high-dose steroid therapy should be combined with standard congestive heart failure treatment. Treatment for gastrointestinal problems in MCTD is identical to that for systemic sclerosis. First-line treatment for chronic reflux symptoms includes proton-pump inhibitors, H2-receptor antagonists, lifestyle changes, and oesophageal PH monitoring. Kidney involvement can lead to nephrotic syndrome, which may be treated with high-dose corticosteroid therapy. Corticosteroids are used to treat nervous system involvement in low-dose oral, high-dose oral, or high-dose intravenous regimens, depending on the severity of the potential harm. == Outlook == The long-term course of MCTD may vary. Long-term follow-up studies have shown that MCTD can progress to a moderate disease with a favorable prognosis, or patients can acquire a significant condition with vascular alterations driven by pulmonary hypertension and increased mortality. Approximately one-third of people with MCTD have a benign course and go into remission, while the other one-third have a more aggressive course with a poor response to treatment. Approximately one-third of MCTD patients improved with immunosuppressive medication but continued to require immunosuppressive therapy after several years. The prevalence of pulmonary hypertension was related with the worst prognosis and a high mortality rate, making it the most significant complication in MCTD. == Epidemiology == There is currently very little epidemiologic data on MCTD. Japan's statewide multicenter collaborative survey found a prevalence of 2.7% for MCTD. Globally, the prevalence of MCTD has been reported to be significantly lower. While there are ethnic differences in the development of anti-RNP antibodies and the prevalence of MCTD, the rate of clinical manifestations among patients from different ethnic groups remains consistent. MCTD is more frequent in women than men. A Japanese nationwide survey indicated a 16:1 female-to-male ratio for MCTD, while a longitudinal prospective clinical series from a tertiary referral institution in the midwestern US found an 11:1 ratio of women to men. == History == Gordon C. Sharp first described mixed connective tissue disease (MCTD) in 1972 as an entity with mixed features of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), polymyositis/dermatomyositis (PM/DM), and rheumatoid arthritis (RA) along with an elevated level of high-titre anti-U1small nuclear (sn) anti-ribonucleoprotein (anti-RNP) antibodies. == See also == Overlap syndrome Undifferentiated connective tissue disease == References == == Further reading == Aringer, Martin; Smolen, Josef S. (2007). "Mixed connective tissue disease: what is behind the curtain?". Best Practice & Research Clinical Rheumatology. 21 (6): 1037–1049. doi:10.1016/j.berh.2007.10.002. PMID 18068860. Gunnarsson, Ragnar; Hetlevik, Siri Opsahl; Lilleby, Vibke; Molberg, Øyvind (2016). "Mixed connective tissue disease". Best Practice & Research Clinical Rheumatology. 30 (1): 95–111. doi:10.1016/j.berh.2016.03.002. PMID 27421219. == External links == "Mixed Connective Tissue Disease: Causes, Symptoms & Treatment". Cleveland Clinic. 2016-05-26. Nevares, Alana M. (2022-10-06). "Mixed Connective Tissue Disease (MCTD)". Merck Manual Consumer Version.	Wikipedia/Mixed_connective_tissue_disease
Liver kidney microsomal type 1 antibody (anti-LKM1) is an autoantibody associated with autoimmune hepatitis (AIH). Specifically, its presence in AIH defines type 2 AIH, although it has been proposed that anti-liver cytosol type 1 autoantibody without detectable anti-LKM1 can be seen in type 2 AIH. It is one of the several subtypes of anti–liver-kidney microsome antibodies that are known. The frequent association of anti-LKM-1 antibodies and hepatitis C virus (HCV) infections and the probable existence of an infection-associated autoimmune form of anti-LKM-1-associated hepatitis, requiring a different therapeutic strategy, necessitate the exact determination of anti-LKM-1 specificities. == See also == CYP2D6 – The target of anti-LKM-1 == References ==	Wikipedia/Liver_kidney_microsomal_type_1_antibody
MuSK (for Muscle-Specific Kinase) is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin, which is similarly also required for neuromuscular junction formation. == MuSK signaling == Upon activation by its ligand agrin, MuSK signals via the proteins called casein kinase 2 (CK2), Dok-7 and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Both CK2 and Dok-7 are required for MuSK-induced formation of the neuromuscular junction, since mice lacking Dok-7 failed to form AChR clusters or neuromuscular synapses, and since downregulation of CK2 also impedes recruitment of AChR to the primary MuSK scaffold. In addition to the proteins mentioned, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure required to transmit nerve impulses to the muscle, and thus initiating muscle contraction. == Role in disease == Antibodies directed against this protein (Anti-MuSK autoantibodies) are found in some people with myasthenia gravis not demonstrating antibodies to the acetylcholine receptor. The disease still causes loss of acetylcholine receptor activity, but the symptoms affected people experience may differ from those of people with other causes of myasthenia gravis. == References ==	Wikipedia/MuSK_protein
In molecular biology, an intrabody (from intracellular and antibody) is an antibody that works within the cell to bind to an intracellular protein. Due to the lack of a reliable mechanism for bringing antibodies into a living cell from the extracellular environment, this typically requires the expression of the antibody within the target cell, which can be accomplished in transgenic animals or by gene therapy. As a result, intrabodies are defined as antibodies that have been modified for intracellular localization, and the term has rapidly come to be used even when antibodies are produced in prokaryotes or other non-target cells. This term can apply to several types of protein targeting: the antibody may remain in the cytoplasm, or it may have a nuclear localization signal, or it may undergo cotranslational translocation across the membrane into the lumen of the endoplasmic reticulum, provided that it is retained in that compartment through a KDEL sequence. Because naturally occurring antibodies are optimised to be secreted from the cell, cytosolic intrabodies require special alterations, including the use of single-chain antibodies (scFvs), modification of immunoglobulin VL domains for hyperstability, selection of antibodies resistant to the more reducing cytosolic environment, or expression as a fusion protein with maltose binding protein or other stable intracellular proteins. Such optimizations have improved the stability and structure of intrabodies, allowing the publication of a variety of promising applications against hepatitis B, avian influenza, prion diseases, inflammation, Parkinson's disease, and Huntington's disease. Optimizations required for cytosolic intrabodies are not needed for ER retained intrabodies, which fold in the compartment in which antibodies are naturally produced. Since the 1990s ER intrabodies have been used in various research areas to knock down membrane proteins and secreted proteins. == References ==	Wikipedia/Intrabody_(protein)
Quality by design (QbD) is a concept first outlined by quality expert Joseph M. Juran in publications, most notably Juran on Quality by Design. Designing for quality and innovation is one of the three universal processes of the Juran Trilogy, in which Juran describes what is required to achieve breakthroughs in new products, services, and processes. Juran believed that quality could be planned, and that most quality crises and problems relate to the way in which quality was planned. While quality by design principles have been used to advance product and process quality in industry, and particularly the automotive industry, they have also been adopted by the U.S. Food and Drug Administration (FDA) for the discovery, development, and manufacture of drugs. == Juran on quality by design == The Juran Trilogy defines the word "quality" as having two meanings: first, the presence of features that create customer satisfaction; second, the reliability of those features. Failures in features create dissatisfactions, so removing failures is the purpose of quality improvement, while creating features is the purpose of quality by design. Juran's process seeks to create features in response to understanding customer needs. These are customer-driven features. The sum of all features is the new product, service, or process. The quality by design model consists of the following steps: Establish the project design targets and goals. Define the market and customers that will be targeted. Discover the market, customers, and societal needs. Develop the features of the new design that will meet the needs. Develop or redevelop the processes to produce the features. Develop process controls to be able to transfer the new designs to operations. It is not a statistical design method like Design for Six Sigma. === Integrated planning === Integrated planning requires a team with a leader whose sole accountability is for the total success of the new product from defining the opportunity through customer purchase, use, service, and recommendation to others. This team leader reports directly to a senior executive, or the team leader can be a senior executive. Each team member's job is to ensure the success of the new product. In addition to organizational integration, a successful team must begin with clearly articulated common goals for the product that are measurable and authorized by the enterprise. These goals must, at a minimum, cover such elements as: The customers or customer segments to be served by the new product The relative and absolute quality goals The volume of sales or revenue to be generated in an initial time period and for the long run Market share, penetration, or sales relative to key competitors The release date The team will follow a structured process. The structure is the common framework for all participants in launching the new product and helps ensure success. === Customer-focused optimization === Quality by design starts and ends with the customer. Every new product introduction has some amount of trade-off involved. If there are multiple customers, they may have conflicting needs. Even the same customer may have needs that compete with each other. Capacity and speed compete with cost of operation. Capacity can compete with speed. Flexibility and feature-rich offerings may have reduced ease of use, and so on. Quality by design offers a range of tools and methods intended to make these tradeoffs explicit and optimal for the customer. Some tools are highly mathematical, and others relate more to customer behavior. Quality by design sets strong expectations for creative approaches to functional design, product features and goals, and production design. === Control over variation and transfer to operations === Quality by design incorporates modern tools to preemptively control variation. These tools and methods begin by measuring and understanding the variation that exists by using historical data, testing, and modeling to help forecast, analyze, and eliminate the deleterious effects of variation using standard statistical techniques. Process control consists of three basic activities: Evaluate the actual performance of the process Compare actual performance with goals Take action on the difference The final activity of the quality by design process is to implement the plan and validate that the transfer has occurred. == Pharmaceutical quality by design == The FDA imperative is outlined in its report "Pharmaceutical Quality for the 21st Century: A Risk-Based Approach." In the past few years, the agency has implemented the concepts of QbD into its pre-market processes. The focus of this concept is that quality should be built into a product with an understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks. This is a successor to the "quality by QC" (or "quality after design") approach that the companies have taken up until the 1990s. The QbD initiative, which originated from the Office of Biotechnology Products (OBP), attempts to provide guidance on pharmaceutical development to facilitate design of products and processes that maximizes the product's efficacy and safety profile while enhancing product manufacturability. === QbD activities within FDA === The following activities are guiding the implementation of QbD: In FDA's Office of New Drug Quality Assessment (ONDQA), a new risk-based pharmaceutical quality assessment system (PQAS) was established based on the application of product and process understanding. Implementation of a pilot program to allow manufacturers in the pharmaceutical industry to submit information for a new drug application demonstrating use of QbD principles, product knowledge, and process understanding. In 2006, Merck & Co.'s Januvia became the first product approved based upon such an application. Implementation of a Question-based Review (QbR) Process has occurred in CDER's Office of Generic Drugs. CDER's Office of Compliance has played a role in complementing the QbD initiative by optimizing pre-approval inspection processes to evaluate commercial process feasibility and determining if a state of process control is maintained throughout the lifecycle, in accord with the ICH Q10 lifecycle Quality System. First QbD Approval - including design space - for Biologic License Application (BLA) is Gazyva (Roche) While QbD will provide better design predictions, there is also a recognition that industrial scale-up and commercial manufacturing experience provides knowledge about the process and the raw materials used therein. FDA's release of the Process Validation guidance in January 2011 notes the need for companies to continue benefiting from knowledge gained, and continually improve throughout the process lifecycle by making adaptations to assure root causes of manufacturing problems are corrected. === ICH activities === Working with regulators in the European Union (the European Medicines Agency) and Japan, the FDA has furthered quality by design objectives through the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The ICH Guidelines Q8 through Q11 encapsulate these unified recommendations and provide some assistance for manufacturers to implement quality by design into their own operations. ICH Guideline Q8 describes QbD-based drug formulation development and was first published in 2004, being subsequently revised in 2008 (Q8(R2)). The ICH Guideline Q9 describes Quality Risk Management plans, Q10 explains Pharmaceutical Quality Systems, and Q11 refer to the development of active pharmacological substances including biologicals. In November 2017, the ICH issued Guideline Q12 for public consultation to extend the recommendations for the Product Lifecycle Management Plan that were initially defined in the Guideline Q10. According to the ICH, Guideline Q13 will extend the previous guidelines to accommodate continuous pharmaceutical manufacturing and Q2 (Analytical Validation) will be revised and extended into the guideline Q2(R2)/Q14 to include Analytical quality by design or AQbD. The ICH Steering Committee meets twice a year to discuss the progress of its efforts. This practical input should help ensure that quality risk management and knowledge management are used to make lifecycle adaptations that maintain process control and product quality. == See also == Laboratory quality control Quality control == Further reading == Godfrey, A. Blanton; Kenett, Ron S. (2007). "Joseph M. Juran, a perspective on past contributions and future impact". Quality and Reliability Engineering International. 23 (6): 653–663. doi:10.1002/qre.861. S2CID 23806604. Kenett, Ron S.; Kenett, Dan A. (2008). "Quality by Design applications in biosimilar pharmaceutical products". Accreditation and Quality Assurance. 13 (12): 681–690. doi:10.1007/s00769-008-0459-6. S2CID 110606284. == References == == External links == Implementing Quality by Design, by Helen Winkle, FDA Implementation of QbD Principles in CMC Review, by Chi-Wan Chen, PhD, Deputy Director, Office of New Drug Chemistry Quality-by-Design Case Studies in Pharmaceuticals and Biologics Juran.com	Wikipedia/Quality_by_Design
Affibody molecules are small, robust proteins engineered to bind to a large number of target proteins or peptides with high affinity, imitating monoclonal antibodies, and are therefore a member of the family of antibody mimetics. Affibody molecules are used in biochemical research and are being developed as potential new biopharmaceutical drugs. These molecules can be used for molecular recognition in diagnostic and therapeutic applications. == Development == As with other antibody mimetics, the idea behind developing the Affibody molecule was to apply a combinatorial protein engineering approach on a small and robust protein scaffold. The aim was to generate new binders capable of specific binding to different target proteins with almost good affinity, while retaining the favorable folding and stability properties, and ease of bacterial expression of the parent molecule. The original Affibody protein scaffold was designed based on the Z domain (the immunoglobulin G binding domain) of protein A. These molecules are the newly developed class of scaffold proteins derived from the randomization of 13 amino acids located in two alpha helices involved in the binding activity of the parent protein domain. Lately, amino acids outside of the binding surface have been substituted in the scaffold to create a surface entirely different from the ancestral protein A domain. In contrast to antibodies, Affibody molecules are composed of alpha helices and lack disulfide bridges. The parent three-helix bundle structure is currently the fastest folding protein structure known. Specific Affibody molecules binding a desired target protein can be “fished out” from pools (libraries) containing billions of different variants, using phage display. == Production == Affibody molecules are based on a three-helix bundle domain, which can be expressed in soluble and proteolytically stable forms in various host cells on its own or via fusion with other protein partners. They tolerate modification and are independently folding when incorporated into fusion proteins. Head-to-tail fusions of Affibody molecules of the same specificity have proven to give avidity effects in target binding, and head-to-tail fusion of Affibody molecules of different specificities makes it possible to get bi- or multi-specific affinity proteins. Fusions with other proteins can also be created genetically or by spontaneous isopeptide bond formation. A site for site-specific conjugation is facilitated by introduction of a single cysteine at a desired position, therefore this engineered protein can be used to conjugate to radionuclides such as technetium-99m and indium-111 to visualize receptor-overexpressing tumors. A number of different Affibody molecules have been produced by chemical synthesis. Since they do not contain cysteines or disulfide bridges, they fold spontaneously and reversibly into the correct three-dimensional structures when the protection groups are removed after synthesis. In some studies, temperatures above the melting temperature have been used, with retained binding properties following return to ambient conditions. Cross-linked variants have been produced as well. == Properties == An Affibody molecule consists of three alpha helices with 58 amino acids and has a molar mass of about 6 kDa. A monoclonal antibody, for comparison, is 150 kDa, and a single-domain antibody, the smallest type of antigen-binding antibody fragment, 12–15 kDa. Affibody molecules have been shown to withstand high temperatures (90 °C (194 °F)) or acidic and alkaline conditions (pH 2.5 or pH 11, respectively). Affibody molecules have ashort plasma half-life because of their small size.While this is advantageous for imaging,as the unbound tracer is rapidly cleared from the bloodstream, a longer plasma half-life is generally preferred for therapeutic applications. One approach to extend the plasma half-life of small molecules, such as affibody molecules,is to link them to an albumin-binding domain (ABD). A highly effective ABD is the 46-amino acid G148-GA3 domain, which is derived from streptococcal protein G, along with its engineered variant ABD035. This version has a strong femtomolar affinity for human serum albumin (HSA) [28]. The ABD can help prolong the serum half-life by forming a complex with serum albumin (SA) in the bloodstream, increasing the size of the complex and preventing it from being filtered by the kidneys. Binders with an affinity of down to sub-nanomolar have been obtained from native library selections, and binders with picomolar affinity have been obtained following affinity maturation. Affibodies conjugated to weak electrophiles bind their targets covalently. Combination of small size, ease of engineering, high affinity and specificity makes Affibody molecules suitable alternative as monoclonal antibodies for both molecular imaging and therapeutical applications, especially for the receptor-overexpressing tumors. These proteins are characterized by a high rate of extravasation and rapid clearance of non-bound tracer from the circulation, as well as other nonspecific compartments, when compared to antibodies and their fragments == Applications == Affibody molecules can be used for protein purification, enzyme inhibition, research reagents for protein capture and detection, diagnostic imaging and targeted therapy. The second generation of Affibody molecule, ABY-025, binds selectively to HER2 receptors with picomolar affinity. These Affibody molecules are in clinical development for tumor diagnosis. Anti-HER2 Affibody molecule, fused with albumin binding domain (ABD), denoted as ABY-027, labeled with Lutetium-177 provided reduction of renal and hepatic uptake of radioactivity in mice xenografts. Recently, anti-ZEGFR Affibody ZEGFR:2377 labeled with technetium-99m was successfully used to visualize ZEGR expressing tumor in mice xenograft also. == References == == External links == Affibody: Official homepage	Wikipedia/Affibody_molecule
Anti-amyloid antibodies (AAA), are a class of monoclonal antibodies developed to treat Alzheimer's disease. The first drug in the class to be developed, in the early 2000s, is bapineuzumab, but it did not show effectiveness in later-stage trials. The first drug to be approved by the US Food and Drug Administration (FDA) is aducanumab—in 2021. == Approved drugs == As of 2022, none of these drugs has been approved by the European Medicines Agency. === Aducanumab === === Lecanemab === === Donanemab === == Efficacy == A 2023 review found that "Anti-Aβ drugs have relatively low efficacy in preventing cognitive decline, and they reduce pathological productions with acceptable safety." A 2022 review finds "a statistically significant but slight clinical effect of these drugs emerges in patients with early AD after 18 months" and states, "The risk/benefit ratio of this class of drugs in early AD remains so far questionable after 18 months." From a 2023 statement by the European Association of Neurology and the European Psychiatric Association, "Anti-Aβ antibodies represent a significant advance in the treatment of AD, but their effectiveness is moderate and much work remains to be done to improve their efficacy, safety and accessibility." In a 2023 commentary, the authors express concern that the results of the trials, which are based on scoring by patients and their caregivers, of these drugs could be confounded by unblinding produced by adverse effects. They also support running studies designed to distinguish between disease-modifying and symptomatic effects. A 2024 study suggests that the cognitive benefits of monoclonal antibody treatments for Alzheimer’s disease may result from increases in Aβ42 levels, rather than solely from the removal of amyloid plaques. This challenges traditional amyloid-focused hypotheses, highlighting the need for further research into the role of Aβ42 and the risk/benefit balance of these treatments. == Adverse effects == === Amyloid related imaging abnormalities === Amyloid-related imaging abnormalities (ARIA) are a serious adverse effect; with higher rates of ARIA associated with higher amyloid clearance. There are two categories of ARIA, based on signal changes believed to be associated with vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H). === Accelerated brain volume loss === Brain volume loss is a symptom of Alzheimer's disease and is accelerated by anti-amyloid drugs developed to treat it. One meta-analysis found that people with mild cognitive impairment treated with anti-amyloid drugs would reach the brain volume associated with full Alzheimer's disease eight months earlier than those who received no such treatment. The significance of the brain volume loss caused by these drugs is unknown. The mechanism is not understood. Amyloid-related imaging abnormalities (ARIA) have been suggested as a possible cause of the accelerated brain volume loss. Others say it may be attributed to the reduction in amyloid plaques. Accelerated brain volume loss has been reported with lecanemab, aducanumab, donanemab, and other anti-amyloid drugs. Hippocampal, ventricular, and whole brain volumes are reported in studies and declines in all three have been found. However, the affected parts of the brain are not fully understood. == Society and culture == === Drug development === The approved anti-amyloid antibodies were developed after years of unsuccessful attempts to develop a disease-modifying treatment for Alzheimer's disease. === Cost === Concerns have been raised about the high cost of the drugs and accessibility to patients. == See also == Anti-α-synuclein drug UB-311 – β-amyloid vaccine == References ==	Wikipedia/Anti-amyloid_drugs
Human anti-mouse antibody or human anti-murine antibody (HAMA) is an antibody found in humans which reacts to immunoglobins found in mice. == The HAMA response == Antibody treatment is a type of therapy that is used to treat certain types of cancer and immune disorders. Antibodies are proteins which are naturally formed by the body in response to a foreign substance, known as an antigen. Antibodies can also be grown outside of the patient’s body and injected into them to help aid the immune system to fight disease. These types of antibodies are typically called monoclonal antibodies because they are created to target one specific antigen. Herceptin and Avastin, two widely used cancer fighting drugs, are examples of monoclonal antibodies. For several decades, and until recently, mice were used extensively in the production of monoclonal antibodies (MAbs). But the treatments were not as effective as doctors had hoped. One problem was that patients reacted to the mouse antibodies as if they were a foreign substance, and created a new set of antibodies to the mouse antibodies. Doctors have termed this the “HAMA response,” referring to the development of Human Anti-Mouse Antibodies (HAMA). The HAMA response is essentially an allergic reaction to the mouse antibodies that can range from a mild form, like a rash, to a more extreme and life-threatening response, such as kidney failure. HAMA can also decrease the effectiveness of the treatment, or create a future reaction if the patient is given a subsequent treatment containing mouse antibodies. It has been observed that anywhere from one-third to more than half of patients receiving mouse-derived antibodies will develop some form of HAMA response. Even more startling, at least ten percent of the general population has been observed to carry some form of animal-derived antibodies, most often from mice, due to the preponderance of medical agents made from the serum of animals. Monoclonal antibodies can be generated for human use without mice by using in vitro techniques. MAbs manufactured using these methods do not suffer from the drawbacks related to the HAMA response. Animal protection groups fought for years to end MAb production in mice because it causes intense suffering for the animals that includes severe abdominal pain, difficulty breathing and death. It took considerable, sustained pressure from animal welfare groups, led by legal efforts initiated by the American Anti-Vivisection Society, before this would change. Today in vitro methods of MAb production are recognized and promoted by the National Institutes of Health and are required of all investigators who receive federal funding if their work involves producing MAbs. The existence of HAMA can complicate laboratory measurements. HAMA interferences can give false positive or negative immunoassay results. HAMA bridging interference produces artificially higher results because HAMA's bind to immobilized mouse antibodies in place of substrate, secondary labeled antibodies will then bind to HAMA and produce a positive signal falsely indicative of substrate presence. In this manner, HAMA provides a bridge between immobilized antibodies and labeled secondary antibodies. In contrast, HAMA blocking interference produces no signal for substrate presence when substrate is present. HAMAs will capture immobilized mouse antibodies. In the heterogeneous immunoassay the separation step will wash away the free substrate unable to bind due to HAMA blocking; only the immobilized mouse antibodies and the HAMA remain in the immunoassay when the labeled secondary antibodies are administered. Since the substrate will no longer be able to bind to the immobilized mouse antibodies because of HAMA interference, labeled secondary antibodies will not give a signal for substrate presence. == References ==	Wikipedia/Human_anti-mouse_antibody
A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen. BsAbs can be manufactured in several structural formats. BsAbs can be designed to recruit and activate immune cells, to interfere with receptor signaling and inactivate signaling ligands, and to force association of protein complexes. BsAbs have been explored for cancer immunotherapy, drug delivery, and Alzheimer's disease. == Development history == The original concept of BsAbs was proposed by Nisonoff and his collaborators in the 1960s, including the first idea of antibody architecture and other findings. In 1975, the problem of producing pure antibodies was solved by the creation of hybridoma technology, and the new era of monoclonal antibodies (MoAbs) came. In 1983, Milstein and Cuello created hybrid-hybridoma (quadroma) technology. In 1988, the single-chain variable fragment (scFv) was invented by the Huston team to minimize the refolding problems, which contains the incorrect domain pairing or aggregation of two-chain species. In 1996, the BsAbs became more developed when the knobs-into-holes technology emerged. == Structural types and manufacturing methods == There are many formats of BsAbs, but the two main categories are IgG-like and non-IgG-like. The main types of manufacturing methods are quadromas, chemical conjugation, and genetic recombination, and each method results in a unique format. === IgG-like === This format retains the traditional monoclonal antibody (mAb) structure of two Fab arms and one Fc region, except the two Fab sites bind different antigens. The most common types are called trifunctional antibodies, as they have three unique binding sites on the antibody: the two Fab regions, and the Fc region. Each heavy and light chain pair is from a unique mAb. The Fc region made from the two heavy chains forms the third binding site. These BsAbs are often manufactured with the quadroma, or the hybrid hybridoma, method. However, the quadroma method relies on random chance to form usable BsAb, and can be inefficient. Another method for manufacturing IgG-like BsAb is called "knobs into holes," and relies on introducing a mutation for a large amino acid in the heavy chain from one mAb, and a mutation for a small amino acid in the other mAb's heavy chain. This allows the target heavy chains (and their corresponding light chains) to fit together better, and makes the production of BsAbs more reliable. === Non-IgG-like === There are other BsAbs that lack an Fc region entirely, and thus leads to relatively simple design strategies. These include chemically linked Fabs, consisting of only the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (ScFvs). There are also fusion proteins mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs), which uses the G4S linker to connect two ScFvs-one CD3 antibody ScFv and one tumor-associated antigen (TAA) or tumor-specific ScFv-to redirect T cells to cancer cells for target killing. Other platforms include tetravalent antiparallel structure (TandAbs) and VH only (Bi-Nanobody). The TandAb platform is formed by a tetravalent antibody molecule containing two binding sites for each of two antigens. In this platform, the reverse pairing of two peptide chains forms a homodimer molecule. As an example, AFM11 is based on the TandAbs platform and targets both CD3 and CD19 to achieve therapeutic effects. AFM11 showed dose-dependent inhibition of Raji tumors in vivo. The Bi-Nanobody platform forms multi-specific binding through the connection between the VH regions of two or more antibody molecules. The products that are designed based on this platform are small molecules and these small molecules have high stability and better tissue permeability in vivo. Even though non-IgG-like BsAbs have low molecular weight and thus high tumor tissue permeability, their half-life is relatively short and they require multiple doses. Despite the considerable differences between the various types and formats of bispecific antibodies, their manufacturing processes correspond in several steps: Genetic engineering and cloning – Different monoclonal antibodies or antibody fragments are fused. Recombinant DNA technology is applied to generate one single, bispecific antibody. Preparation of expression system – An expression system is chosen and prepared for antibody expression. Frequently used expression systems for therapeutic bispecific antibodies are mammalian cells, such as CHO cells, as they are effective in performing complex post-translational modifications. Transfection and protein production – Either via stable or transient transfection, genetic information of the desired bispecific antibodies is inserted into the expression system, which consequently expresses the proteins accordingly. Protein purification – Steps to isolate and enrich bispecific antibodies are taken. This can include several purification processes, such as protein A affinity chromatography or peptide tagging. Antibody characterization – Characterization and quality control conclude the production process. Effector functions, stability and binding specificity are examined at this stage. == Mechanism of action == === Recruiting and activating of immune cells === The binding of a BsAb to its target antigens can lead to a variety of effects. The most widely used application of this approach is in cancer immunotherapy, where BsAbs are engineered to simultaneously bind a cytotoxic cell and a target (a tumour cell) to be destroyed. It is possible to observe the bridging effect that BsAbs have on T cell/cancer cell interactions using label-free live cell imaging. Catumaxomab, one of the first trifunctional antibodies approved for therapeutic use, binds both CD3 on cytotoxic T cells and EpCAM on human adenocarcinomas. The Fc region additionally binds to a cell that expresses Fc receptors, like a macrophage, natural killer cell or dendritic cell. Since the Fc region is still intact, this allows for the BsAb to trigger common immune responses when recognized by an Fc receptor, such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity. === Interfering with receptor signaling and inactivating signaling ligands === The growth of tumor cells can be simulated or modulated by receptor tyrosine kinase (RTKs), including members of the Her family or insulin-like growth factor (IGF). The RTKs are therefore preferred targets in cancer therapy. Although monospecific RTK-targeting IgGs have already been available in the market, such as cetuximab (Erbitux) and panitumumab (Vectibix), both of which are directed against HER1. However, cancer cells can switch to a different pathway to escape the growth inhibition generated by blocking one signaling pathway. To improve the therapeutic efficacy, simultaneously interfering/blocking of two (or more) RTK signaling pathways, achieved through the mediation of BsAb to inactivate either the RTKs or their ligand, reduces the possibility of the escape mechanisms adopted by the tumor cells. In addition, in working with Ebolavirus vaccines, a study has shown that a DVD-Ig antibody can be used to prevent viral escape from the endosome. Ebolaviruses infect cells by receptor-mediated endocytosis. Researchers developed DVD-Igs where the outer variable regions bind to the surface glycoproteins of the viral coat and enter the cell with the virus. These outer regions are cleaved in the viral endosome, revealing the inner variable regions that then bind to both the virus and internal receptors in the endosome. Blocking the interaction between the virus and endosomal proteins prevents viral escape from the endosome and further infection. === Forcing association of protein complexes === As an example, emicizumab (formerly RG6013) is an IgG derivative containing H-chain heterodimerization motifs, which was combined with the common light chain approach to prevent L-chain mispairing issues. With a bivalent composition, emicizumab brings two protein antigens together into one complex. Factor IXa and Factor X in the coagulation cascade are the cognate antigens which are bound by RG6013. These two factors are brought together by coagulation factor VIIIa in a healthy individual, while patients with bleeding disorder hemophilia A do not have VIIIa. Current treatment of this disorder is to supplement the patients with FVIII to reduce bleeding complications. But FVIII can be recognized as a foreign protein in these patients due to the absence of this protein and thus an immune response will be generated against this protein. Besides, FVIII has a short half-life (less than 15 hours) and thus is cleared rapidly. However, the humanized BsAb has lower immunogenicity and long serum half-life compared with FVIII and thus provide a better treatment for hemophilia. == Advantages over ordinary monoclonal antibodies == Cancer immunotherapy with ordinary monoclonal antibodies does not activate T-lymphocytes because the Fab regions are already used for binding the tumor cells, and this type of cell does not have Fc receptors. Bispecific antibodies also have a higher cytotoxic potential, and bind to antigens that are expressed relatively weakly. The effective dose is around 0.01 mg·m−2·d−1 (milligrams per square meter body surface area per day), which is several orders of magnitude lower than with ordinary antibodies. For non-IgG-like BsAbs, their smaller size allows them to reach antigens usually unavailable to conventional antibodies. In the case of Ebola vaccines, this method allows the antibody to target intracellular targets not usually accessible by traditional monoclonal antibody treatments. Additionally, targeting more than one molecule can be useful to circumvent the regulation of parallel pathways and avoid resistance to the treatment. Binding or blocking multiple targets in a pathway can be beneficial to stopping disease, as most conditions have complicated multifaceted effects throughout the body. Together with combination therapies, BsAbs are being used more and more to treat certain types of cancers, as, over time, some tumors develop resistances to checkpoint inhibitors and/or co-stimulatory molecules. == Current Scenario of bsAb drugs == Several bsAb drugs have been approved by the US FDA / EMA and over 180 are currently in clinical trials. The first bispecific antibody to gain regulatory approval, blinatumomab, targets CD19 on B cells and CD3 on T cells, leading to the activation of T cells and the destruction of B cells. Additional bispecific antibody drugs have since been approved by the US FDA: emicizumab, amivantamab, tebentafusp, faricimab, teclistamab, mosunetuzumab, epcoritamab, glofitamab. Among the bsAb programs currently under development, the combination of CD3 and tumor surface targets are the most popular targets pairs. Other popular targets are HER2, PD-1, PD-L1, EGFR, CTLA-4, etc., which as well as immune targets of PD-1, PD-L1, BCMA, CD47, CTLA-4, LAG-3, 4 -1BB. Additionally, with the approval of the several new bsAb since 2022, and new mechanisms for improving efficacy like development of hetero-dimer bispecific molecules, several additional possibilities of target pairs have emerged. == Problems and current disadvantages == A primary issue accompanying BsAb development since the early stages has been achieving a high ratio of correctly paired bispecific antibodies. Early attempts to produce BsAbs resulted in large amounts of homodimers and other mispaired fragments. Novel pairing technologies have been developed to increase the heterodimerization rate, leading to higher yields and reduced production costs. Furthermore, IgG-like antibodies can be immunogenic, which means the Fc region could cause detrimental downstream immune responses caused by cells that are activated by Fc receptors. The therapeutic use of BsAbs as a whole is still largely in development, with many clinical trials currently ongoing that are determining the efficacy and safety of BsAbs for treatment. One major area of concern is the feasibility of administration and management of side effects, where the potential for therapeutic success must be weighed against possible risks. The occurrence of side effects primarily depends on the specific antibody, its target, and patient-specific factors. These factors have to be individually examined for each patient in order to evaluate the feasibility of a bispecific antibody treatment, and to assess the risk of infusion-related, immune-related, organ-specific, and hematologic side effects. == Applications == Bispecific antibodies have a wide variety of applications in diagnosis and therapy. BsAbs can be combined with HRPO, can be used in pre-targeting strategies, and can be used to provide better imaging for early detection in diagnosis. To treat cancer, BsAbs can target immune cells precisely, help and reactive the immune cells, fine-tune the fate and function of immune cells, improve the tolerance of immune cells, and promote the return to immune homeostasis. BsAbs can also be applied to treat other diseases, including hemophilia A, diabetes, Alzheimer's disease, and ophthalmological diseases. === BsAbs on the market === Several bispecific antibodies are presently in clinical use. Blinatumomab, which targets CD19 and CD3, is used in the treatment of Philadelphia chromosome negative B cell acute lymphoblastic leukemia (ALL). Emicizumab, which targets clotting factors IXa and X, is used in the treatment of hemophilia A. Catumaxomab was withdrawn from the European market in 2017 for commercial reasons. Amivantamab, which targets epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Teclistamab, which targets CD3 and B-cell maturation antigen (BCMA), is used in the treatment of multiple myeloma, and zenocutuzumab. == See also == Ivonescimab == References == This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute. == External links == Bispecific monoclonal antibody entry in the public domain NCI Dictionary of Cancer Terms Bispecific+antibodies at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Bispecific_antibody
Anion-exchange chromatography is a process that separates substances based on their charges using an ion-exchange resin containing positively charged groups, such as diethyl-aminoethyl groups (DEAE). In solution, the resin is coated with positively charged counter-ions (cations). Anion exchange resins will bind to negatively charged molecules, displacing the counter-ion. Anion exchange chromatography is commonly used to purify proteins, amino acids, sugars/carbohydrates and other acidic substances with a negative charge at higher pH levels. The tightness of the binding between the substance and the resin is based on the strength of the negative charge of the substance. == General technique for protein purification == A slurry of resin, such as DEAE-Sephadex is poured into the column. The matrix that is used is insoluble with charged groups that are covalently attached. These charged groups are referred to as exchangers like cation and anion exchangers. After it settles, the column is pre-equilibrated in buffer before the protein mixture is applied. DEAE-Sephadex is a positively-charged slurry that will have electrostatic interactions with the negatively charged atoms, making them elute later than the positively-charged molecules in the interested sample. This is a separation technique used widely to discover specific proteins, or enzymes in the body. Unbound proteins are collected in the flow-through and/or in subsequent buffer washes. Proteins that bind to the positively charged resin are retained and can be eluted in one of two ways. First, the salt concentration in the elution buffer is gradually increased. The negative ions in the salt solution (e.g. Cl−) compete with protein in binding to the resin. Second, the pH of the solution can be gradually decreased which results in a more positive charge on the protein, releasing it from the resin. Both of these techniques can displace the negatively charged protein which is then eluted into test tubes fractions with the buffer. The separation of proteins will depend on the differences in total charge. Composition of ionizable side chain groups will determine the total charge of the protein at a particular pH. At the isoelectric point (pI), the total charge on the protein is 0 and it will not bind to the matrix. If the pH is above the pI, the protein will have a negative charge and bind to the matrix in an anion exchange column. The stability of the protein at values above or below the pI, will determine if an anion exchange column or cation exchange column should be used. If it is stable at pH values below the pI, the cation exchange column be used. If it is stable at pH values above the pI then the anion exchange column can be used. == References ==	Wikipedia/Anion_exchange_chromatography
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans (for example, antibodies developed as anti-cancer drugs). Humanization can be necessary when the process of developing a specific antibody involves generation in a non-human immune system (such as that in mice). The protein sequences of antibodies produced in this way are partially distinct from homologous antibodies occurring naturally in humans, and are therefore potentially immunogenic when administered to human patients (see also Human anti-mouse antibody). Until 2021, the International Nonproprietary Names of new humanized antibodies ended in -zumab, as in omalizumab, but a new nomenclature has since been adopted and new names now end in different stems (see Nomenclature of monoclonal antibodies). Humanized antibodies are distinct from chimeric antibodies. The latter also have their protein sequences made more similar to human antibodies, but carry a larger stretch of non-human protein. There are other ways to develop monoclonal antibodies. This list covers many of the monoclonals developed for use in humans. == Use of recombinant DNA in humanization process == The humanization process takes advantage of the fact that production of monoclonal antibodies can be accomplished using recombinant DNA to create constructs capable of expression in mammalian cell culture. That is, gene segments capable of producing antibodies are isolated and cloned into cells that can be grown in a bioreactor such that antibody proteins produced from the DNA of the cloned genes can be harvested en masse. The step involving recombinant DNA provides an intervention point that can be readily exploited to alter the protein sequence of the expressed antibody. The alterations to antibody structure that are achieved in the humanization process are therefore all effectuated through techniques at the DNA level. Not all methods for deriving antibodies intended for human therapy require a humanization step (e.g. phage display) but essentially all are dependent on techniques that similarly allow the "insertion" or "swapping-out" of portions of the antibody molecule. == Distinction from "chimeric antibody" == Humanization is usually seen as distinct from the creation of a mouse-human antibody chimera. So, although the creation of an antibody chimera is normally undertaken to achieve a more human-like antibody (by replacing constant region of the mouse antibody with that from human) simple chimeras of this type are not usually referred to as humanized. Rather, the protein sequence of a humanized antibody is essentially identical to that of a human variant, despite the non-human origin of some of its complementarity-determining region (CDR) segments responsible for the ability of the antibody to bind to its target antigen. Chimeric antibody names contain a -xi- stem. Examples of chimeric antibodies approved for human therapy include abciximab (ReoPro), basiliximab (Simulect), cetuximab (Erbitux), infliximab (Remicade) and rituximab (MabThera). There are also several examples of chimerics currently in clinical trials (e.g. bavituximab, see sortable list for additional examples). == Humanizing via a chimeric intermediate == The humanization process may also include the creation of a mouse-human chimera as an initial step. In this case, a mouse variable region is spliced to a human constant region. The chimera can then be further humanized by selectively altering the sequence of amino acids in the variable region of the molecule. The alteration process must be "selective" to retain the specificity for which the antibody was originally developed. That is, since the CDR portions of the variable region are essential to the ability of the antibody to bind to its intended target, the amino acids in these portions cannot be altered without the risk of undermining the purpose of the development. Aside from the CDR segments, the portions of the variable regions that differ from those in humans can be corrected by exchanging the appropriate individual amino acids. This is accomplished at the DNA level through mutagenesis. Naming of humanized chimeras includes the stem for both designations (-xi- + -zu-). Otelixizumab is an example of a humanized chimera currently in clinical trials for treatment of rheumatoid arthritis and diabetes mellitus. == Humanization by insertion of relevant CDRs into human antibody "scaffold" == It is possible to produce a humanized antibody without creating a chimeric intermediate. "Direct" creation of a humanized antibody can be accomplished by inserting the appropriate CDR coding segments (so-called 'donor', responsible for the desired binding properties) into a human antibody "scaffold" (so-called 'acceptor'). As discussed above, this is achieved through recombinant DNA methods using an appropriate vector and expression in mammalian cells. That is, after an antibody is developed to have the desired properties in a mouse (or other non-human), the DNA coding for that antibody can be isolated, cloned into a vector and sequenced (or the DNA can be sequenced directly using single-cell methods). The DNA sequence corresponding to the antibody CDRs can then be determined. Once the precise sequence of the desired CDRs are known, a strategy can be devised for inserting these sequences appropriately into a construct containing the DNA for a human antibody variant. The strategy may also employ synthesis of linear DNA fragments based on the reading of CDR sequences. The process requires computer-modelling software to determine which of the antibody's amino acids can be changed from murine-sequence to human-sequence without the changes compromising the conformation of the binding site. In the United States, this software was developed, patented, and demonstrated, by Protein Design Labs, Inc. in Mountain View, California, in the 1980s and 1990s. Alemtuzumab is an early example of an antibody whose humanization did not include a chimeric intermediate. In this case, a monoclonal dubbed "Campath-1" was developed to bind CD52 using a mouse system. The hypervariable loops of Campath-1 (that contain its CDRs and thereby impart its ability to bind CD52) were then extracted and inserted into a human antibody framework. Alemtuzumab is approved for treatment of B-cell chronic lymphocytic leukemia and is currently in clinical trials for a variety of other conditions including multiple sclerosis. == Derivation from sources other than mice == There are technologies that completely avoid the use of mice or other non-human mammals in the process of discovering antibodies for human therapy. Examples of such systems include various "display" methods (primarily phage display) as well as methods that exploit the elevated B-cell levels that occur during a human immune response. === Display methods === These employ the selective principles of specific antibody production but exploit micro-organisms (as in phage display) or even cell free extracts (as in ribosome display). These systems rely on the creation of antibody gene "libraries" which can be wholly derived from human RNA isolated from peripheral blood. The immediate products of these systems are antibody fragments, normally Fab or scFv. This means that, although antibody fragments created using display methods are of fully human sequence, they are not full antibodies. Therefore, processes in essence identical to humanization are used to incorporate and express the derived affinities within a full antibody. Adalimumab (Humira) is an example of an antibody approved for human therapy that was created through phage display. === Antibodies from human patients or vaccine recipients === It is possible to exploit human immune reaction in the discovery of monoclonal antibodies. Simply put, human immune response works in the same way as that in a mouse or other non-human mammal. Therefore, persons experiencing a challenge to their immune system, such as an infectious disease, cancer or a vaccination are a potential source of monoclonal antibodies directed at that challenge. This approach seems especially apt for the development of anti-viral therapies that exploit the principles of passive immunity. Variants of this approach have been demonstrated in principle and some are finding their way into commercial development. == See also == List of therapeutic monoclonal antibodies == References ==	Wikipedia/Humanized_antibody
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this fusion gene results in a single or multiple polypeptides with functional properties derived from each of the original proteins. Recombinant fusion proteins are created artificially by recombinant DNA technology for use in biological research or therapeutics. Chimeric or chimera usually designate hybrid proteins made of polypeptides having different functions or physico-chemical patterns. Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes. Naturally occurring fusion proteins are commonly found in cancer cells, where they may function as oncoproteins. The bcr-abl fusion protein is a well-known example of an oncogenic fusion protein, and is considered to be the primary oncogenic driver of chronic myelogenous leukemia. == Functions == Some fusion proteins combine whole peptides and therefore contain all functional domains of the original proteins. However, other fusion proteins, especially those that occur naturally, combine only portions of coding sequences and therefore do not maintain the original functions of the parental genes that formed them. Many whole gene fusions are fully functional and can still act to replace the original peptides. Some, however, experience interactions between the two proteins that can modify their functions. Beyond these effects, some gene fusions may cause regulatory changes that alter when and where these genes act. For partial gene fusions, the shuffling of different active sites and binding domains have the potential to result in new proteins with novel functions. === Fluorescent protein tags === The fusion of fluorescent tags to proteins in a host cell is a widely popular technique used in experimental cell and biology research in order to track protein interactions in real time. The first fluorescent tag, green fluorescent protein (GFP), was isolated from Aequorea victoria and is still used frequently in modern research. More recent derivations include photoconvertible fluorescent proteins (PCFPs), which were first isolated from Anthozoa. The most commonly used PCFP is the Kaede fluorescent tag, but the development of Kikume green-red (KikGR) in 2005 offers a brighter signal and more efficient photoconversion. The advantage of using PCFP fluorescent tags is the ability to track the interaction of overlapping biochemical pathways in real time. The tag will change color from green to red once the protein reaches a point of interest in the pathway, and the alternate colored protein can be monitored through the duration of pathway. This technique is especially useful when studying G-protein coupled receptor (GPCR) recycling pathways. The fates of recycled G-protein receptors may either be sent to the plasma membrane to be recycled, marked by a green fluorescent tag, or may be sent to a lysosome for degradation, marked by a red fluorescent tag. === Chimeric protein drugs === The purpose of creating fusion proteins in drug development is to impart properties from each of the "parent" proteins to the resulting chimeric protein. Several chimeric protein drugs are currently available for medical use. Many chimeric protein drugs are monoclonal antibodies whose specificity for a target molecule was developed using mice and hence were initially "mouse" antibodies. As non-human proteins, mouse antibodies tend to evoke an immune reaction if administered to humans. The chimerization process involves engineering the replacement of segments of the antibody molecule that distinguish it from a human antibody. For example, human constant domains can be introduced, thereby eliminating most of the potentially immunogenic portions of the drug without altering its specificity for the intended therapeutic target. Antibody nomenclature indicates this type of modification by inserting -xi- into the non-proprietary name (e.g., abci-xi-mab). If parts of the variable domains are also replaced by human portions, humanized antibodies are obtained. Although not conceptually distinct from chimeras, this type is indicated using -zu- such as in dacli-zu-mab. See the list of monoclonal antibodies for more examples. In addition to chimeric and humanized antibodies, there are other pharmaceutical purposes for the creation of chimeric constructs. Etanercept, for example, is a TNFα blocker created through the combination of a tumor necrosis factor receptor (TNFR) with the immunoglobulin G1 Fc segment. TNFR provides specificity for the drug target and the antibody Fc segment is believed to add stability and deliverability of the drug. Additional chimeric proteins used for therapeutic applications include: Aflibercept: A human recombinant protein that aids in the treatment of oxaliplatin-resistant metastatic colorectal cancer, neo-vascular macular degeneration, and macular edema. Rilonacept: Reduces inflammation by preventing activation of IL-1 receptors to treat cryopyrin-associated periodic syndromes (CAPS). Alefacept: Regulated T-cell responses by selectively targeting effector memory T-cells to treat psoriasis vulgaris. Romiplostim: A peptibody that treats immune thrombocytopenia. Abatacept/Belatacept: Interferes with T-cell co-stimulation to treat autoimmune disorders like rheumatoid arthritis, psoriatic arthritis, and psoriasis. Denileukin-diftitox: Treats cutaneous lymphoma. == Recombinant technology == A recombinant fusion protein is a protein created through genetic engineering of a fusion gene. This typically involves removing the stop codon from a cDNA sequence coding for the first protein, then appending the cDNA sequence of the second protein in frame through ligation or overlap extension PCR. That DNA sequence will then be expressed by a cell as a single protein. The protein can be engineered to include the full sequence of both original proteins, or only a portion of either. If the two entities are proteins, often linker (or "spacer") peptides are also added, which make it more likely that the proteins fold independently and behave as expected. Especially in the case where the linkers enable protein purification, linkers in protein or peptide fusions are sometimes engineered with cleavage sites for proteases or chemical agents that enable the liberation of the two separate proteins. This technique is often used for identification and purification of proteins, by fusing a GST protein, FLAG peptide, or a hexa-his peptide (6xHis-tag), which can be isolated using affinity chromatography with nickel or cobalt resins. Di- or multimeric chimeric proteins can be manufactured through genetic engineering by fusion to the original proteins of peptide domains that induce artificial protein di- or multimerization (e.g., streptavidin or leucine zippers). Fusion proteins can also be manufactured with toxins or antibodies attached to them in order to study disease development. Hydrogenase promoter, PSH, was studied constructing a PSH promoter-gfp fusion by using green fluorescent protein (gfp) reporter gene. === Recombinant functionality === Novel recombinant technologies have made it possible to improve fusion protein design for use in fields as diverse as biodetection, paper and food industries, and biopharmaceuticals. Recent improvements have involved the fusion of single peptides or protein fragments to regions of existing proteins, such as N and C termini, and are known to increase the following properties: Catalytic efficiency: Fusion of certain peptides allow for greater catalytic efficiency by altering the tertiary and quaternary structure of the target protein. Solubility: A common challenge in fusion protein design is the issue of insolubility of newly synthesized fusion proteins in the recombinant host, leading to an over-aggregation of the target protein in the cell. Molecular chaperones that are able to aid in protein folding may be added, thereby better segregating hydrophobic and hydrophilic interactions in the solute to increase protein solubility. Thermostability: Singular peptides or protein fragments are typically added to reduce flexibility of either the N or C terminus of the target protein, which reinforces thermostability and stabilizes pH range. Enzyme activity: Fusion that involves the introduction of hydrogen bonds may be used to expand overall enzyme activity. Expression levels: Addition of numerous fusion fragments, such as maltose binding protein (MBP) or small ubiquitin-like molecule (SUMO), serve to enhance enzyme expression and secretion of the target protein. Immobilization: PHA synthase, an enzyme that allows for the immobilization of proteins of interest, is an important fusion tag in industrial research. Crystal quality: Crystal quality can be improved by adding covalent links between proteins, aiding in structure determination techniques. == Recombinant protein design == The earliest applications of recombinant protein design can be documented in the use of single peptide tags for purification of proteins in affinity chromatography. Since then, a variety of fusion protein design techniques have been developed for applications as diverse as fluorescent protein tags to recombinant fusion protein drugs. Three commonly used design techniques include tandem fusion, domain insertion, and post-translational conjugation. === Tandem fusion === The proteins of interest are simply connected end-to-end via fusion of N or C termini between the proteins. This provides a flexible bridge structure allowing enough space between fusion partners to ensure proper folding. However, the N or C termini of the peptide are often crucial components in obtaining the desired folding pattern for the recombinant protein, making simple end-to-end conjoining of domains ineffective in this case. For this reason, a protein linker is often needed to maintain the functionality of the protein domains of interest. === Domain insertion === This technique involves the fusion of consecutive protein domains by encoding desired structures into a single polypeptide chain, but sometimes may require insertion of a domain within another domain. This technique is typically regarding as more difficult to carry out than tandem fusion, due to difficulty finding an appropriate ligation site in the gene of interest. === Post-translational conjugation === This technique fuses protein domains following ribosomal translation of the proteins of interest, in contrast to genetic fusion prior to translation used in other recombinant technologies. === Protein linkers === Protein linkers aid fusion protein design by providing appropriate spacing between domains, supporting correct protein folding in the case that N or C termini interactions are crucial to folding. Commonly, protein linkers permit important domain interactions, reinforce stability, and reduce steric hindrance, making them preferred for use in fusion protein design even when N and C termini can be fused. Three major types of linkers are flexible, rigid, and in vivo cleavable. Flexible linkers may consist of many small glycine residues, giving them the ability curl into a dynamic, adaptable shape. Rigid linkers may be formed of large, cyclic proline residues, which can be helpful when highly specific spacing between domains must be maintained. In vivo cleavable linkers are unique in that they are designed to allow the release of one or more fused domains under certain reaction conditions, such as a specific pH gradient, or when coming in contact with another biomolecule in the cell. == Natural occurrence == Naturally occurring fusion genes are most commonly created when a chromosomal translocation replaces the terminal exons of one gene with intact exons from a second gene. This creates a single gene that can be transcribed, spliced, and translated to produce a functional fusion protein. Many important cancer-promoting oncogenes are fusion genes produced in this way. Examples include: Gag-onc fusion protein Bcr-abl fusion protein Tpr-met fusion protein Antibodies are fusion proteins produced by V(D)J recombination. There are also rare examples of naturally occurring polypeptides that appear to be a fusion of two clearly defined modules, in which each module displays its characteristic activity or function, independent of the other. Two major examples are: double PP2C chimera in Plasmodium falciparum (the malaria parasite), in which each PP2C module exhibits protein phosphatase 2C enzymatic activity, and the dual-family immunophilins that occur in a number of unicellular organisms (such as protozoan parasites and Flavobacteria) and contain full-length cyclophilin and FKBP chaperone modules. The evolutionary origin of such chimera remains unclear. == See also == Genetic engineering Protein engineering Cell–cell fusogens == References == == External links == Mutant+Chimeric+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) ChiPPI Archived 2021-11-10 at the Wayback Machine: The Server Protein–Protein Interaction of Chimeric Proteins.	Wikipedia/Chimeric_antibody
A myeloma protein is an abnormal antibody (immunoglobulin) or (more often) a fragment thereof, such as an immunoglobulin light chain, that is produced in excess by an abnormal monoclonal proliferation of plasma cells, typically in multiple myeloma or Monoclonal gammopathy of undetermined significance. Other terms for such a protein are monoclonal protein, M protein, M component, M spike, spike protein, or paraprotein. This proliferation of the myeloma protein has several deleterious effects on the body, including impaired immune function, abnormally high blood viscosity ("thickness" of the blood), and kidney damage. == History == In 1940, senior pathologist Kurt Apitz of the Charité – Berlin University Medicine hospital, introduced the concept and word paraprotein. == Cause == Myeloma is a malignancy of plasma cells. Plasma cells produce immunoglobulins, which are commonly called antibodies. There are thousands of different antibodies, each consisting of pairs of heavy and light chains. Antibodies are typically grouped into five classes: IgA, IgD, IgE, IgG, and IgM. When someone has myeloma, a malignant clone, a rogue plasma cell, reproduces in an uncontrolled fashion, resulting in overproduction of the specific antibody the original cell was generated to produce. Each type of antibody has a different number of light chain and heavy chain pairs. As a result, there is a characteristic normal distribution of these antibodies in the blood by molecular weight. When there is a malignant clone, there is usually overproduction of a single antibody, resulting in a "spike" on the normal distribution (sharp peak on the graph), which is called an M spike (or monoclonal spike). People will sometimes develop a condition called MGUS (Monoclonal gammopathy of undetermined significance), where there is overproduction of one antibody but the condition is benign (non-cancerous). An explanation of the difference between multiple myeloma and MGUS can be found in the International Myeloma Foundation's Patient Handbook. and Concise Review Detection of paraproteins in the urine or blood is most often associated with MGUS, where they remain "silent", and multiple myeloma. An excess in the blood is known as paraproteinemia. Paraproteins form a narrow band, or 'spike' in protein electrophoresis as they are all exactly the same protein. Unlike normal immunoglobulin antibodies, paraproteins cannot fight infection. Serum free light-chain measurement can detect free light chains in the blood. Monoclonal free light chains in the serum or urine are called Bence Jones proteins. == Interpretation upon detection == Blood serum paraprotein levels of more than 30 g/L is diagnostic of smouldering myeloma, an intermediate in a spectrum of step-wise progressive diseases termed plasma cell dyscrasias. Elevated paraprotein level (above 30 g/L) in conjunction with end organ damage (elevated calcium, kidney failure, anemia, or bone lesions) or other biomarkers of malignancy, is diagnostic of multiple myeloma, according to the diagnostic criteria of the International Myeloma Working Group, which were updated in 2014. Detection of paraprotein in serum of less than 30 g/L is classified as monoclonal gammopathy of undetermined significance in cases where clonal plasma cells constitute less than 10% on bone marrow biopsy and there is no myeloma-related organ or tissue impairment. == See also == Tuftsin Monoclonal gammopathy of undetermined significance Smouldering myeloma Multiple myeloma Plasma cell dyscrasia == References == == External links == Paraproteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) Educational Resource for Paraproteins Paraprotein typing	Wikipedia/Paraprotein
A bispecific monoclonal antibody (BsMAb, BsAb) is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen. BsAbs can be manufactured in several structural formats. BsAbs can be designed to recruit and activate immune cells, to interfere with receptor signaling and inactivate signaling ligands, and to force association of protein complexes. BsAbs have been explored for cancer immunotherapy, drug delivery, and Alzheimer's disease. == Development history == The original concept of BsAbs was proposed by Nisonoff and his collaborators in the 1960s, including the first idea of antibody architecture and other findings. In 1975, the problem of producing pure antibodies was solved by the creation of hybridoma technology, and the new era of monoclonal antibodies (MoAbs) came. In 1983, Milstein and Cuello created hybrid-hybridoma (quadroma) technology. In 1988, the single-chain variable fragment (scFv) was invented by the Huston team to minimize the refolding problems, which contains the incorrect domain pairing or aggregation of two-chain species. In 1996, the BsAbs became more developed when the knobs-into-holes technology emerged. == Structural types and manufacturing methods == There are many formats of BsAbs, but the two main categories are IgG-like and non-IgG-like. The main types of manufacturing methods are quadromas, chemical conjugation, and genetic recombination, and each method results in a unique format. === IgG-like === This format retains the traditional monoclonal antibody (mAb) structure of two Fab arms and one Fc region, except the two Fab sites bind different antigens. The most common types are called trifunctional antibodies, as they have three unique binding sites on the antibody: the two Fab regions, and the Fc region. Each heavy and light chain pair is from a unique mAb. The Fc region made from the two heavy chains forms the third binding site. These BsAbs are often manufactured with the quadroma, or the hybrid hybridoma, method. However, the quadroma method relies on random chance to form usable BsAb, and can be inefficient. Another method for manufacturing IgG-like BsAb is called "knobs into holes," and relies on introducing a mutation for a large amino acid in the heavy chain from one mAb, and a mutation for a small amino acid in the other mAb's heavy chain. This allows the target heavy chains (and their corresponding light chains) to fit together better, and makes the production of BsAbs more reliable. === Non-IgG-like === There are other BsAbs that lack an Fc region entirely, and thus leads to relatively simple design strategies. These include chemically linked Fabs, consisting of only the Fab regions, and various types of bivalent and trivalent single-chain variable fragments (ScFvs). There are also fusion proteins mimicking the variable domains of two antibodies. The furthest developed of these newer formats are the bi-specific T-cell engagers (BiTEs), which uses the G4S linker to connect two ScFvs-one CD3 antibody ScFv and one tumor-associated antigen (TAA) or tumor-specific ScFv-to redirect T cells to cancer cells for target killing. Other platforms include tetravalent antiparallel structure (TandAbs) and VH only (Bi-Nanobody). The TandAb platform is formed by a tetravalent antibody molecule containing two binding sites for each of two antigens. In this platform, the reverse pairing of two peptide chains forms a homodimer molecule. As an example, AFM11 is based on the TandAbs platform and targets both CD3 and CD19 to achieve therapeutic effects. AFM11 showed dose-dependent inhibition of Raji tumors in vivo. The Bi-Nanobody platform forms multi-specific binding through the connection between the VH regions of two or more antibody molecules. The products that are designed based on this platform are small molecules and these small molecules have high stability and better tissue permeability in vivo. Even though non-IgG-like BsAbs have low molecular weight and thus high tumor tissue permeability, their half-life is relatively short and they require multiple doses. Despite the considerable differences between the various types and formats of bispecific antibodies, their manufacturing processes correspond in several steps: Genetic engineering and cloning – Different monoclonal antibodies or antibody fragments are fused. Recombinant DNA technology is applied to generate one single, bispecific antibody. Preparation of expression system – An expression system is chosen and prepared for antibody expression. Frequently used expression systems for therapeutic bispecific antibodies are mammalian cells, such as CHO cells, as they are effective in performing complex post-translational modifications. Transfection and protein production – Either via stable or transient transfection, genetic information of the desired bispecific antibodies is inserted into the expression system, which consequently expresses the proteins accordingly. Protein purification – Steps to isolate and enrich bispecific antibodies are taken. This can include several purification processes, such as protein A affinity chromatography or peptide tagging. Antibody characterization – Characterization and quality control conclude the production process. Effector functions, stability and binding specificity are examined at this stage. == Mechanism of action == === Recruiting and activating of immune cells === The binding of a BsAb to its target antigens can lead to a variety of effects. The most widely used application of this approach is in cancer immunotherapy, where BsAbs are engineered to simultaneously bind a cytotoxic cell and a target (a tumour cell) to be destroyed. It is possible to observe the bridging effect that BsAbs have on T cell/cancer cell interactions using label-free live cell imaging. Catumaxomab, one of the first trifunctional antibodies approved for therapeutic use, binds both CD3 on cytotoxic T cells and EpCAM on human adenocarcinomas. The Fc region additionally binds to a cell that expresses Fc receptors, like a macrophage, natural killer cell or dendritic cell. Since the Fc region is still intact, this allows for the BsAb to trigger common immune responses when recognized by an Fc receptor, such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity. === Interfering with receptor signaling and inactivating signaling ligands === The growth of tumor cells can be simulated or modulated by receptor tyrosine kinase (RTKs), including members of the Her family or insulin-like growth factor (IGF). The RTKs are therefore preferred targets in cancer therapy. Although monospecific RTK-targeting IgGs have already been available in the market, such as cetuximab (Erbitux) and panitumumab (Vectibix), both of which are directed against HER1. However, cancer cells can switch to a different pathway to escape the growth inhibition generated by blocking one signaling pathway. To improve the therapeutic efficacy, simultaneously interfering/blocking of two (or more) RTK signaling pathways, achieved through the mediation of BsAb to inactivate either the RTKs or their ligand, reduces the possibility of the escape mechanisms adopted by the tumor cells. In addition, in working with Ebolavirus vaccines, a study has shown that a DVD-Ig antibody can be used to prevent viral escape from the endosome. Ebolaviruses infect cells by receptor-mediated endocytosis. Researchers developed DVD-Igs where the outer variable regions bind to the surface glycoproteins of the viral coat and enter the cell with the virus. These outer regions are cleaved in the viral endosome, revealing the inner variable regions that then bind to both the virus and internal receptors in the endosome. Blocking the interaction between the virus and endosomal proteins prevents viral escape from the endosome and further infection. === Forcing association of protein complexes === As an example, emicizumab (formerly RG6013) is an IgG derivative containing H-chain heterodimerization motifs, which was combined with the common light chain approach to prevent L-chain mispairing issues. With a bivalent composition, emicizumab brings two protein antigens together into one complex. Factor IXa and Factor X in the coagulation cascade are the cognate antigens which are bound by RG6013. These two factors are brought together by coagulation factor VIIIa in a healthy individual, while patients with bleeding disorder hemophilia A do not have VIIIa. Current treatment of this disorder is to supplement the patients with FVIII to reduce bleeding complications. But FVIII can be recognized as a foreign protein in these patients due to the absence of this protein and thus an immune response will be generated against this protein. Besides, FVIII has a short half-life (less than 15 hours) and thus is cleared rapidly. However, the humanized BsAb has lower immunogenicity and long serum half-life compared with FVIII and thus provide a better treatment for hemophilia. == Advantages over ordinary monoclonal antibodies == Cancer immunotherapy with ordinary monoclonal antibodies does not activate T-lymphocytes because the Fab regions are already used for binding the tumor cells, and this type of cell does not have Fc receptors. Bispecific antibodies also have a higher cytotoxic potential, and bind to antigens that are expressed relatively weakly. The effective dose is around 0.01 mg·m−2·d−1 (milligrams per square meter body surface area per day), which is several orders of magnitude lower than with ordinary antibodies. For non-IgG-like BsAbs, their smaller size allows them to reach antigens usually unavailable to conventional antibodies. In the case of Ebola vaccines, this method allows the antibody to target intracellular targets not usually accessible by traditional monoclonal antibody treatments. Additionally, targeting more than one molecule can be useful to circumvent the regulation of parallel pathways and avoid resistance to the treatment. Binding or blocking multiple targets in a pathway can be beneficial to stopping disease, as most conditions have complicated multifaceted effects throughout the body. Together with combination therapies, BsAbs are being used more and more to treat certain types of cancers, as, over time, some tumors develop resistances to checkpoint inhibitors and/or co-stimulatory molecules. == Current Scenario of bsAb drugs == Several bsAb drugs have been approved by the US FDA / EMA and over 180 are currently in clinical trials. The first bispecific antibody to gain regulatory approval, blinatumomab, targets CD19 on B cells and CD3 on T cells, leading to the activation of T cells and the destruction of B cells. Additional bispecific antibody drugs have since been approved by the US FDA: emicizumab, amivantamab, tebentafusp, faricimab, teclistamab, mosunetuzumab, epcoritamab, glofitamab. Among the bsAb programs currently under development, the combination of CD3 and tumor surface targets are the most popular targets pairs. Other popular targets are HER2, PD-1, PD-L1, EGFR, CTLA-4, etc., which as well as immune targets of PD-1, PD-L1, BCMA, CD47, CTLA-4, LAG-3, 4 -1BB. Additionally, with the approval of the several new bsAb since 2022, and new mechanisms for improving efficacy like development of hetero-dimer bispecific molecules, several additional possibilities of target pairs have emerged. == Problems and current disadvantages == A primary issue accompanying BsAb development since the early stages has been achieving a high ratio of correctly paired bispecific antibodies. Early attempts to produce BsAbs resulted in large amounts of homodimers and other mispaired fragments. Novel pairing technologies have been developed to increase the heterodimerization rate, leading to higher yields and reduced production costs. Furthermore, IgG-like antibodies can be immunogenic, which means the Fc region could cause detrimental downstream immune responses caused by cells that are activated by Fc receptors. The therapeutic use of BsAbs as a whole is still largely in development, with many clinical trials currently ongoing that are determining the efficacy and safety of BsAbs for treatment. One major area of concern is the feasibility of administration and management of side effects, where the potential for therapeutic success must be weighed against possible risks. The occurrence of side effects primarily depends on the specific antibody, its target, and patient-specific factors. These factors have to be individually examined for each patient in order to evaluate the feasibility of a bispecific antibody treatment, and to assess the risk of infusion-related, immune-related, organ-specific, and hematologic side effects. == Applications == Bispecific antibodies have a wide variety of applications in diagnosis and therapy. BsAbs can be combined with HRPO, can be used in pre-targeting strategies, and can be used to provide better imaging for early detection in diagnosis. To treat cancer, BsAbs can target immune cells precisely, help and reactive the immune cells, fine-tune the fate and function of immune cells, improve the tolerance of immune cells, and promote the return to immune homeostasis. BsAbs can also be applied to treat other diseases, including hemophilia A, diabetes, Alzheimer's disease, and ophthalmological diseases. === BsAbs on the market === Several bispecific antibodies are presently in clinical use. Blinatumomab, which targets CD19 and CD3, is used in the treatment of Philadelphia chromosome negative B cell acute lymphoblastic leukemia (ALL). Emicizumab, which targets clotting factors IXa and X, is used in the treatment of hemophilia A. Catumaxomab was withdrawn from the European market in 2017 for commercial reasons. Amivantamab, which targets epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. Teclistamab, which targets CD3 and B-cell maturation antigen (BCMA), is used in the treatment of multiple myeloma, and zenocutuzumab. == See also == Ivonescimab == References == This article incorporates public domain material from Dictionary of Cancer Terms. U.S. National Cancer Institute. == External links == Bispecific monoclonal antibody entry in the public domain NCI Dictionary of Cancer Terms Bispecific+antibodies at the U.S. National Library of Medicine Medical Subject Headings (MeSH)	Wikipedia/Bispecific_monoclonal_antibody
Coronary artery bypass surgery, also known as coronary artery bypass graft (CABG, pronounced "cabbage"), is a surgical procedure to treat coronary artery disease (CAD), the buildup of plaques in the arteries of the heart. It can relieve chest pain caused by CAD, slow the progression of CAD, and increase life expectancy. It aims to bypass narrowings in heart arteries by using arteries or veins harvested from other parts of the body, thus restoring adequate blood supply to the previously ischemic (deprived of blood) heart. There are two main approaches. The first uses a cardiopulmonary bypass machine, a machine which takes over the functions of the heart and lungs during surgery by circulating blood and oxygen. With the heart in cardioplegic arrest, harvested arteries and veins are used to connect across problematic regions—a construction known as surgical anastomosis. In the second approach, called the off-pump coronary artery bypass (OPCAB), these anastomoses are constructed while the heart is still beating. The anastomosis supplying the left anterior descending branch is the most significant one and usually, the left internal mammary artery is harvested for use. Other commonly employed sources are the right internal mammary artery, the radial artery, and the great saphenous vein. Effective ways to treat chest pain (specifically, angina, a common symptom of CAD) have been sought since the beginning of the 20th century. In the 1960s, CABG was introduced in its modern form and has since become the main treatment for significant CAD. Significant complications of the operation include bleeding, heart problems (heart attack, arrhythmias), stroke, infections (often pneumonia) and injury to the kidneys. == Uses == Coronary artery bypass surgery aims to prevent death from coronary artery disease and improve quality of life by relieving angina, the associated feeling of chest pain. The decision to perform surgery is informed by studies of CABG's efficacy in different patient subgroups, based on the lesions' anatomy or how well the heart is functioning. These results are compared with that of other strategies, most importantly percutaneous coronary intervention (PCI). === Coronary artery disease === Coronary artery disease is caused when coronary arteries of the heart accumulate atheromatous plaques, causing stenosis (narrowing) in one or more arteries and risking myocardial infarction, the interruption of blood supply to the heart. CAD can occur in any of the major vessels of the coronary circulation: the left main stem, left ascending artery, circumflex artery, and right coronary artery, and branches thereof. CAD symptoms vary from none, to chest pain only when exercising (stable angina), to chest pain even at rest (unstable angina). It can even manifest as a myocardial infarction; if blood flow to the heart is not restored within a few hours, whether spontaneously or by medical intervention, the blood-deprived part of the heart becomes necrotic (dies) and is scarred. It may lead to other complications such as arrhythmias, rupture of the papillary muscles of the heart, or sudden death. There are various methods of detecting and assessing CAD. Apart from history and clinical examination, noninvasive methods include electrocardiography (ECG) at rest or during exercise, and X-ray of the chest. Echocardiography can quantify heart functioning by measuring, for example, enlargement of the left ventricle, the ejection fraction, and the situation of the heart valves. The most accurate ways to detect CAD are the coronary angiogram and the coronary CT angiography. An angiogram can provide detailed anatomy of coronary circulation and lesions. The significance of each lesion is determined by the diameter loss. A diameter loss of 50% translates to a 75% cross-sectional area loss, considered moderate by most groups. Severe stenosis constitutes a diameter loss of 2/3 or more—a greater-than-90% loss of cross-sectional area. To more accurately determine the severity of stenosis, interventional cardiologists may also employ intravascular ultrasound, which can determine the severity and provide information on the composition of the atheromatous plaque. With the technique of fractional flow reserve, the pressure after the stenosis is compared to mean aortic pressure. If the ratio is less than 0.80, then the stenosis is deemed significant. === Indications for CABG === ==== Stable patients ==== People with angina during exercise are usually first treated with medical therapy. Noninvasive tests help estimate which patients might benefit from undergoing coronary angiography. Generally, if portions of cardiac wall are receiving less blood than normal, coronary angiography is indicated; then, lesions are identified and inform a decision to undergo PCI or CABG. CABG is generally preferred over PCI when there is a significant burden of plaque on the coronary arteries, that is extensive and complex, due to survival benefit. Other indicators that a patient will benefit more from CABG rather than PCI include: decreased left-ventricle function; left main disease; diabetes; and complex triple system disease (including LAD, Cx and RCA), especially when the lesion in the LAD is at its proximal part. ==== Acute coronary syndrome ==== During an acute heart event, known as acute coronary syndrome, it is paramount to quickly restore blood flow to heart tissue. Typically, patients arrive at the hospital with chest pain. They are first treated with drugs, particularly the strongest drugs that prevent clots within vessels (dual anti-platelet therapy: aspirin and clopidogrel). Patients at risk of ongoing ischemia undergo PCI to restore blood flow and thus oxygen delivery to the struggling heart. If PCI failed to restore blood flow because of anatomical considerations or other technical problems, urgent CABG is indicated to save heart tissue. The timing of the operation plays a role in survival: It is preferable to delay the surgery if possible (three days if the infarction affecting the total thickness of the cardiac muscle, and six hours if it does not). CABG is also indicated when there are mechanical complications of an infarction (ventricular septal defect, papillary muscle rupture or myocardial rupture). There are no absolute contraindications of CABG, but severe disease of other organs such as the liver or brain, limited life expectancy, and patient fragility are considered. ==== Other cardiac surgery ==== CABG is also performed when a patient is to undergo another cardiac surgical procedure, most commonly for valve disease, and angiography reveals a significant lesion of the coronary arteries. CABG can also address dissection of coronary arteries, where a rupture of the coronary layers creates a pseudo-lumen (cavity) and diminishes blood delivery to the heart. Such a dissection may be caused by pregnancy, tissue diseases like Ehlers–Danlos syndromes and Marfan syndrome, cocaine abuse, or PCI. A coronary aneurysm may also indicate CABG: A blood clot might develop within the vessel and travel downstream. === CABG versus PCI === CABG and percutaneous coronary intervention (PCI) are the two methods to restore blood flow caused by stenotic lesions of the coronary arteries. The choice of method is still a matter of debate, but it is clear that in the presence of complex lesions, significant left main disease, or diabetes, CABG yields better long-term survival and outcomes. Strong indications for CABG also include symptomatic patients and impaired left ventricle function. CABG offers better results than PCI in left main disease and in CAD that affects multiple vessels, because of the protection arterial conduits offer to the native arteries of the heart, by producing vasodilator factors and preventing the advancement of plaques. Studies published in 2023 show that CABG in patients with left main disease is associated with lower mortality and fewer adverse events compared to PCI. Patients with unprotected left main disease—when the runoff of the left main artery is not protected by a patent graft since a previous CABG operation—have been studied as a group. A 2016 European study found that in these patients, CABG outperforms PCI in the long run (5 years). Another 2016 study found that PCI has similar results to CABG at 3 years, but that CABG becomes better than PCI after 4 years. A 2012 trial and followup in diabetic patients demonstrated a significant advantage to CABG over PCI. The relative advantage remained evident at 3.8-year and 7.5-year follow ups, which found particular benefits in smokers and younger patients. A 2015 trial compared CABG and the latest technological advancement of PCI, second-generation drug-eluting stents in multivessel disease. Their results indicated that CABG is a better option for CAD patients. A trial published in 2021, comparing results after one year, also concluded that CABG is a safer option than PCI. A large study published in 2023 showed that PCI patients had higher mortality than CABG patients with left main coronary artery disease. == Procedure == === Preoperative examination and strategy === Routine preoperative examination aims to check the status of systems and organs besides the heart. The examination typically includes a chest X-ray to check the lungs, a complete blood count, and kidney and liver function tests. Physical examination to determine the quality of the grafts or the safety of removing them, such as varicosities in the legs, or the Allen test in the arm is performed to be sure that blood supply to the arm will not be critically disturbed. A patient taking anticoagulants—aspirin, clopidogrel, ticagrelol and others—will stop taking them several days before, to prevent excessive bleeding during and after the operation. Warfarin is also stopped for the same reason and the patient starts taking heparin products after the INR falls below 2.0. After the angiogram is reviewed by the surgical team, targets are selected (that is, which native arteries will be bypassed and where the anastomosis should be placed). Ideally, all major lesions in significant vessels should be addressed. Most commonly, the left internal thoracic artery (LITA; formerly, left internal mammary artery, LIMA) is anastomosed to the left anterior descending artery (LAD) because the LAD is the most significant artery of the heart and supplies blood to a larger portion of myocardium than other arteries. A conduit can be used to graft one or more native arteries. In the latter case, an end-to-side anastomosis is performed. In the former, using a sequential anastomosis, a graft can then deliver blood to two or more native vessels of the heart. Also, the proximal part of a conduit can be anastomosed to the side of another conduit. It is preferred not to harvest too much conduit because it might necessitate re-operation. === With cardiopulmonary bypass machine (on-pump) === The intubated patient is brought to the operating theater. Lines (e.g., peripheral IV cannulae, central lines such as internal jugular cannulae) are inserted for drug administration and monitoring. A description of a traditional CABG follows. Harvesting An incision in the sternum is made while vessels are being harvested, either from the arms or chest or from the leg, usually from the internal mammary artery or the saphenous vein. The LITA is harvested through the sternotomy. There are two common ways of mobilizing the LITA: the pedicle (i.e., a pedicle consisting of the artery plus surrounding fat and veins) and the skeletonized (i.e., freed of other tissues). Before the LITA is divided in its more distal part, the anticoagulant heparin is administered to the patient via a peripheral line, to prevent clots. Catheterization and establishment of cardiopulmonary bypass After harvesting, the pericardium—the sac that surrounds the heart—is opened and stay sutures are placed to keep it open. Purse string sutures are placed in the aorta to prepare the insertions of the cannula into the aorta, and a catheter which temporarily arrests the heart using a solution high in potassium. Another purse string is placed in the right atrium for the venous cannula. Once the cannulas and the catheter are placed, cardiopulmonary bypass (CPB) is commenced. Deoxygenated blood arriving to the heart from veins is forwarded to the CPB machine to get oxygenated, then delivered to the aorta to keep the rest of the body saturated. The blood is often cooled to 32–34 °C (90–93 °F) to slow metabolism and minimize the demand for oxygen. A clamp is placed on the aorta between the cardioplegic catheter and aortic cannula, so that the flow of cardioplegic solution may be controlled by adjusting the clamp. Within minutes, the heart stops beating. Anastomosis (grafting) With the heart still, the tip of the heart is taken out of pericardium so that native arteries lying on the posterior side of the heart are accessible. Usually, distal anastomoses are constructed first (first to the right coronary system, then to the circumflex) and then the sequential anastomosis if necessary. Surgeons check the anastomosis for patency (whether it is sufficiently open) or leaking. They then insert the graft within the pericardium, sometimes attached to the cardioplegic catheter. The anastomosis of the LIMA to the LAD is usually the last distal anastomosis to be constructed; while it is being constructed the blood rewarming process starts (by the CPB). After the anastomosis is completed and checked for leaks, the proximal anastomoses of the conduits, if any, are next. They can be done either with the clamp still on, or after removing the aortic clamp and isolating a small segment of the aorta by placing a partial clamp. That said, aortas burdened by plaques might be damaged or release atheromatous debris by being overhandled. Weaning from cardiopulmonary bypass and closure After the proximal anastomoses are done, the clamp is removed and the aorta and conduits de-aired. Pacing wires, which supply a current to assist the heartbeat, might be placed. If the heart and other systems are functioning, CPB is discontinued and cannulae are removed. Protamine is administered to reverse the effect of the anticoagulant heparin. After possible bleeding sites are checked, chest tubes are placed and the sternum is closed. === Off-pump === Off-pump coronary artery bypass (OPCAB) surgery avoids using the CPB machine by stabilizing small segments of the heart at a time. The surgical team and anesthesiologists must coordinate and take great care to not manipulate the heart too much, lest they compromise the stability of blood flow. Compromise should be detected immediately and appropriate action taken. Keeping a healthy heartbeat may involve maneuvers like placing atrial wires to protect from bradycardia, or by placing stitches or incisions into the pericardium to help exposure. Snares and tapes are used to facilitate exposure. The aim is to avoid distal ischemia caused by blockage of the vessel supplying distal portions of the left ventricle, so usually LITA to LAD is the first to be anastomosed and others follow. For the anastomosis, a fine tube blowing humidified CO2 keeps the surgical field clean of blood. Also, a shunt might be used so the blood can travel past the site of anastomosis. After the distal anastomoses are completed, proximal anastomoses to the aorta are constructed with a partially closed aortic clamp. The rest of the process is similar to on-pump CABG. === Alternative approaches and special situations === When CABG is performed as an emergency because of a myocardial infarction, the highest priority is to salvage the struggling myocardium. Before operation, an intra-aortic balloon pump (IABP) might be inserted to relieve some of the burden of pumping blood, effectively reducing the amount of oxygen needed by myocardium. During operation, the standard practice is to place the patient on CPB as soon as possible and revascularize the heart with three saphenous veins. A calcified aorta also poses a problem because it is very dangerous to clamp. In this case, the operation can be done as an off-pump CAB using both inferior mesenteric arteries (IMA) or Y, T and sequential grafts. Deep arrest may be induced with hypothermia, lowering the temperature of the body to slightly above 20 °C (68 °F). In cases where a significant artery is totally blocked, it may be possible to remove the plaque and use the same hole in the artery to perform an anastomosis. This technique is called endarterectomy and is usually performed at the right coronary system. Re-operations of CABG (another CABG operation after a previous one) pose difficulties. The heart may be positioned too close to the sternum and thus at risk when cutting the sternum again, so an oscillating saw is used. The heart may be covered with strong adhesions to adjusting structures. Doctors must decide whether aging grafts should be replaced. Manipulation of vein grafts is avoided because it risks dislodgement of plaque. Minimally invasive direct coronary artery bypass (MIDCAB) strives to avoid a large incision in the sternum. It utilizes off-pump techniques to place a graft, usually of the LIMA at the LAD. The LIMA is freed through an incision between the left ribs (thoractomy), or even using an endoscope placed in the left chest. Robot-assisted coronary revascularization, which is not yet widely used, avoids the sternum incision to prevent infections and bleeding. Both conduit harvesting and the anastomosis are performed with the aid of a robot, through a thoracotomy. Usually, the procedure is combined with hybrid coronary revascularization, in which methods of CABG and PCI are both employed. Anastomosis of the LIMA to the LAD is performed in the operating theater and other lesions are treated with PCI—either at the operating room immediately following the anastomosis, or several days later. == Post-operative care == After the procedure, the patient is usually transferred to the intensive care unit (ICU), where intubations are removed if not already done in the operating theater. They usually exit the ICU by the following day, and four days later, if no complications occur, the patient is discharged from the hospital. A series of drugs are commonly used in early post-operative care. Dobutamine, a beta agent, can increase the cardiac output and is administered some hours after the operation. Beta blockers are used to prevent atrial fibrillation and other supraventricular arrhythmias. Pacing wires attached to both atria, inserted during the operation, may help prevent atrial fibrillation. Aspirin (80 mg) is used to prevent graft failure. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are used to control blood pressure, especially in patients with low cardiac function (<40%). Amlodipine, a calcium channel blocker, is used for patients whose radial artery was used as a graft. After the discharge, patients may experience insomnia, low appetite, decreased sex drive, and memory problems. This effect is usually transient and lasts 6 to 8 weeks. A tailored exercise plan is usually beneficial. == Results == CABG is the best procedure to reduce mortality from severe CAD and improve quality of life.: 153 Operative mortality strongly relates to the patient's age. According to a study by Eagle et al., patients 50–59 years old have an operative mortality rate of 1.8%, while patients older than 80 have a rate of 8.3%. Other factors that increase mortality are being female, re-operation, dysfunction of the left ventricle, and left main disease. CABG usually relieves angina, but in some patients it reoccurs. Around 60% of patients will be angina-free 10 years after their operation. Myocardial infarction is rare five years after a CABG, but its risk increases with time. The risk of sudden death for CABG patients is low. Quality of life is also high for at least five years, then can slowly start to decline. However, the use of bilateral mammary artery in patients of younger age and those without specific comorbidities (diabetes, obesity, steroid use) can provide excellent long-term survival and quality of life. The beneficial effects of CABG are clear at the cardiac level. Left-ventricle function is improved and malfunctioning segments of the heart—dyskinetic (moving inefficiently) or even akinetic (not moving)—can show signs of improvement. Both systolic and diastolic functions are improved and keep improving for up to five years in some cases. Left-ventricle function and myocardial perfusion during exercise also improves after CABG. When the left ventricle is severely impaired before operation (ejection fraction below 30%), however, benefits are less impressive in terms of segmental wall movement but still significant because other parameters might improve as LV function improves; the pulmonary hypertension might be relieved and lengthen survival. Determining the total risk of the procedure is difficult because of the diversity of patients undergoing CABG; different subgroups have different risk, but younger patients see better results than older ones. A CABG using two, rather than one, internal mammary arteries (IMAs) may offer greater protection from CAD, but results are not yet conclusive. === Grafts === Conduits that can be used for CABG may be arteries or veins. Arteries have a superior long-term patency (expandedness), but veins are more commonly used due to their practicality. Arterial grafts originate from the part of the internal thoracic artery (ITA) that runs near the edge of sternum, and can easily be mobilized and anastomosed to the native target vessel of the heart. The left artery is most often used because it is closer to the heart, but the right artery is sometimes used, depending on patient and surgeon preferences. The ITAs are advantageous because of their endothelial cells, which produce endothelium-derived relaxing factor and prostacyclin, protecting the artery from atherosclerosis and thus stenosis or occlusion. Disadvantages include a high rate of complications, such as deep sternal wound infections, in some subgroups of patients—mainly obese and diabetic ones. The left radial artery and left gastroepiploic artery can be also used. Long-term patency is influenced by the type of artery used and intrinsic factors of the cardiac arterial circulation. Veins used are mostly great saphenous veins and, in some cases, the lesser saphenous vein. Their patency rate is lower than that of arteries. Aspirin protects grafts from occlusion; adding clopidogrel does not improve rates. === Compared to PCI === CABG and PCI are the two methods to revascularize stenotic lesions of the cardiac arteries. The preferences for each patient is still a matter of debate but in the presence of complex lesions and significant Left Main Disease, and in diabetic patients, CABG seems to offer better results in patients than PCI. Strong indications for CABG also include symptomatic patients and those with impaired LV function. == Complications == The most common complications of CABG are postoperative bleeding, heart failure, atrial fibrillation (a form of arrhythmia), stroke, kidney dysfunction, and infection of the wound near the sternum. Postoperative bleeding occurs in 2–5% of cases and may require returning to the operating room; the most common indicator is the amount of blood being drained by chest tubes, which are inserted during the operation to drain fluid or air from the chest. Bleeding may originate from the aorta, the anastomosis, an insufficiently sealed branch of the conduit, or from the sternum. Other causes include platelet abnormalities or their failure to clot—perhaps due to the bypass or to the rebound heparin effect, which occurs when the anti-coagulant heparin is administered at the beginning of surgery and reappears in the blood after its neutralization by protamine. Low cardiac output syndrome (LCOS) can occur in up to 14% of CABG patients. According to its severity, LCOS is treated with inotropes, an intra-aortic balloon pump (IABP), optimization of pre-load and afterload, or correction of blood gauzes and electrolytes. The aim is to maintain a systolic blood pressure above 90 mmHg and a cardiac index of more than 2.2 L/min/m2. LCOS is often transient. Myocardial infarction can occur after the operation because of either technical or patient-specific factors. Its incidence is difficult to estimate due to varying definitions, but most studies place its occurrence at between 2% and 5%. The incidence is also dependent on whether it is isolated CABG (average, 4%, range, 0.3%–10%) or a combined operation (average, 2.0%, range, 0.7%–12%). New electrocardiogram features, such as Q waves or ultrasound-documented alternation of cardiac wall motions, are indicative. Ongoing ischemia might prompt emergency angiography and PCI or re-operation. Immediate coronary angiography offers the most expeditious modality not only for diagnosis but also for potential reintervention. Echocardiography is less valuable for the detection or confirmation of postoperative myocardial ischemia. Arrhythmias can also occur, most-commonly atrial fibrillation (incidence of 20–40%) that is treated with correcting electrolyte balance, and rate and rhythm control. However, arrhythmia such as ventricular tachycardia or fibrillation can be a sign of postoperative myocardial ischemia that is treated depending on the cause. Adverse neurological effects occur after CABG in about 1.5% of patients. They can manifest as type-1 deficits—focal deficits such as stroke or coma—or type-2 global deficits such as delirium caused by CPB, hypoperfusion, or cerebral embolism. Cognitive impairment has been reported in up to 80% cases after CABG at discharge and lasts for a year in up to 40% of cases. The cause remains unclear; CPB is an unlikely cause because even in CABG patients without CPB, as in off-pump CABG, and PCI patients, the incidence is the same. Infections, such as wound infections in the sternum (superficial or deep) are most commonly caused by Staphylococcus aureus, and may complicate the post-operation process. The harvesting of both two thoracic arteries is a risk factor because it significantly impairs the perfusion of blood through the sternum. Pneumonia can also occur. Complications in the gastrointestinal tract have been described and are most commonly due to medications administered during the operation. == History == === Pre-CABG === In the early 20th century, surgical interventions aiming to relieve angina and prevent death were either sympathectomy — a cut on the sympathetic chain that supplies the heart—or pericardial abrasion, with the hope adhesions would create significant collateral circulation. Sympathectomy produced disappointing and inconsistent results. French surgeon Alexis Carrel was the first to anastomose a vessel—a branch of the carotid artery—to a native artery in the heart of a dog, but the experiment could not be reproduced. In the mid-20th century, revascularization efforts continued. Beck C. S. used a carotid conduit to connect the descending aorta to the coronary sinus, the biggest vein of the heart. In the "Vineberg Procedure", Arthur Vineberg used skeletonized LITA, placing it in a small tunnel he created next to the LAD and hoping spontaneous collateral circulation would form. This occurred in canine experiments but not in humans. Goetz RH was the first to perform an anastomosis of the ITA to LAD in the 1960 using a sutureless technique. The development of coronary angiography in 1962 by Mason Sones helped medical doctors to identify patients in need of operation, and which native heart vessels should be bypassed. In 1964, Soviet cardiac surgeon Vasilii Kolesov performed the first successful internal thoracic artery–coronary artery anastomosis, followed by Michael DeBakey in the United States. Argentine surgeon René Favaloro standardized the procedure. Their advances made CABG the standard of care of CAD patients. === The CABG era === The modern era of the CABG began in 1964 when Soviet cardiac surgeon Vasilii Kolesov performed the first successful internal thoracic artery–coronary artery anastomosis. The same year, American surgeon Michael DeBakey used a saphenous vein to create an aorta-coronary artery bypass. Argentinean surgeon René Favaloro advanced and standardized the CABG technique using the patient's saphenous vein. The introduction of arresting the heart during operation (cardioplegia) made CABG much less risky. A major obstacle of CABG was ischemia and infarction occurring while the heart was stopped to allow surgeons to construct the distal anastomosis. In the 1970s, potassium-based cardioplegia was used. Cardioplegia minimized the oxygen demands of the heart, thus reducing the effects of ischemia. Refinement of cardioplegia in the 1980s made CABG less risky, lowering mortality during operation. In the late 1960s, after the work of René Favaloro, the operation was performed in only a few centers, but was anticipated to more broadly change the outcome of coronary artery disease. By 1979, there were 114,000 procedures per year in the US. The introduction of percutaneous coronary intervention (PCI) did not obsolesce CABG; rates of both procedures continued to increase, but PCIs grew more rapidly. In the following decades, CABG was extensively studied and compared to PCI. The absence of a clear advantage of CABG over PCI led to a small decrease in numbers of CABGs in some countries (like the US) by 2000. In Europe—mainly Germany—CABG was increasingly performed. As of 2023, research comparing the two techniques is continuing. Meta-analysis published in 2023 suggests that CABG provides a consistent survival benefit over PCI with drug-eluting stents (DES). Favaloro's work is fundamental to the history of graft selection. He established the use of bilateral ITAs as superior to vein grafts. Surgeons examined the use of other arterial grafts—splenic, gastroepiploic mesenteric, subscapular and others—but none matched the patency rates of ITA. In 1971, Carpentier introduced the use of the radial artery, which was initially prone to failure, but the development of harvesting techniques in the following 20 years significantly improved patency. == Other animals == Pigs, sheep, and dogs have been used as experimental models, for the development of CABG. Performing CABG to treat a sick animal though is extremely rare. == See also == Angioplasty Cardiothoracic surgery Dressler's syndrome Totally endoscopic coronary artery bypass surgery == References == == Sources == Al-Atassi, Talal; Toeg, Hadi D.; Chan, Vincent; Ruel, Marc (2016). "Coronary Artery Bypass Grafting". In Frank Sellke; Pedro J. del Nido (eds.). Sabiston and Spencer Surgery of the Chest. ISBN 978-0-323-24126-7. Bojar, R.M. (2021). Manual of Perioperative Care in Adult Cardiac Surgery. Wiley. ISBN 978-1-119-58255-7. Retrieved 2022-10-26. Connolly, John E. (2001-03-25). "The Development of Coronary Artery Surgery: Personal Recollections". Texas Heart Institute Journal. 29 (1): 10–14. PMC 101261. PMID 11995842. Cordova, Melanie Greaver (2020-05-05). "Veterinarians, MDs team up for canine open-heart surgery". Cornell Chronicle. Retrieved 2023-08-24. Farina, Piero; Gaudino, Mario Fulvio Luigi; Taggart, David Paul (2020). 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"Fractional Flow Reserve–Guided PCI as Compared with Coronary Bypass Surgery". New England Journal of Medicine. 386 (2). Massachusetts Medical Society: 128–137. doi:10.1056/nejmoa2112299. ISSN 0028-4793. PMID 34735046. S2CID 242940936. Head, S. J.; Kieser, T. M.; Falk, V.; Huysmans, H. A.; Kappetein, A. P. (2013-10-01). "Coronary artery bypass grafting: Part 1—the evolution over the first 50 years". European Heart Journal. 34 (37). Oxford University Press (OUP): 2862–2872. doi:10.1093/eurheartj/eht330. ISSN 0195-668X. PMID 24086085. "Corrigendum to: 2018 ESC/EACTS Guidelines on myocardial revascularization". European Heart Journal. 40 (37): 3096. 2019-10-01. doi:10.1093/eurheartj/ehz507. ISSN 0195-668X. PMID 31292611. Smith, Peter K.; Schroder, Jacob N. (2016). "On-Pump Coronary Artery Bypass Grafting". In Josef E. Fischer (ed.). Master Techniques in Surgery CARDIAC SURGERY. Wolters Kluwer. ISBN 9781451193534. Kouchoukos, Nicholas; Blackstone, E. H.; Hanley, F. L.; Kirklin, J. K. (2013). Kirklin/Barratt-Boyes Cardiac Surgery E-Book (4th ed.). Elsevier. ISBN 978-1-4160-6391-9. Mick, Stephanie; Keshavamurthy, Suresh; Mihaljevicl, Tomislav; Bonatti, Johannes (2016). "Robotic and Alternative Approaches to Coronary Artery Bypass Grafting". In Frank Sellke; Pedro J. del Nido (eds.). Sabiston and Spencer Surgery of the Chest. pp. 1603–1615. ISBN 978-0-323-24126-7. Ngu, Janet M. C.; Sun, Louise Y.; Ruel, Marc (2018). "Pivotal contemporary trials of percutaneous coronary intervention vs. coronary artery bypass grafting: a surgical perspective". Annals of Cardiothoracic Surgery. 7 (4). AME Publishing Company: 527–532. doi:10.21037/acs.2018.05.12. ISSN 2225-319X. PMC 6082775. PMID 30094218. Welt, Frederick G.P. (2022-01-13). "CABG versus PCI — End of the Debate?". New England Journal of Medicine. 386 (2). Massachusetts Medical Society: 185–187. doi:10.1056/nejme2117325. ISSN 0028-4793. PMID 35020989. S2CID 245907473. == External links == Media related to Coronary artery bypass at Wikimedia Commons Lawton JS, Tamis-Holland JE, Bangalore S, Bates ER, Beckie TM, Bischoff JM, Bittl JA, Cohen MG, DiMaio JM, Don CW, Fremes SE, Gaudino MF, Goldberger ZD, Grant MC, Jaswal JB, Kurlansky PA, Mehran R, Metkus TS Jr, Nnacheta LC, Rao SV, Sellke FW, Sharma G, Yong CM, Zwischenberger BA. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. 2022;79:e21-e129	Wikipedia/Coronary_artery_bypass_surgery
Human resource management (HRM) is the strategic and coherent approach to the effective and efficient management of people in a company or organization such that they help their business gain a competitive advantage. It is designed to maximize employee performance in service of an employer's strategic objectives. Human resource management is primarily concerned with the management of people within organizations, focusing on policies and systems. HR departments are responsible for overseeing employee-benefits design, employee recruitment, training and development, performance appraisal, and reward management, such as managing pay and employee benefits systems. HR also concerns itself with organizational change and industrial relations, or the balancing of organizational practices with requirements arising from collective bargaining and governmental laws. The overall purpose of human resources (HR) is to ensure that the organization can achieve success through people. HR professionals manage the human capital of an organization and focus on implementing policies and processes. They can specialize in finding, recruiting, selecting, training, and developing employees, as well as maintaining employee relations or benefits. Training and development professionals ensure that employees are trained and have continuous development. This is done through training programs, performance evaluations, and reward programs. Employee relations deals with the concerns of employees when policies are broken, such as in cases involving harassment or discrimination. Managing employee benefits includes developing compensation structures, parental leave programs, discounts, and other benefits. On the other side of the field are HR generalists or business partners. These HR professionals could work in all areas or be labour relations representatives working with unionized employees. HR is a product of the human relations movement of the early 20th century when researchers began documenting ways of creating business value through the strategic management of the workforce. It was initially dominated by transactional work, such as payroll and benefits administration, but due to globalization, company consolidation, technological advances, and further research, HR as of 2015 focuses on strategic initiatives like mergers and acquisitions, talent management, succession planning, industrial and labor relations, and diversity and inclusion. In the current global work environment, most companies focus on lowering employee turnover and on retaining the talent and knowledge held by their workforce. == History == === Precedent theoretical developments === The human resources field began to take shape in 19th century Europe. It is built on a simple idea by Robert Owen (1771–1858) and Charles Babbage (1791–1871) during the Industrial Revolution. These men concluded that people were crucial to the success of an organization. They expressed the thought that well-being of employees led to perfect work; without healthy workers, the organization would not survive. HR emerged as a specific field in the early 20th century, influenced by Frederick Winslow Taylor (1856–1915). Taylor explored what he termed "scientific management" (sometimes referred to as "Taylorism"), striving to improve economic efficiency in manufacturing jobs. He eventually focused on one of the principal inputs into the manufacturing process—labor—sparking inquiry into workforce productivity. Meanwhile, in London C S Myers inspired by unexpected problems among soldiers who alarmed generals and politicians. During First World War 1914–1918, co-founded the National Institute of Industrial Psychology (NIIP) in 1921. He set seeds for the human relations movement, this movement, on both sides of the Atlantic, built on the research of Elton Mayo (1880–1949) and others to document through the Hawthorne studies (1924–1932) and other studies how stimuli, unrelated to financial compensation and working conditions, could yield more productive workers. Work by Abraham Maslow (1908–1970), Kurt Lewin (1890–1947), Max Weber (1864–1920), Frederick Herzberg (1923–2000), and David McClelland (1917–1998), forming the basis for studies in industrial and organizational psychology, organizational behavior and organizational theory, was interpreted in such a way as to further claims of legitimacy for an applied discipline. === Birth and development of the discipline === By the time there was enough theoretical evidence to make a business case for strategic workforce management, changes in the business landscape—à la Andrew Carnegie (1835–1919) and John Rockefeller (1839–1937)—and in public policy—à la Sidney (1859–1947) and Beatrice Webb (1858–1943), Franklin D. Roosevelt and the New Deal of 1933 to 1939—had transformed employer-employee relationships, and the HRM discipline became formalized as "industrial and labor relations". In 1913 one of the oldest known professional HR associations—the Chartered Institute of Personnel and Development (CIPD)—started in England as the Welfare Workers' Association; it changed its name a decade later to the Institute of Industrial Welfare Workers, and again the next decade to Institute of Labour Management before settling upon its current name in 2000. From 1918 the early Soviet state institutions began to implement a distinct ideological HRM focus alongside technical management—first in the Red Army (through political commissars alongside military officers), later (from 1933) in work sites more generally (through partorg posts alongside conventional managers). In 1920, James R. Angell delivered an address to a conference on personnel research in Washington detailing the need for personnel research. This preceded and led to the organization of the Personnel Research Federation. In 1922 the first volume of The Journal of Personnel Research was published, a joint initiative between the National Research Council and the Engineering Foundation. Likewise in the United States, the world's first institution of higher education dedicated to workplace studies—the School of Industrial and Labor Relations—formed at Cornell University in 1945. In 1948 what would later become the largest professional HR association—the Society for Human Resource Management (SHRM)—formed as the American Society for Personnel Administration (ASPA). In the Soviet Union, Stalin's use of patronage exercised through the "HR Department" equivalent in the Bolshevik Party, its Orgburo, demonstrated the effectiveness and influence of human-resource policies and practices, and Stalin himself acknowledged the importance of the human resource, exemplified in his mass deployment of it, as in the five-year plans and in the Gulag system. During the latter half of the 20th century, union membership declined significantly, while workforce-management specialists continued to expand their influence within organizations. In US, the phrase "industrial and labor relations" came into use to refer specifically to issues concerning collective representation, and many companies began referring to the proto-HR profession as "personnel administration". Many current HR practices originated with the needs of companies in the 1950s to develop and retain talent. In the late 20th century, advances in transportation and communications greatly facilitated workforce mobility and collaboration. Corporations began viewing employees as assets. "Human resources management" consequently, became the dominant term for the function—the ASPA even changing its name to the Society for Human Resource Management (SHRM) in 1998. "Human capital management" (HCM) is sometimes used synonymously with "HR", although "human capital" typically refers to a narrower view of human resources; i.e. the knowledge the individuals embody and can contribute to an organization. Other terms sometimes used to describe the HRM field include "organizational management", "manpower management", "talent management", "personnel management", "workforce management", and simply "people management". === In popular media === Several popular media productions have depicted human resource management in operation. The U.S. television series The Office, HR representative Toby Flenderson is sometimes portrayed as a nag because he constantly reminds coworkers of company policies and government regulations. Long-running American comic strip Dilbert frequently portrays sadistic HR policies through the character Catbert, the "evil director of human resources". An HR manager is the title character in the 2010 Israeli film The Human Resources Manager, while an HR intern is the protagonist in 1999 French film Ressources humaines. The main character in the BBC sitcom dinnerladies, Philippa, is an HR manager. The protagonist of the Mexican telenovela Mañana es para siempre is a director of human resources. Up In the Air is centered on corporate "downsizer" Ryan Bingham (George Clooney) and his travels. As the film progresses, HR is portrayed as a data-driven function that deals with people as human resource metrics, which can lead to absurd outcomes for real people. == Practice == === Business function === Dave Ulrich lists the function of human resources as: Aligning human resource strategy and human resource metrics with business strategy Re-engineering organization processes Listening and responding to employees, and managing transformation and change. At the macro level, HR is in charge of overseeing organizational leadership and culture. HR also ensures compliance with employment and labor laws and often oversees employee health, safety, and security. Labor laws may vary from one jurisdiction to the next. In a workplace administered by the federal government, HR managers may need to be familiar with certain crucial federal laws, in order to protect both their company and its employees. In the United States of America, important federal laws and regulations include: Fair Labor Standards Act of 1938: It establishes a minimum wage and protects the right of certain workers to earn overtime. Equal Employment Opportunity Act of 1972: It strengthens the Equal Employment Opportunity Commission's authority to prevent and address workplace discrimination and prohibits employers from making hiring, firing, or employment decisions based on race, color, religion, sex, national origin, or age. Family and Medical Leave Act of 1993: It allows eligible employees to take up to twelve weeks of unpaid leave for family and medical reasons while ensuring they can return to their job afterward. Immigration Reform and Control Act: It requires employers to verify the identity and employment eligibility of all employees, prohibits the hiring of unauthorized workers, and establishes penalties for employers who hire undocumented immigrants while protecting employees from discrimination based on nationality or citizenship. An important responsibility of HR is to ensure that a company complies with all laws and regulations, thus protecting the company from legal liability. In circumstances where employees exercise their legal authorization to negotiate a collective bargaining agreement, HR will typically also serve as the company's primary liaison with employee representatives (usually a labor union). Consequently, the HR industry lobbies governmental agencies (e.g., in the United States, the United States Department of Labor and the National Labor Relations Board) to advance its priorities. === Functions of Human resource management === Staffing: The process of the recruitment and selection of employees through the use of interviews, applications and networking. Staffing involves two main factors. The first is to attract talented recruits who meet the organization's requirements, and doing so by using tools such as mass media; the second is to manage hiring resources. Managers can use hiring resources to exercise different strategies. Training and Development: It involves a continuous process of training and developing competent and adapted employees. Here, motivation is seen as key to keeping employees highly productive. This includes employee benefits, performance appraisals, and rewards. Employee benefits, appraisals, and rewards are all encouragements to bring forward the best employees. Maintenance: Involves keeping the employees' commitment and loyalty to the organization. Managing for employee retention involves strategic actions to keep employees motivated and focused so they remain employed and fully productive for the benefit of the organization. Some businesses globalize and form more diverse teams. HR departments have the role of making sure that these teams can function and that people can communicate across cultures and across borders. The discipline may also engage in mobility management, especially for expatriates; and it is frequently involved in the merger and acquisition process. HR is generally viewed as a support function to the business, helping to minimize costs and reduce risk. Other Activities: Talent Acquisition: focuses on the long-term strategic planning required to identify, attract, and hire the top talent necessary to meet the organization's needs. Talent Recruitment: involves identifying, attracting, and hiring suitable candidates to fulfill specific job openings and meet business needs. Talent Management: helps organizations identify key positions vital for long-term success, develop a pool of high-potential employees to fill these roles, and establish a framework for managing performance, developing leaders, retaining talent, and fostering organizational commitment. Compensation and Benefits: design competitive compensation and benefits packages to attract and retain talent. Employee Relations: manage employee relations issues, such as conflict resolution, employee grievances, and workplace investigations. Training and Development: develop and implement training programs and professional development opportunities for their employees. Performance Management: a systematic process focused on enhancing organizational effectiveness according to the organization’s tactical and strategic goals, using performance management systems and designing human resource metrics. Performance is considered a function of ability, motivation, and environment; hence, this approach provides employees with clear feedback on their performance outcomes and support areas for improvement, ensuring that active learning and cultural engagement take place in alignment with organizational objectives. Legal Compliance: ensure that organizations are compliant with labor laws and regulations, including employment standards, workplace safety, and anti-discrimination policies. In startup companies, trained professionals may perform HR duties. In larger companies, an entire functional group is typically dedicated to the discipline, with staff specializing in various HR tasks and functional leadership engaging in strategic decision-making across the business. To train practitioners for the profession, institutions of higher education, professional associations, and companies have established programs of study dedicated explicitly to the duties of the function. Academic and practitioner organizations may produce field-specific publications. HR is also a field of research study that is popular within the fields of management and industrial/organizational psychology. One of the important goal of HRM is establishing with the notion of unitarism (seeing a company as a cohesive whole, in which both employers and employees should work together for its common good) and securing a long-term partnership of employees and employers with common interests. === Code of ethics === Code of ethics provides a framework for ethical behavior and professional conduct in HRM. It ensures integrity, fairness, and responsibility. Its function is to guide HR professionals and departments in upholding the rights, safety, and interests of all stakeholders. They are generally categorized into the following: Duties to the Public: HR professionals must act ethically, lawfully, and with integrity. They should address illegal acts, uphold public trust, maintain competence, and engage in continuous professional development. Duties to the Profession: HR professionals must uphold the reputation of the profession by avoiding misconduct, adhering to ethical codes, promoting a positive image, and cooperating with investigations or disciplinary processes. Duties to Clients and Employers: HR professionals must prioritize the best interests of employers and clients, ensure impartiality, disclose conflicts of interest, maintain accurate records, and safeguard confidentiality. Duties to Individuals: HR professionals must advance dignity, equity, and safety for all. They should respect privacy, avoid discrimination or harassment, report imminent risks of harm, and foster an inclusive workplace. Overarching Duties: HR professionals must foster trust, respect, and fairness in all relationships. They must act impartially, comply with laws, promote diversity, and resolve disputes ethically and professionally. == Modern HR practices == Technology has a significant impact on HR practices. Utilizing technology makes information more accessible within organizations, eliminates time doing administrative tasks, allows businesses to function globally, and cuts costs. The adoption of modern business practices and information technology has transformed HR practices in the following ways: === E-recruiting === Recruiting has mostly been influenced by information technology. In the past, recruiters relied on printing in publications and word of mouth to fill open positions. Human Resource professionals were not able to post a job in more than one location and did not have access to millions of people, causing the lead time of new hires to be drawn out and tiresome. With the use of e-recruiting tools, HR professionals can post jobs and track applicants for thousands of jobs in various locations all in one place. Interview feedback, background checks and drug tests, and onboarding can all be viewed online. This helps HR professionals keep track of all of their open jobs and applicants in a way that is faster and easier than before. E-recruiting also helps eliminate limitations of geographic location. === Human resources information systems === HR professionals generally handle large amounts of paperwork on a daily basis, ranging from department transfer requests to confidential employee tax forms. Forms must be on file for a considerable period of time. The use of human resources information systems (HRIS) has made it possible for companies to store and retrieve files in an electronic format for people within the organization to access when needed, thereby eliminating the need for physical files and freeing up space within the office. HRIS also allows for information to be accessed in a timelier manner; files can be accessible within seconds. Having all of the information in one place also allows for professionals to analyze data quickly and across multiple locations because the information is in a centralized location. Human resource analytics can improve human resource management. === Virtual management === Technology allows HR professionals to train new staff members in a more efficient manner. This gives employees the ability to access onboarding and training programs from virtually anywhere. This eliminates the need of organizing costly face-to-face training and onboarding sessions. It allows management's to provide necessary training for job success and monitor progress of their employees through virtual classrooms and computerized testing, predict the risk of employee turnover through data analysis, help HR to formulate relevant talent retention and incentive strategies, improve the personal development of the company, and maintain metrics that aid in performance management. Virtual management also allows HR departments to quickly complete necessary paperwork for large numbers of new employees and maintain contact with them throughout their entire professional cycle within the organization. Through virtual management, employees gain greater control over their learning and development, feel more engaged with the organizational culture, and can participate in training at a time and place of their choosing, helping them manage their work–life balance and reducing layoffs and turnover. === Employer of record === An Employer of Record (EOR) is an arrangement in which a third-party organization serves as the official employer for a company's workforce, handling various HR functions such as payroll, tax compliance, and employee benefits, while the client company retains day-to-day management of the workers. This arrangement eliminates the need for an organization to directly engage in HRM matters, allowing it to focus on other priorities. === HRM consultancies === HRM consultancies are private organizations that offer tailored solutions through specialized expertise for a fee. They design customized human resource strategies and processes to address each company's unique needs. Their services include developing recruitment plans, compensation frameworks, training programs, and performance management systems, all aligned with specific HR practices and the organization's goals and culture. By acting as consultants, they provide targeted solutions that help businesses optimize their workforce and achieve organizational objectives in complex and evolving market conditions. == Careers == There are half a million HR practitioners in the United States and millions more worldwide. The Chief HR Officer or HR Director is the highest ranking HR executive in most companies. He or she typically reports directly to the chief executive officer and works with the Board of Directors on CEO succession. Within companies, HR positions generally fall into one of two categories: generalist and specialist. Generalists support employees directly with their questions, grievances, and work on a range of projects within the organization. They "may handle all aspects of human resources work, and thus require an extensive range of knowledge. The responsibilities of human resources generalists can vary widely, depending on their employer's needs." Specialists, conversely, work in a specific HR function. Some practitioners will spend an entire career as either a generalist or a specialist while others will obtain experiences from each and choose a path later. Human resource consulting is a related career path where individuals may work as advisers to companies and complete tasks outsourced from companies. Some individuals with PhDs in HR and related fields, such as industrial and organizational psychology and management, are professors who teach HR principles at colleges and universities. They are most often found in Colleges of Business in departments of HR or Management. Many professors conduct research on topics that fall within the HR domain, such as financial compensation, recruitment, and training. Women were found over-represented in human resource management. == Professional associations == There are a number of professional associations, some of which offer training and certification. The Society for Human Resource Management, which is based in the United States, is the largest professional association dedicated to HR, with over 285,000 members in 165 countries. It offers a suite of Professional in Human Resources (PHR) certifications through its HR Certification Institute. An international provider of specialized certifications is Academy to Innovate HR (AIHR). The Chartered Institute of Personnel and Development, based in England, is the oldest professional HR association, with its predecessor institution being founded in 1918. Several associations also serve specific niches within HR. The Institute of Recruiters (IOR) is a recruitment professional association, offering members education, support and training. WorldatWork focuses on "total rewards" (i.e., compensation, benefits, work life, performance, recognition, and career development), offering several certifications and training programs dealing with remuneration and work–life balance. Other niche associations include the American Society for Training & Development and Recognition Professionals International. A largely academic organization that is relevant to HR is the Academy of Management that has an HR division. This division is concerned with finding ways to improve the effectiveness of HR. The academy publishes several journals devoted in part to research on HR, including Academy of Management Journal and Academy of Management Review, and it hosts an annual meeting. == Education == Some universities offer programs of study for human resources and related fields. The School of Industrial and Labor Relations at Cornell University was the world's first school for college-level study in HR. It currently offers education at the undergraduate, graduate, and professional levels, and it operates a joint degree program with the Samuel Curtis Johnson Graduate School of Management. In the United States of America, the Human Resources University trains federal employees. Many colleges and universities house departments and institutes related to the field, either within a business school or in another college. Most business schools offer courses in HR, often in their departments of management. In general, schools of human resources management offer education and research in the HRM field from diplomas to doctorate-level opportunities. The master's-level courses include MBA (HR), MM (HR), MHRM, MIR, etc. (See Master of Science in Human Resource Development for curriculum.) Various universities all over the world have taken up the responsibility of training human-resource managers and equipping them with interpersonal and intrapersonal skills so as to relate better at their places of work. As Human resource management field is continuously evolving due to technology advances of the Fourth Industrial Revolution, it is essential for universities and colleges to offer courses which are future oriented. === Theory and research === Ongoing research investigates the relationship between human research management and performance and includes organization studies, industrial and organizational psychology, organizational theory and management science. Human resource management research can improve human resource management and HR initiatives. The effect size of human resource management decreases when correcting for past performance of employees. === Publications === Academic and practitioner publications dealing exclusively with HR: Cornell HR Review HR Magazine (SHRM) Human Resource Management Human Resource Management Review International Journal of Human Resource Management Perspectives on Work (LERA) Related publications: Academy of Management Journal Academy of Management Review Administrative Science Quarterly International Journal of Selection and Assessment Journal of Applied Psychology Journal of Management Journal of Occupational and Organizational Psychology Journal of Personnel Psychology Organization Science Personnel Psychology == See also == People Operations Aspiration management Domestic inquiry Employment agency Human resource management system Organization development Organizational theory Realistic job preview Recruitment == Notes == == References == Johnason, P. (2009). HRM in changing organizational contexts. In D. G. Collings & G. Wood (Eds.), Human resource management: A critical approach (pp. 19–37). London: Routledge. McGaughey, E. (2020). "A Human is not a Resource". King's Law Journal. 31 (2): 1. doi:10.1080/09615768.2020.1789441. SSRN 3099470. == External links == Media related to Human resources management at Wikimedia Commons Quotations related to Human resource management at Wikiquote	Wikipedia/Workforce_planning
Left atrial appendage occlusion (LAAO), also referred to as left atrial appendage closure (LAAC), is a procedure used to reduce the risk of blood clots from the left atrial appendage entering the bloodstream and causing a stroke in those with non-valvular atrial fibrillation. == Rationale == The left atrial appendage is a pouch-like structure located in the upper part of the left atrium. Left atrial appendage occlusion (LAAO) is an alternative therapy to oral anticoagulation in a certain subset of patients with atrial fibrillation. Atrial fibrillation is characterized by an irregular and uncoordinated pumping function of the atria. This chaotic pattern of contraction can lead to reduced pumping efficiency and subsequent formation of blood clots, most notably in the left atrial appendage. Over 90% of stroke-causing clots that originate in the heart in patients with non-valvular AF are formed in the left atrial appendage. LAAO does not completely eliminate the risk of stroke in patients with AF but it does reduce the risk of stroke from emboli that originate in the left atrial appendage. The left atrial appendage can be purposefully occluded (i.e. closed) to help prevent the formation of clots in one of two ways. The Lariat procedure is a surgical procedure that can be performed to ligate the left atrial appendage from outside the heart. Endovascular implant is a catheter-based procedure used to place an occlusion device inside the orifice of the left atrial appendage. == Indications == The most common treatment aimed at alleviating the burden of stroke in the setting of AF includes anticoagulation (blood-thinners), which are used to reduce the chance of blood clot formation. These medications, specifically direct oral anticoagulants (i.e. dabigatran, apixaban, rivaroxaban, edoxaban) and vitamin K antagonists (i.e. warfarin), are very effective in lowering the risk of stroke in AF patients. Most patients can tolerate anticoagulation for years (and even decades) without serious side effects. However, there are certain subsets of individuals who are unable to tolerate anticoagulation, and may be subject to increased bleeding or hematological risks. These patients may be good candidates for LAAO: Patients with poor anticoagulation therapy compliance (approximately 45% of patients who are eligible for warfarin are not being treated, due to tolerance or adherence issues) Patients with intolerable side effects to anticoagulation therapy Patients with chronic thrombocytopenia (low platelets) or a known coagulation defect associated with bleeding Patients with a prior history of severe bleeding (e.g., intracranial hemorrhage, major gastrointestinal bleeding) Patients with a high risk of falling or a history of prior falls that resulted in injury Patients with AF that are already undergoing cardiac surgery for other indications == Devices and alternatives == === Surgical procedure === ==== Lariat procedure ==== Occlusion of the left atrial appendage can be achieved from outside the heart (the Lariat device) or from inside the heart (endovascular) with a blood-exposed implant (the Watchman and Amulet devices). The first method is a form of ligation that eliminates perfusion of the LAA. While effective in preventing many embolic strokes, it also negates the endocrine contribution (atrial natriuretic peptide) of the LAA. The second approach has many hazards as well but preserves the cardiac endocrine properties of the LAA. Further evaluation of both approaches is merited. ==== Over-sewing ==== The LAA can also be surgically removed simultaneously with other cardiac procedures such as the maze procedure or during mitral valve surgery; specifically, it can be occluded or excluded by over-sewing, excision and resection, ligation, stapling with or without amputation of the LAA or application of a clip system Finally, the left atrial appendage has been closed in a limited number of patients using a chest keyhole surgery approach. ==== Clip devices ==== LAA can also be occluded by the placement of clips such as the AtriClip or Penditure devices. === Catheter-based LAAC implant procedure === ==== Watchman device ==== On March 13, 2015, the U.S. Food and Drug Administration approved the Watchman LAAC Implant, from Boston Scientific, to reduce the risk of thromboembolism from the left atrial appendage in patients with non-valvular AF who are at increased risk of stroke have an appropriate reason to seek a non-drug alternative to blood thinning medications. The Watchman implant was studied in two randomized clinical trials and several clinical registries. The implant was approved in Europe in 2009. The Watchman is a one-time implant typically performed under general anesthesia with transesophageal echo guidance (TEE). Similar to a stent procedure, the device is guided into the heart through a flexible tube (catheter) inserted through the femoral vein in the upper leg. The implant is introduced into the right atrium and is then passed into the left atrium through a hole in the septum that divides the two atria of the heart. This small hole in the septum usually disappear within six months. Once the position is confirmed, the implant is released and is left permanently fixed in the heart. The implant does not require open heart surgery and does not need to be replaced. Recovery typically takes twenty-four hours. The patient continues taking warfarin with aspirin for 45 days post implantation at which point in time they return for a transesophageal echocardiography to judge completeness of the closure and the presence of blood clots. If the LAA is completely occluded, then the patient can stop taking warfarin and start clopidogrel and aspirin for six months after implant. At six months post implantation, it is recommended for the patient to continue taking aspirin indefinitely. In the PREVAIL clinical trial, 92% of patients stopped taking warfarin after 45 days and 99% discontinued warfarin at one year. Another device termed PLAATO (percutaneous left atrial appendage transcatheter occlusion) was the first LAA occlusion device, although it is no longer being developed by its manufacturer (Appriva Medical, Inc. from Sunnyvale, California). In 210 patients receiving the PLAATO device, there was an estimated 61% reduction in the calculated stroke risk. ==== Amplatzer Amulet device ==== The Amplatzer device from St. Jude Medical, used to close atrial septal defects, has also been used to occlude the left atrial appendage. This can be performed without general anaesthesia and without echocardiographic guidance. Transcatheter patch obliteration of the LAA has also been reported. The Amulet device is inserted very similarly to the Watchman LAAC implant. A catheter is introduced into the groin and travels up to the heart where it crosses from the right atrium into the left atrium via a hole in the septum. The device is then discharged into the LAA. Eventually tissue grows over the Amulet device and completely occludes the LAA. The ULTRASEAL LAA device, from Cardia, is a percutaneous, transcatheter device intended to prevent thrombus embolization from the left atrial appendage in patients who have non-valvular atrial fibrillation. As with all Cardia devices (such as: Atrial Septal Defect Closure Device or Patent Foramen Ovale Closure Device), the Ultraseal is fully retrievable and repositionable in the Cardia Delivery System used for deployment. The device can be retrieved and redeployed multiple times in a single procedure without replacing the device or delivery sheath. Other devices exist to occlude the left atrial appendage from the inside of the heart such as the Wavecrest device and the Lariat device. The latter technique entails closing a strangling noose around the LAA, which is advanced from the chest wall with a special sheath, after introducing a balloon in the LAA from the inside surface of the heart (endocardium). == Adverse events == The main adverse events related to these procedures include pericardial effusion, incomplete LAA closure, dislodgement of the device, blood clot formation on the device requiring prolonged oral anticoagulation, and the general risks of catheter-based techniques (such as air embolism). The left atrium anatomy can also preclude use of the device in some patients. Theoretical concerns surround the role of the LAA in thirst regulation and water retention because it is an important source of atrial natriuretic factor. Preserving the right atrial appendage might attenuate this effect. == Footnotes ==	Wikipedia/Left_atrial_appendage_occlusion
Atrial septostomy is a surgical procedure in which a small hole is created between the upper two chambers of the heart, the atria. This procedure is primarily used to palliate dextro-Transposition of the great arteries or d-TGA (often imprecisely called transposition of the great arteries), a life-threatening cyanotic congenital heart defect seen in infants. It is performed prior to an arterial switch operation. Atrial septostomy has also seen limited use as a surgical treatment for pulmonary hypertension. The first atrial septostomy (then less precisely called a septectomy) was developed by Vivien Thomas in a canine model and performed in humans by Alfred Blalock. The Rashkind balloon procedure, a common atrial septostomy technique, was developed in 1966 by American cardiologist William Rashkind at the Children's Hospital of Philadelphia. There are two types of this procedure: balloon atrial septostomy (also called endovascular atrial septostomy, Rashkind atrial balloon septostomy, or simply Rashkind's procedure) and blade atrial septostomy (also called static balloon atrial septostomy). == Indications == In a normal heart, oxygen-depleted blood ("blue") is pumped from the right side of the heart, through the pulmonary artery, to the lungs where it is oxygenated. This is the pulmonary circulation part of blood flow. The oxygen-rich ("red") blood then returns to the left heart, via the pulmonary veins, and is pumped through the aorta to the rest of the body, including the heart muscle itself. This is the systemic circulation part of blood flow, the other loop of an interconnected normal cardio-pulmonary system. With d-TGA, certain major blood vessels are connected improperly, so oxygen-poor blood from the right heart is pumped immediately through the aorta and circulated to the body and the heart itself, bypassing the lungs altogether, while the left heart pumps oxygen-rich blood continuously back into the lungs through the pulmonary artery. This is a life-threatening situation due to the resultant low oxygen levels throughout the body. Atrial septostomy allows more of the oxygen-rich blood to circulate throughout the body. The procedure is a temporary measure meant to help the patient survive until further corrective surgery can be done. In the separate case of pulmonary hypertension, abnormally high blood pressure in the blood vessels within and connected to the lungs puts stress on the right side of the heart, potentially leading to right heart failure. Atrial septostomy relieves some of this pressure, but at the cost of lower oxygen levels in the blood (hypoxia). As with d-TGA, this surgery is not a definitive solution to the underlying medical problem. == Procedure == The majority of atrial septostomies are performed on infants with d-TGA or other cyanotic heart defects. In these cases, a balloon catheter is guided through a large vein into the right atrium, during cardiac catheterization. The catheter is threaded into the foramen ovale, a naturally existing hole between the atria that normally closes shortly after birth. The balloon at the end of the catheter is inflated so as to enlarge the foramen ovale enough that it will no longer become sealed. This allows more oxygenated blood to enter the right heart (especially in the case of d-TGA) where it can be pumped to the rest of the body. The balloon is deflated and the catheter is removed. Sometimes the initial surgery is not entirely successful, or there are other factors that make a simple balloon atrial septostomy impossible, such as an older patient whose foramen ovale has already closed. This is when a blade atrial septostomy is performed. The details of the procedure are largely the same, except that a small blade on the end of the catheter is first used to create an opening between the right and left atria, before the insertion of the balloon. The Rashkind balloon atrial septostomy is performed during cardiac catheterization (heart cath), in which a balloon catheter is used to enlarge a foramen ovale, patent foramen ovale (PFO), or atrial septal defect (ASD) in order to increase oxygen saturation in patients with cyanotic congenital heart defects (CHDs). It was developed in 1966 by American surgeons William Rashkind and William Miller at the Children's Hospital of Philadelphia. William Rashkind was not a surgeon, but a pediatric cardiologist at the Children's Hospital of Philadelphia. He was one of the fathers of the field of interventional catheterization, and he developed not only this life-saving technique and device for neonates with transposition of the great arteries, but also devices to close atrial septal defects (ASDs) and persistent patent ductus arteriosus (PDA). He was the chief of the Division of Pediatric Cardiology at the Children's Hospital of Philadelphia until his death in 1986 from malignant melanoma. == Risks == As with any surgery, there are certain risks to atrial septostomy, including tearing of the cardiac tissue, arrhythmias, and rarely, death. == References == == External links == Endovascular atrial septostomy information for the public from the National Institute for Health and Clinical Excellence Interventional procedure overview of balloon or blade atrial septostomy from the National Institute for Health and Clinical Excellence The Merck Manual of Diagnosis and Therapy, 18th edition, pp. 2416, 2417. Merck & Co., Inc., 2006. ISBN 978-0-911910-18-6	Wikipedia/Atrial_septostomy
Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory symptoms (shortness of breath, cough, sputum production or exacerbations) due to abnormalities of the airways (bronchitis, bronchiolitis) or alveoli (emphysema) that cause persistent, often progressive, airflow obstruction. The main symptoms of COPD include shortness of breath and a cough, which may or may not produce mucus. COPD progressively worsens, with everyday activities such as walking or dressing becoming difficult. While COPD is incurable, it is preventable and treatable. The two most common types of COPD are emphysema and chronic bronchitis and have been the two classic COPD phenotypes. However, this basic dogma has been challenged as varying degrees of co-existing emphysema, chronic bronchitis, and potentially significant vascular diseases have all been acknowledged in those with COPD, giving rise to the classification of other phenotypes or subtypes. Emphysema is defined as enlarged airspaces (alveoli) whose walls have broken down resulting in permanent damage to the lung tissue. Chronic bronchitis is defined as a productive cough that is present for at least three months each year for two years. Both of these conditions can exist without airflow limitations when they are not classed as COPD. Emphysema is just one of the structural abnormalities that can limit airflow and can exist without airflow limitation in a significant number of people. Chronic bronchitis does not always result in airflow limitation. However, in young adults with chronic bronchitis who smoke, the risk of developing COPD is high. Many definitions of COPD in the past included emphysema and chronic bronchitis, but these have never been included in GOLD report definitions. Emphysema and chronic bronchitis remain the predominant phenotypes of COPD but there is often overlap between them and a number of other phenotypes have also been described. COPD and asthma may coexist and converge in some individuals. COPD is associated with low-grade systemic inflammation. The most common cause of COPD is tobacco smoking. Other risk factors include indoor and outdoor air pollution including dust, exposure to occupational irritants such as dust from grains, cadmium dust or fumes, and genetics, such as alpha-1 antitrypsin deficiency. In developing countries, common sources of household air pollution are the use of coal and biomass such as wood and dry dung as fuel for cooking and heating. The diagnosis is based on poor airflow as measured by spirometry. Most cases of COPD can be prevented by reducing exposure to risk factors such as smoking and indoor and outdoor pollutants. While treatment can slow worsening, there is no conclusive evidence that any medications can change the long-term decline in lung function. COPD treatments include smoking cessation, vaccinations, pulmonary rehabilitation, inhaled bronchodilators and corticosteroids. Some people may benefit from long-term oxygen therapy, lung volume reduction and lung transplantation. In those who have periods of acute worsening, increased use of medications, antibiotics, corticosteroids and hospitalization may be needed. As of 2021, COPD affected about 213 million people (2.7% of the global population). It typically occurs in males and females over the age of 35–40. In 2021, COPD caused 3.65 million deaths. Almost 90% of COPD deaths in those under 70 years of age occur in low and middle income countries. In 2021, it was the fourth biggest cause of death, responsible for approximately 5% of total deaths. The number of deaths is projected to increase further because of continued exposure to risk factors and an aging population. In the United States, costs of the disease were estimated in 2010 at $50 billion, most of which is due to exacerbation. == Signs and symptoms == === Shortness of breath === A cardinal symptom of COPD is the chronic and progressive shortness of breath which is most characteristic of the condition. Shortness of breath (breathlessness) is often the most distressing symptom responsible for the associated anxiety and level of disability experienced. Symptoms of wheezing and chest tightness associated with breathlessness can be variable over the course of a day or between days and are not always present. Chest tightness often follows exertion. Many people with more advanced COPD breathe through pursed lips, which can improve shortness of breath. Shortness of breath is often responsible for reduced physical activity and low levels of physical activity are associated with worse outcomes. In severe and very severe cases there may be constant tiredness, weight loss, muscle loss and anorexia. People with COPD often have increased breathlessness and frequent colds before seeking treatment. === Cough === The most often first symptom of COPD is a chronic cough, which may or may not be productive of mucus as phlegm. Phlegm coughed up as sputum can be intermittent and may be swallowed or spat out depending on social or cultural factors and is therefore not always easy to evaluate. However, an accompanying productive cough is only seen in up to 30% of cases. Sometimes limited airflow may develop in the absence of a cough. Symptoms are usually worse in the morning. A chronic productive cough is the result of mucus hypersecretion and when it persists for more than three months each year for at least two years, it is defined as chronic bronchitis. Chronic bronchitis can occur before the restricted airflow diagnostic of COPD. Some people with COPD attribute the symptoms to the consequences of smoking. In severe COPD, vigorous coughing may lead to rib fractures or to a brief loss of consciousness. == Exacerbations == An acute exacerbation is a sudden worsening of signs and symptoms that lasts for several days. The key symptom is increased breathlessness, other more pronounced symptoms are of excessive mucus, increased cough and wheeze. A commonly found sign is air trapping giving a difficulty in complete exhalation. The usual cause of an exacerbation is a viral infection, most often the common cold. The common cold is usually associated with the winter months but can occur at any time. Other respiratory infections may be bacterial or in combination sometimes secondary to a viral infection. The most common bacterial infection is caused by Haemophilus influenzae. Other risks include exposure to tobacco smoke (active and passive) and environmental pollutants – both indoor and outdoor. During the COVID-19 pandemic, hospital admissions for COPD exacerbations sharply decreased which may be attributable to reduction of emissions and cleaner air. There has also been a marked decrease in the number of cold and flu infections during this time. Smoke from wildfires is proving an increasing risk in many parts of the world and government agencies have published protective advice on their websites. In the US the EPA advises that the use of dust masks do not give protection from the fine particles in wildfires and instead advise the use of well-fitting particulate masks. This same advice is offered in Canada and Australia to the effects of their forest fires. The number of exacerbations is not seen to relate to any stage of the disease; those with two or more a year are classed as frequent exacerbators and these lead to a worsening in the disease progression. Frailty in ageing increases exacerbations and hospitalization. Acute exacerbations in COPD are often unexplained and thought to have many causes other than infections. A study has emphasized the possibility of a pulmonary embolism as sometimes being responsible in these cases. Signs can include pleuritic chest pain and heart failure without signs of infection. Such emboli could respond to anticoagulants. == Other conditions == COPD often occurs along with a number of other conditions (comorbidities) due in part to shared risk factors. Common comorbidities include cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, osteoporosis, depression, anxiety, asthma and lung cancer. Alpha-1 antitrypsin deficiency (A1AD) is an important risk factor for COPD. It is advised that everybody with COPD be screened for A1AD. Metabolic syndrome has been seen to affect up to fifty percent of those with COPD and significantly affects the outcomes. When comorbid with COPD there is more systemic inflammation. It is not known if it co-exists with COPD or develops as a consequence of the pathology. Metabolic syndrome on its own has a high rate of morbidity and mortality and this rate is amplified when comorbid with COPD. Tuberculosis is a risk factor for the development of COPD, and is also a potential comorbidity. Most people with COPD die from comorbidities and not from respiratory problems. Anxiety and depression are often complications of COPD. Other complications include reduced quality of life and increased disability, cor pulmonale, frequent chest infections including pneumonia, secondary polycythemia, respiratory failure, pneumothorax, lung cancer, and cachexia (muscle wasting). Along with these complications, there is an associated risk of developing pulmonary hypertension. The estimated prevalence of pulmonary hypertension complicating COPD was reported at 39% in a meta-analysis. Of the people with COPD listed for lung transplantation, 82% were documented as having pulmonary hypertension via right heart catheterization, noting a mean pulmonary arterial pressure greater than 20mm Hg. Despite pulmonary hypertension being relatively rare in people with COPD, mild elevations of pulmonary arterial pressure can lead to worse outcomes, including risk of death. Cognitive impairment is common in those with COPD as it is for other lung conditions that affect airflow. Cognitive impairment is associated with the declining ability to cope with the basic activities of daily living. It is unclear if those with COPD are at greater risk of contracting COVID-19, though if infected they are at risk of hospitalization and developing severe COVID-19. However, there are laboratory and clinical studies showing a possibility of certain inhaled corticosteroids for COPD providing a protective role against COVID-19. Differentiating COVID-19 symptoms from an exacerbation is difficult; mild prodromal symptoms may delay its recognition and where they include loss of taste or smell COVID-19 is to be suspected. === Definition === Many definitions of COPD in the past have included chronic bronchitis and emphysema but these have never been included in GOLD report definitions. Emphysema is defined as enlarged airspaces (alveoli) whose walls break down resulting in permanent damage to the lung tissue and is just one of the structural abnormalities that can limit airflow. The condition can exist without airflow limitation but commonly it does. Chronic bronchitis is defined as a productive cough that is present for at least three months each year for two years but does not always result in airflow limitation although the risk of developing COPD is great. These older definitions grouped the two types as type A and type B. Type A were emphysema types known as pink puffers due to their pink complexion, fast breathing rate and pursed lips. Type B were chronic bronchitic types referred to as blue bloaters due to low oxygen levels causing a bluish color to the skin and lips and swollen ankles. These differences were suggested to be due to the presence or not of collateral ventilation, evident in emphysema and lacking in chronic bronchitis. This terminology was no longer accepted as useful, as most people with COPD have a combination of both emphysema and airway disease. These are now recognized as the two major phenotypes of COPD — the emphysematous phenotype and the chronic bronchitic phenotype. == Subtypes == It has since been recognized that COPD is more complex, with a diverse group of disorders of differing risk factors and clinical courses that has resulted in a number of subtypes or phenotypes of COPD being accepted and proposed. The two classic emphysematous and chronic bronchitic phenotypes are fundamentally different conditions with unique underlying mechanisms. Another subtype of COPD, categorized by some as a separate clinical entity, is asthma-COPD overlap, which is a condition sharing clinical features of both asthma and COPD. Spirometry measures are inadequate for defining phenotypes and chest X-ray, CT and MRI scans have been mostly employed. Most cases of COPD are diagnosed at a late stage and the use of imaging methods would allow earlier detection and treatment. The identification and recognition of different phenotypes can guide appropriate treatment approaches. For example, the PDE4 inhibitor roflumilast is targeted at the chronic-bronchitic phenotype. Two inflammatory phenotypes show a phenotype stability: the neutrophilic inflammatory phenotype and the eosinophilic inflammatory phenotype. Mepolizumab, a monoclonal antibody, has been shown to have benefit in treating the eosinophilic inflammatory type rather than the use of oral corticosteroids, but further studies have been called for. Another recognized phenotype is the frequent exacerbator. The frequent exacerbator has two or more exacerbations a year, has a poor prognosis and is described as a moderately stable phenotype. A pulmonary vascular COPD phenotype has been described due to cardiovascular dysfunction. A molecular phenotype of CFTR dysfunction is shared with cystic fibrosis. A combined phenotype of chronic bronchitis and bronchiectasis has been described with a difficulty noted of determining the best treatment. The only genotype is the alpha-1 antitrypsin deficiency (AATD) genetic subtype and this has a specific treatment. == Cause == The most common cause of the development of COPD is the exposure to harmful particles or gases, including tobacco smoke, that irritate the lung causing inflammation that interacts with a number of host factors. Such exposure needs to be significant or long-term. The greatest risk factor for the development of COPD is tobacco smoke. However, less than 50 percent of heavy smokers develop COPD, so other factors need to be considered, including exposure to indoor and outdoor pollutants, allergens, occupational exposure, and host factors. One of the known causes of COPD is exposure to construction dust. The three main types of construction dust are silica dust, non-silica dust (e.g., dust from gypsum, cement, limestone, marble and dolomite) and wood dust. Host factors include a genetic susceptibility, factors associated with poverty, aging and physical inactivity. Asthma and tuberculosis are also recognized as risk factors, as the comorbidity of COPD is reported to be 12 times higher in patients with asthma after adjusting for smoking history. In Europe airway hyperresponsiveness is rated as the second most important risk factor after smoking. A host factor of an airway branching variation, arising during development has been described. The respiratory tree is a filter for harmful substances and any variant has the potential to disrupt this. A variation has been found to be associated with the development of chronic bronchitis and another with the development of emphysema. A branch variant in the central airway is specifically associated with an increased susceptibility for the later development of COPD. A genetic association for the variants has been sometimes found with FGF10. Alcohol abuse can lead to alcoholic lung disease and is seen to be an independent risk factor for COPD. Mucociliary clearance is disrupted by chronic exposure to alcohol; macrophage activity is diminished and an inflammatory response promoted. The damage leads to a susceptibility for infection, including COVID-19, more so when combined with smoking; smoking induces the upregulation of the expression of ACE2, a receptor for the SARS-CoV-2 virus. === Smoking === The primary risk factor for COPD globally is tobacco smoking with an increased rate of developing COPD shown in smokers and ex-smokers. Of those who smoke, about 20% will get COPD, increasing to less than 50% in heavy smokers. In the United States and United Kingdom, of those with COPD, 80–95% are either current or previous smokers. Several studies indicate that women are more susceptible than men to the harmful effects of tobacco smoke. For the same amount of cigarette smoking, women have a higher risk of COPD than men. Women who smoke during pregnancy, and during the early life of the child is a risk factor for the later development of COPD in their child. Inhaled smoke triggers the release of excessive proteases in lungs, which then degrades elastin, the major component of alveoli. Smoke also impairs the action of cilia, inhibiting mucociliary clearance that clears the bronchi of mucus, cellular debris and unwanted fluid. Other types of tobacco smoke, such as from cigar, pipe, water-pipe and hookah use, also confer a risk. Water-pipe or hookah smoke appears to be as harmful or even more harmful than smoking cigarettes. Marijuana is the second most commonly smoked substance, but evidence linking its use to COPD is very limited. Limited evidence shows that marijuana does not accelerate lung function decline. A low use of marijuana gives a bronchodilatory effect rather than the bronchoconstrictive effect from tobacco use, but it is often smoked in combination with tobacco or on its own by tobacco smokers. Higher use however has shown a decline in the FEV1. There is evidence of it causing some respiratory problems and its use in combination may have a cumulative toxic effect suggesting it as a risk factor for spontaneous pneumothorax, bullous emphysema, COPD and lung cancer. A noted difference between marijuana use and tobacco was that respiratory problems were resolved with stopping usage unlike the continued decline with stopping tobacco smoking. Respiratory symptoms reported with marijuana use included chronic cough, increased sputum production and wheezing but not shortness of breath. Also these symptoms were typically reported ten years ahead of their affecting tobacco smokers. Another study found that chronic marijuana smokers even with the additional use of tobacco developed similar respiratory problems, but did not seem to develop airflow limitation and COPD. === Pollution === Exposure to particulates can bring about the development of COPD, or its exacerbations. Those with COPD are more susceptible to the harmful effects of particulate exposure that can cause acute exacerbations brought about by infections. Black carbon also known as soot, is an air pollutant associated with an increased risk of hospitalization due to the exacerbations caused. Long-term exposure is indicated as an increased rate of mortality in COPD. Studies have shown that people who live in large cities have a higher rate of COPD compared to people who live in rural areas. Areas with poor outdoor air quality, including that from exhaust gas, generally have higher rates of COPD. Urban air pollution significantly effects the developing lung and its maturation, and contributes a potential risk factor for the later development of COPD. The overall effect in relation to smoking is believed to be small. Poorly ventilated fires used for cooking and heating, are often fueled by coal or biomass such as wood and dry dung, leading to indoor air pollution and are one of the most common causes of COPD in developing countries. Women are affected more as they have a greater exposure. These fuels are used as the main source of energy in 80% of homes in India, China and sub-Saharan Africa. === Occupational exposure === Intense and prolonged exposure to workplace dusts, chemicals and fumes increases the risk of COPD in smokers, nonsmokers and never-smokers. Substances implicated in occupational exposure and listed in the UK, include organic and inorganic dusts such as cadmium, silica, dust from grains and flour and fumes from cadmium and welding that promote respiratory symptoms. Workplace exposure is believed to be the cause in 10–20% of cases and in the United States, it is believed to be related to around 30% of cases among never smokers and probably represents a greater risk in countries without sufficient regulations. The negative effects of dust exposure and cigarette smoke exposure appear to be cumulative. === Genetics === Genetics play a role in the development of COPD. It is more common among relatives of those with COPD who smoke than unrelated smokers. The most well known genetic risk factor is alpha-1 antitrypsin deficiency (AATD) and this is the only genotype (genetic subtype) with a specific treatment. This risk is particularly high if someone deficient in alpha-1 antitrypsin (AAT) also smokes. It is responsible for about 1–5% of cases and the condition is present in about three to four in 10,000 people. Mutations in MMP1 gene that encodes for interstitial collagenase are associated with COPD. The COPDGene study is an ongoing longitudinal study into the epidemiology of COPD, identifying phenotypes and looking for their likely association with susceptible genes. Genome wide analyses in concert with the International COPD Genetics Consortium has identified more than 80 genome regions associated with COPD and further studies in these regions has been called for. Whole genome sequencing is an ongoing collaboration (2019) with the National Heart, Lung and Blood Institute (NHLBI) to identify rare genetic determinants. == Pathophysiology == COPD is a progressive lung disease in which chronic, incompletely reversible poor airflow (airflow limitation) and an inability to breathe out fully (air trapping) exist. The poor airflow is the result of small airways disease and emphysema (the breakdown of lung tissue). The relative contributions of these two factors vary between people. Air trapping precedes lung hyperinflation. COPD develops as a significant and chronic inflammatory response to inhaled irritants which ultimately leads to bronchial and alveolar remodelling in the lung known as small airways disease. Thus, airway remodelling with narrowing of peripheral airway and emphysema are responsible for the alteration of lung function. Mucociliary clearance is particularly altered with a dysregulation of cilia and mucus production. Small airway disease sometimes called chronic bronchiolitis, appears to be the precursor for the development of emphysema. The inflammatory cells involved include neutrophils and macrophages, two types of white blood cells. Those who smoke additionally have cytotoxic T cell involvement and some people with COPD have eosinophil involvement similar to that in asthma. Part of this cell response is brought on by inflammatory mediators such as chemotactic factors. Other processes involved with lung damage include oxidative stress produced by high concentrations of free radicals in tobacco smoke and released by inflammatory cells and breakdown of the connective tissue of the lungs by proteases (particularly elastase) that are insufficiently inhibited by protease inhibitors. The destruction of the connective tissue of the lungs leads to emphysema, which then contributes to the poor airflow and finally, poor absorption and release of respiratory gases. General muscle wasting that often occurs in COPD may be partly due to inflammatory mediators released by the lungs into the blood. Narrowing of the airways occurs due to inflammation and subsequent scarring within them. This contributes to the inability to breathe out fully. The greatest reduction in air flow occurs when breathing out, as the pressure in the chest is compressing the airways at this time. This can result in more air from the previous breath remaining within the lungs when the next breath is started, resulting in an increase in the total volume of air in the lungs at any given time, a process called air trapping which is closely followed by hyperinflation. Hyperinflation from exercise is linked to shortness of breath in COPD, as breathing in is less comfortable when the lungs are already partly filled. Hyperinflation may also worsen during an exacerbation. There may also be a degree of airway hyperresponsiveness to irritants similar to those found in asthma. Low oxygen levels and eventually, high carbon dioxide levels in the blood, can occur from poor gas exchange due to decreased ventilation from airway obstruction, hyperinflation and a reduced desire to breathe. During exacerbations, airway inflammation is also increased, resulting in increased hyperinflation, reduced expiratory airflow and worsening of gas transfer. This can lead to low blood oxygen levels which if present for a prolonged period, can result in narrowing of the arteries in the lungs, while emphysema leads to the breakdown of capillaries in the lungs. Both of these conditions may result in pulmonary heart disease also classically known as cor pulmonale. == Diagnosis == The diagnosis of COPD should be considered in anyone over the age of 35 to 40 who has shortness of breath, a chronic cough, sputum production, or frequent winter colds and a history of exposure to risk factors for the disease. Spirometry is then used to confirm the diagnosis. === Spirometry === Spirometry measures the amount of airflow obstruction present and is generally carried out after the use of a bronchodilator, a medication to open up the airways. Two main components are measured to make the diagnosis, the forced expiratory volume in one second (FEV1), which is the greatest volume of air that can be breathed out in the first second of a breath and the forced vital capacity (FVC), which is the greatest volume of air that can be breathed out in a single large breath. Normally, 75–80% of the FVC comes out in the first second and a FEV1/FVC ratio less than 70% in someone with symptoms of COPD defines a person as having the disease. Based on these measurements, spirometry would lead to over-diagnosis of COPD in the elderly. The National Institute for Health and Care Excellence criteria additionally require a FEV1 less than 80% of predicted. People with COPD also exhibit a decrease in diffusing capacity of the lung for carbon monoxide due to decreased surface area in the alveoli, as well as damage to the capillary bed. Testing the peak expiratory flow (the maximum speed of expiration), commonly used in asthma diagnosis, is not sufficient for the diagnosis of COPD. Screening using spirometry in those without symptoms has uncertain effects and is generally not recommended; however, it is recommended for those without symptoms but with a known risk factor. === Assessment === A number of methods can be used to assess the effects and severity of COPD. The MRC breathlessness scale or the COPD assessment test (CAT) are simple questionnaires that may be used. GOLD refers to a modified MRC scale that if used, needs to include other tests since it is simply a test of breathlessness experienced. Scores on CAT range from 0–40 with the higher the score, the more severe the disease. Spirometry may help to determine the severity of airflow limitation. This is typically based on the FEV1 expressed as a percentage of the predicted "normal" for the person's age, gender, height and weight. Guidelines published in 2011 by American and European medical societies recommend partly basing treatment recommendations on the FEV1. The GOLD guidelines group people into four categories based on symptoms assessment, degree of airflow limitation and history of exacerbations. Weight loss, muscle loss and fatigue are seen in severe and very severe cases. Use of screening questionnaires, such as COPD diagnostic questionnaire (CDQ), alone or in combination with hand-held flow meters is appropriate for screening of COPD in primary care. === Other tests === A chest X-ray is not useful to establish a diagnosis of COPD but it is of use in either excluding other conditions or including comorbidities such as pulmonary fibrosis and bronchiectasis. Characteristic signs of COPD on X-ray include hyperinflation (shown by a flattened diaphragm and an increased retrosternal air space) and lung hyperlucency. A saber-sheath trachea may also be shown that is indicative of COPD. A CT scan is not routinely used except for the exclusion of bronchiectasis. Pulse oximetry measurement of peripheral oxygen saturation is recommended in people with clinical signs of respiratory failure or right heart failure. An analysis of arterial blood is recommended in those with a peripheral oxygen saturation of 92% or less to determine actual blood oxygen level and assess for high levels of carbon dioxide in the blood, which may have therapeutic implications such as need for non-invasive ventilation or oxygen supplementation. WHO recommends that all those diagnosed with COPD be screened for alpha-1 antitrypsin deficiency. === Differential diagnosis === COPD may need to be differentiated from other conditions such as congestive heart failure, asthma, bronchiectasis, tuberculosis, obliterative bronchiolitis and diffuse panbronchiolitis. The distinction between asthma and COPD is made on the basis of the symptoms, smoking history and whether airflow limitation is reversible with bronchodilators at spirometry. Chronic bronchitis with normal airflow is not classified as COPD. == Prevention == Most cases of COPD are potentially preventable through decreasing exposure to tobacco smoke and other indoor and outdoor pollutants. === Smoking cessation === The policies of governments, public health agencies and antismoking organizations can reduce smoking rates by discouraging people from starting and encouraging people to stop smoking. Smoking bans in public areas and places of work are important measures to decrease exposure to secondhand smoke and while many places have instituted bans, more are recommended. In those who smoke, stopping smoking is the only measure shown to slow down the worsening of COPD. Even at a late stage of the disease, it can reduce the rate of worsening lung function and delay the onset of disability and death. Often, several attempts are required before long-term abstinence is achieved. Attempts over 5 years lead to success in nearly 40% of people. Some smokers can achieve long-term smoking cessation through willpower alone. Smoking, however, is highly addictive and many smokers need further support. The chance of quitting is improved with social support, engagement in a smoking cessation program and the use of medications such as nicotine replacement therapy, bupropion, or varenicline. Combining smoking-cessation medication with behavioral therapy is more than twice as likely to be effective in helping people with COPD stop smoking, compared with behavioral therapy alone. === Occupational health === A number of measures have been taken to reduce the likelihood that workers in at-risk industries—such as coal mining, construction and stonemasonry—will develop COPD. Examples of these measures include the creation of public policy, education of workers and management about the risks, promoting smoking cessation, checking workers for early signs of COPD, use of respirators and dust control. Effective dust control can be achieved by improving ventilation, using water sprays and by using mining techniques that minimize dust generation. If a worker develops COPD, further lung damage can be reduced by avoiding ongoing dust exposure, for example by changing their work role. === Pollution control === Both indoor and outdoor air quality can be improved, which may prevent COPD or slow the worsening of existing disease. This may be achieved by public policy efforts, cultural changes and personal involvement. Many developed countries have successfully improved outdoor air quality through regulations which has resulted in improvements in the lung function of their populations. Individuals are also advised to avoid irritants of indoor and outdoor pollution. In developing countries one key effort is to reduce exposure to smoke from cooking and heating fuels through improved ventilation of homes and better stoves and chimneys. Proper stoves may improve indoor air quality by 85%. Using alternative energy sources such as solar cooking and electrical heating is also effective. Using fuels such as kerosene or coal might produce less household particulate matter than traditional biomass such as wood or dung, but whether this is better health wise is unclear. == Management == COPD currently has no cure, but the symptoms are treatable and its progression can be delayed, particularly by stopping smoking. The major goals of management are to reduce exposure to risk factors including offering non-pharmacological treatments such as help with stopping smoking. Stopping smoking can reduce the rate of lung function decline and also reduce mortality from smoking-related diseases such as lung cancer and cardiovascular disease. Other recommendations include pneumococcal vaccination and yearly influenza vaccination to help reduce the risk of exacerbations; as of 2024 CDC and GOLD also recommend RSV vaccine for individuals above 60 years. Guidance is also advised as to managing breathlessness and stress. Other illnesses are also being managed. An action plan is drawn up and is to be reviewed. Providing people with a personalized action plan, an educational session and support for use of their action plan in the event of an exacerbation, reduces the number of hospital visits and encourages early treatment of exacerbations. When self-management interventions, such as taking corticosteroids and using supplemental oxygen, is combined with action plans, health-related quality of life is improved compared to usual care. In those with COPD who are malnourished, supplementation with vitamin C, vitamin E, zinc and selenium can improve weight, strength of respiratory muscles and health-related quality of life. Significant vitamin D deficiency is common in those with COPD and can cause increased exacerbations. Supplementation when deficient can give a 50% reduction in the number of exacerbations. A number of medical treatments are used in the management of stable COPD and exacerbations. These include bronchodilators, corticosteroids and antibiotics. In those with a severe exacerbation, antibiotics improve outcomes. A number of different antibiotics may be used including amoxicillin, doxycycline and azithromycin; whether one is better than the others is unclear. There is no clear evidence of improved outcomes for those with less severe cases. The FDA recommends against the use of fluoroquinolones when other options are available due to higher risks of serious side effects. In treating acute hypercapnic respiratory failure (acutely raised levels of carbon dioxide), bilevel positive airway pressure (BPAP) can decrease mortality and the need of intensive care. In those with end-stage disease, palliative care is focused on relieving symptoms. Morphine can improve exercise tolerance. Non-invasive ventilation may be used to support breathing and also reduce daytime breathlessness. === Bronchodilators === Inhaled short-acting bronchodilators are the primary medications used on an as needed basis; their use on a regular basis is not recommended. The two major types are beta2-adrenergic agonists and anticholinergics; either in long-acting or short-acting forms. Beta2–adrenergic agonists target receptors in the smooth muscle cells in bronchioles causing them to relax and allow improved airflow. They reduce shortness of breath, tend to reduce dynamic hyperinflation and improve exercise tolerance. Short-acting bronchodilators have an effect for four hours and for maintenance therapy long acting bronchodilators with an effect of over twelve hours are used. In times of more severe symptoms a short acting agent may be used in combination. An inhaled corticosteroid used with a long-acting beta-2 agonist is more effective than either one on its own. Which type of long-acting agent, long-acting muscarinic antagonist (LAMA) such as tiotropium or long-acting beta agonist (LABA), is better is unclear and trying each and continuing with the one that works best may be advisable. Both types of agent appear to reduce the risk of acute exacerbations by 15–25%. The combination of LABA/LAMA may reduce COPD exacerbations and improve quality-of-life compared to long-acting bronchodilators alone. The 2018 NICE guideline recommends use of dual long-acting bronchodilators with economic modelling suggesting that this approach is preferable to starting one long acting bronchodilator and adding another later. Several short-acting β2 agonists are available, including salbutamol (albuterol) and terbutaline. They provide relief of symptoms for four to six hours. A long-acting beta agonist (LABA) such as salmeterol, formoterol and indacaterol are often used as maintenance therapy, with a duration of action of 12 to 24 hours. Some feel the evidence of benefits is limited, while others view the evidence of benefit as established. Long-term use of LABAs appears safe in COPD, with adverse effects include shakiness and heart palpitations. When used with inhaled steroids they increase the risk of pneumonia. While steroids and LABAs may work better together, it is unclear if this slight benefit outweighs the increased risks. There is some evidence that combined treatment of LABAs with long-acting muscarinic antagonists (LAMA), an anticholinergic, and LABA +ICS (inhaled corticosteroid) may be similar in benefits in terms of fewer exacerbation's and quality of life measures for moderate to severe COPD, but LAMA+LABA offers better improvements in forced expiratory volume (FEV1%) and a lower risk of pneumonia. All three together, LABA, LAMA and ICS, have some evidence of benefits. Indacaterol requires an inhaled dose once a day and is as effective as the other long-acting β2 agonist drugs that require twice-daily dosing for people with stable COPD. The two main anticholinergics used in COPD are ipratropium and tiotropium. Ipratropium is a short-acting muscarinic antagonist (SAMA), while tiotropium is long-acting muscarinic antagonist (LAMA). Tiotropium is associated with a decrease in exacerbations and improved quality of life, and tiotropium provides those benefits better than ipratropium. Tiotropium does not appear to affect mortality or the overall hospitalization rate. Anticholinergics can cause dry mouth and urinary tract symptoms. They are also associated with increased risk of heart disease and stroke. Aclidinium, another long-acting agent, reduces hospitalizations associated with COPD and improves quality of life. The LAMA umeclidinium bromide is another anticholinergic alternative. When compared to tiotropium, the LAMAs aclidinium, glycopyrronium, and umeclidinium appear to have a similar level of efficacy; with all four being more effective than placebo. Further research is needed comparing aclidinium to tiotropium. === Corticosteroids === Inhaled corticosteroids are anti-inflammatories that are recommended by GOLD as a first-line maintenance treatment in COPD cases with repeated exacerbations. Their regular use increases the risk of pneumonia in severe cases. Studies have shown that the risk of pneumonia is associated with all types of corticosteroids; is related to the disease severity and a dose-response relationship has been noted. Oral glucocorticoids can be effective in treating an acute exacerbation. They appear to have fewer side effects than those given intravenously. Five days of steroids work as well as ten or fourteen days. The use of corticosteroids is associated with a decrease in the number of lymphoid follicles (in the bronchial lymphoid tissue). A triple inhaled therapy of LABA/LAMA/ICS improves lung function, reduces symptoms and exacerbations and is seen to be more effective than mono or dual therapies. NICE guidelines recommend the use of ICSs in people with asthmatic features or features suggesting steroid responsiveness. === PDE4 inhibitors === Phosphodiesterase-4 inhibitors (PDE4 inhibitors) are anti-inflammatories that improve lung function and reduce exacerbations in moderate to severe illness. Roflumilast is a PDE4 inhibitor used orally once daily to reduce inflammation, it has no direct bronchodilatory effects. It is essentially used in treating those with chronic bronchitis along with systemic corticosteroids. Reported adverse effects of roflumilast appear early in treatment, become less with continued treatment and are reversible. One effect is dramatic weight loss and its use is to be avoided in underweight people. It is also advised to be used with caution in those who have depression. === Other medications === Long-term preventive use of antibiotics, specifically those from the macrolide class such as erythromycin, reduce the frequency of exacerbations in those who have two or more a year. This practice may be cost effective in some areas of the world. Concerns include the potential for antibiotic resistance and side effects including hearing loss, tinnitus and changes to the heart rhythm known as long QT syndrome. Methylxanthines such as theophylline are widely used. Theophylline is seen to have a mild bronchodilatory effect in stable COPD. Inspiratory muscle function is seen to be improved but the causal effect is unclear. Theophylline is seen to improve breathlessness when used as an add-on to salmeterol. All instances of improvement have been reported using sustained release preparations. Methylxanthines are not recommended for use in exacerbations due to adverse effects. Mucolytics may help to reduce exacerbations in some people with chronic bronchitis; noticed by less hospitalization and less days of disability in one month. Erdosteine is recommended by NICE. GOLD also supports the use of some mucolytics that are advised against when inhaled corticosteroids are being used and singles out erdosteine as having good effects regardless of corticosteroid use. Erdosteine also has antioxidant properties but there is not enough evidence to support the general use of antioxidants. Erdosteine has been shown to significantly reduce the risk of exacerbations, shorten their duration and hospital stays. Cough medicines are not recommended. Beta blockers are not contraindicated for those with COPD and should only be used where there is concomitant cardiovascular disease. Recent studies show that metformin plays a role in reducing systemic inflammation by reducing biomarker levels that are increased during COPD exacerbations. === Oxygen therapy === Supplemental oxygen is recommended for those with low oxygen levels in respiratory failure at rest (a partial pressure of oxygen less than 50–55 mmHg or oxygen saturations of less than 88%). When taking into account complications including cor pulmonale and pulmonary hypertension, the levels involved are 56–59 mmHg. Oxygen therapy is to be used for between 15 and 18 hours per day and is said to decrease the risk of heart failure and death. In those with normal or mildly low oxygen levels, oxygen supplementation (ambulatory) may improve shortness of breath when given during exercise, but may not improve breathlessness during normal daily activities or affect the quality of life. During acute exacerbations, many require oxygen therapy; the use of high concentrations of oxygen without taking into account a person's oxygen saturations may lead to increased levels of carbon dioxide and worsened outcomes. In those at high risk of high carbon dioxide levels, oxygen saturations of 88–92% are recommended, while for those without this risk, recommended levels are 94–98%. Once prescribed long-term oxygen therapy, patients should be re-assessed after 60 to 90 days, to determine whether supplemental oxygen is still indicated and if prescribed supplemental oxygen is effective. === Rehabilitation === Pulmonary rehabilitation is a program of exercise, disease management and counseling, coordinated to benefit the individual. A severe exacerbation leads to hospital admission, high mortality and a decline in the ability to carry out daily activities. Following a hospital admission pulmonary rehabilitation has been shown to significantly reduce future hospital admissions, mortality and improve quality of life. The optimal exercise routine, use of noninvasive ventilation during exercise and intensity of exercise suggested for people with COPD, is unknown. Performing endurance arm exercises improves arm movement for people with COPD and may result in a small improvement in breathlessness. Performing arm exercises alone does not appear to improve quality of life. Pursed-lip breathing exercises may be useful. Tai chi exercises appear to be safe to practice for people with COPD and may be beneficial for pulmonary function and pulmonary capacity when compared to a regular treatment program. Tai Chi was not found to be more effective than other exercise intervention programs. Inspiratory and expiratory muscle training (IMT, EMT) have been suggested and may provide some improvements when compared to no treatment. A combination of IMT and walking exercises at home may help limit breathlessness in cases of severe COPD. Additionally, the use of low amplitude high velocity joint mobilization together with exercise improves lung function and exercise capacity. The goal of spinal manipulation therapy is to improve thoracic mobility in an effort to reduce the work on the lungs during respiration, however, the evidence supporting manual therapy for people with COPD is very weak. Airway clearance techniques (ACTs), such as postural drainage, percussion/vibration, autogenic drainage, hand-held positive expiratory pressure (PEP) devices and other mechanical devices, may reduce the need for increased ventilatory assistance, the duration of ventilatory assistance and the length of hospital stay in people with acute COPD. In people with stable COPD, ACTs may lead to short-term improvements in health-related quality of life and a reduced long-term need for hospitalizations related to respiratory issues. Being either underweight or overweight can affect the symptoms, degree of disability and prognosis of COPD. People with COPD who are underweight can improve their breathing muscle strength by increasing their calorie intake. When combined with regular exercise or a pulmonary rehabilitation program, this can lead to improvements in COPD symptoms. Supplemental nutrition may be useful in those who are malnourished. === Management of exacerbations === People with COPD can experience exacerbations (flare-ups) that are commonly caused by respiratory tract infections. The symptoms that worsen are not specific to COPD and differential diagnoses need to be considered. Acute exacerbations are typically treated by increasing the use of short-acting bronchodilators including a combination of a short-acting inhaled beta agonist and short-acting anticholinergic. These medications can be given either via a metered-dose inhaler with a spacer or via a nebulizer, with both appearing to be equally effective. Nebulization may be easier for those who are more unwell. Oxygen supplementation can be useful. Excessive oxygen; however, can result in increased CO2 levels and a decreased level of consciousness. Corticosteroids given orally can improve lung function and shorten hospital stays but their use is recommended for only five to seven days; longer courses increase the risk of pneumonia and death. === Room temperature === Maintaining room temperature of at least 21 °C (70 °F) for a minimum of nine hours a day was associated with better health in those with COPD, especially for smokers. The World Health Organization (WHO) recommends indoor temperatures of a slightly higher range between 18 and 24 °C (64 and 75 °F). === Room humidity === For people with COPD, the ideal indoor humidity levels are 30–50% RH. Maintaining indoor humidity can be difficult in the winter, especially in cold climates where the heating system is constantly running. Keeping the indoor relative humidity above 40% RH significantly reduces the infectivity of aerosolized viruses. == Procedures for emphysema == There are a number of procedures to reduce the volume of a lung in cases of severe emphysema with hyperinflation. === Surgical === For severe emphysema that has proved unresponsive to other therapies lung volume reduction surgery (LVRS) may be an option. LVRS involves the removal of damaged tissue, which improves lung function by allowing the rest of the lungs to expand. It is considered when the emphysema is in the upper lobes and when there are no comorbidities. === Bronchoscopic === Minimally invasive bronchoscopic procedures may be carried out to reduce lung volume. These include the use of valves, coils, or thermal ablation. Endobronchial valves are one-way valves that may be used in those with severe hyperinflation resulting from advanced emphysema; a suitable target lobe and no collateral ventilation are required for this procedure. The placement of one or more valves in the lobe induces a partial collapse of the lobe that ensures a reduction in residual volume that improves lung function, the capacity for exercise and quality of life. The placement of nitinol coils instead of valves is recommended where there is collateral ventilation that would prevent the use of valves. Nitinol is a biocompatible alloy. Both of these techniques are associated with adverse effects including persistent air leaks and cardiovascular complications. Thermal vapor ablation has an improved profile. Heated water vapor is used to target lobe regions which leads to permanent fibrosis and volume reduction. The procedure is able to target individual lobe segments, can be carried out regardless of collateral ventilation and can be repeated with the natural advance of emphysema. === Other surgeries === In very severe cases lung transplantation might be considered. A CT scan may be useful in surgery considerations. Ventilation/perfusion scintigraphy is another imaging method that may be used to evaluate cases for surgical interventions and also to evaluate post-surgery responses. A bullectomy may be carried out when a giant bulla occupies more than a third of a hemithorax. == Prognosis == COPD is progressive and can lead to premature death. It is estimated that 3% of all disability is related to COPD. The proportion of disability from COPD globally has decreased from 1990 to 2010 due to improved indoor air quality primarily in Asia. The overall number of years lived with disability from COPD, however, has increased. There are many variables affecting the long-term outcome in COPD and GOLD recommends the use of a composite test (BODE) that includes the main variables of body-mass index, obstruction of airways, dyspnea (breathlessness) and exercise and not just spirometry results. NICE recommends against the use of BODE for the prognosis assessment in stable COPD; factors such as exacerbations and frailty need to be considered. Other factors that contribute to a poor outcome include older age, comorbidities such as lung cancer and cardiovascular disease and the number and severity of exacerbations needing hospital admission. == Epidemiology == Estimates of prevalence have considerable variation due to differences in analytical and surveying approach and the choice of diagnostic criteria. An estimated 213 million people had COPD in 2021, corresponding to a global prevalence of 2.7%, whereas epidemiological studies indicated an estimation of 384 million having COPD in 2010, corresponding to a global prevalence of 12%. The disease affects men and women. The increase in the developing world between 1970 and the 2000s is believed to be related to increasing rates of smoking in this region, an increasing population and an aging population due to fewer deaths from other causes such as infectious diseases. Some developed countries have seen increased rates, some have remained stable and some have seen a decrease in COPD prevalence. Around three million people die of COPD each year. In some countries, mortality has decreased in men but increased in women. This is most likely due to rates of smoking in women and men becoming more similar. A higher rate of COPD is found in those over 40 years and this increases greatly with advancing age with the highest rate found in those over 60 years. Sex differences in the anatomy of the respiratory system include smaller airway lumens and thicker airway walls in women, which contribute to a greater severity of COPD symptoms like dyspnea and frequency of COPD exacerbation. In the UK, three million people are reported to be affected by COPD – two million of these being undiagnosed. On average, the number of COPD-related deaths between 2007 and 2016 was 28,600. The estimated number of deaths due to occupational exposure was estimated to be about 15% at around 4,000. In the United States in 2018, almost 15.7 million people had been diagnosed with COPD and it is estimated that millions more have not been diagnosed. In 2011, there were approximately 730,000 hospitalizations in the United States for COPD. Globally, COPD in 2019 was the third-leading cause of death. In low-income countries, COPD does not appear in the Top 10 causes of death; in other income groups, it is in the Top 5. == History == The name chronic obstructive pulmonary disease is believed to have first been used in 1965. Previously it has been known by a number of different names, including chronic obstructive bronchopulmonary disease, chronic airflow obstruction, chronic obstructive lung disease, nonspecific chronic pulmonary disease, and diffuse obstructive pulmonary syndrome. The terms emphysema and chronic bronchitis were formally defined as components of COPD in 1959 at the CIBA guest symposium and in 1962 at the American Thoracic Society Committee meeting on Diagnostic Standards. Early descriptions of probable emphysema began in 1679 by T. Bonet of a condition of "voluminous lungs" and in 1769 by Giovanni Morgagni of lungs which were "turgid particularly from air". In 1721 the first drawings of emphysema were made by Ruysh. René Laennec, used the term emphysema in his book A Treatise on the Diseases of the Chest and of Mediate Auscultation (1837) to describe lungs that did not collapse when he opened the chest during an autopsy. He noted that they did not collapse as usual because they were full of air and the airways were filled with mucus. In 1842, John Hutchinson invented the spirometer, which allowed the measurement of vital capacity of the lungs. However, his spirometer could only measure volume, not airflow. Tiffeneau and Pinelli in 1947 described the principles of measuring airflow. Air pollution and the increase in cigarette smoking in Great Britain at the start of the 20th century led to high rates of chronic lung disease, though it received little attention until the Great Smog of London in December 1952. This spurred epidemiological research in the United Kingdom, Holland and elsewhere. In 1953, George L. Waldbott, an American allergist, first described a new disease he named smoker's respiratory syndrome in the 1953 Journal of the American Medical Association. This was the first association between tobacco smoking and chronic respiratory disease. Modern treatments were developed during the second half of the 20th century. Evidence supporting the use of steroids in COPD was published in the late 1950s. Bronchodilators came into use in the 1960s following a promising trial of isoprenaline. Further bronchodilators, such as short-acting salbutamol, were developed in the 1970s and the use of long-acting bronchodilators began in the mid-1990s. == Society and culture == It is generally accepted that COPD is widely underdiagnosed and many people remain untreated. In the US the NIH has promoted November as COPD Awareness Month to be an annual focus on increasing awareness of the condition. === Economics === Globally, as of 2010, COPD is estimated to result in economic costs of $2.1 trillion, half of which occurring in the developing world. Of this total an estimated $1.9 trillion are direct costs such as medical care, while $0.2 trillion are indirect costs such as missed work. This is expected to more than double by 2030. In Europe, COPD represents 3% of healthcare spending. In the United States, costs of the disease were estimated at $50 billion in 2010, most of which is due to exacerbation. In the United Kingdom this cost was in 2021 estimated at £3.8 billion annually. == Research == Stem-cell therapy using mesenchymal stem cells was in June 2021 studied in eight clinical trials had been completed and seventeen were underway. The effectiveness of alpha-1 antitrypsin augmentation treatment for people who have alpha-1 antitrypsin deficiency is unclear. Metabolomic approaches to diagnosing and differentiating subtypes of COPD are being studied. Research continues into the use of telehealthcare to treat people with COPD when they experience episodes of shortness of breath; treating people remotely may reduce the number of emergency-room visits and improve the person's quality of life. American people with COPD and their caregivers consider the following COPD-related research areas as the most important: family/social/community research, well-being of people with COPD, curative research, biomedical therapies, policy, and holistic therapies. == Other animals == Chronic obstructive pulmonary disease may occur in a number of other animals and may be caused by exposure to tobacco smoke. Most cases of the disease, however, are relatively mild. In horses it is known as recurrent airway obstruction (RAO) or heaves. RAO can be quite severe and most often is linked to exposure to common allergens. COPD is also commonly found in old dogs. == References == === Works cited === == External links == WHO fact sheet on COPD "COPD". MedlinePlus. U.S. National Library of Medicine.	Wikipedia/Chronic_obstructive_pulmonary_disease
The Journal of Thoracic and Cardiovascular Surgery is a monthly peer-reviewed medical journal covering cardiothoracic surgery, cardiology, pulmonary medicine, and vascular disease published by Elsevier. It is the official journal of the American Association for Thoracic Surgery and the Western Thoracic Surgical Association. == History and Impact == The journal was established in 1931 as the Journal of Thoracic Surgery. The journal has the second highest impact factor of all cardiothoracic surgery journals. According to the Journal Citation Reports, its 2020 impact factor is 5.209, ranking it 21st out of 212 journals in the category "Surgery". == References == == External links == Official website Journal page at publisher's website	Wikipedia/Journal_of_Thoracic_and_Cardiovascular_Surgery
Cardiac resynchronisation therapy (CRT or CRT-P) is the insertion of electrodes in the left and right ventricles of the heart, as well as on occasion the right atrium, to treat heart failure by coordinating the function of the left and right ventricles via a pacemaker, a small device inserted into the anterior chest wall. CRT is indicated in patients with a low ejection fraction (typically <35%) indicating heart failure, where electrical activity has been compromised, with prolonged QRS duration to >120 ms. The insertion of electrodes into the ventricles is done under local anesthetic, with access to the ventricles most commonly via the subclavian vein, although access may be conferred from the axillary or cephalic veins. Right ventricular access is direct, while left ventricular access is conferred via the coronary sinus (CS). CRT defibrillators (CRT-D) also incorporate the additional function of an implantable cardioverter-defibrillator (ICD), to quickly terminate an abnormally fast, life-threatening heart rhythm. CRT and CRT-D have become increasingly important therapeutic options for patients with moderate and severe heart failure. CRT with pacemaker only is often termed "CRT-P" to help distinguish it from CRT with defibrillator (CRT-D). == Indications == The key indication for CRT is left bundle branch block (LBBB) of the heart, a cardiac abnormality leading to delayed left ventricular contraction. LBBB causes a QRS prolongation of ≥120 ms on the electrocardiogram, contributing to poor left ventricular coordination and reduced systolic function, thereby reduced ejection fraction (<35%). This reduction in ejection fraction is considered heart failure. Heart failure patients are generally considered if in New York Heart Association (NYHA) class II or III heart failure. Current National Institute for Health and Care Excellence (NICE) guidelines state that CRT-D device placement is inappropriate for class IV heart failure, but placement of CRT-P devices may be appropriate in certain circumstances. == Method == CRT requires the placement of an electrical device for biventricular pacing, along with placement of (at least) two pacing leads, to facilitate stable left ventricular and right ventricular pacing. For all elements, the first stage of the process is local anaesthetic followed by incision to allow for approach from the appropriate vein. From here, the leads and device can be inserted. === Right ventricular lead placement === A venipuncture is made, and a guide wire inserted into the vein, where it is guided, with use of real time X-ray imaging, through to the right ventricle. The guide wire is then used to assist in the placement of the electrode lead, which travels through the venous system into the right ventricle where the electrode is embedded. === Left ventricular lead placement === This is generally performed subsequent to RV lead placement, with the RV lead providing a backup in case of accidental damage to the electric fibers of the heart, causing an asystolic event. As with the RV lead, a guide wire is first inserted, allowing for the insertion of a multi-delivery catheter. The catheter is subsequently maneuvered to the opening of the coronary sinus in the right atrium. From here a contrast media is injected, allowing the surgical team to obtain a coronary sinus phlebogram to direct the placement of the lead into the most suitable coronary vein. Once the phlebogram has been obtained, the multi-delivery catheter is used to guide in the lead, from the chosen vein of entry, into the right atrium, through the coronary sinus and into the relevant cardiac vein. Left ventricular lead placement is the most complicated and potentially hazardous element of the operation, due to the significant variability of coronary venous structure. Alterations in heart structure, fatty deposits, valves and natural variations all cause additional complications in the process of cannulation. However, this risk can be reduced using AI-based preoperative visualization of LV venous anatomy using computer tomography (CT) imaging. === Device placement === The device is inserted in a subcutaneous pocket created by the surgeon, the choice of left or right side of the chest wall is determined mainly by the patient's preference or location of preexisting device. The device, similar to that of a traditional pacemaker, is generally no larger than a pocket watch and has inserts for the electrode leads. == Benefits == Several studies have also shown that CRT can decrease mortality, reverse left ventricular remodeling, and improve quality of life, walking distance, and peak oxygen uptake (VO2 max). A 2013 study showed that CRT improved the left ventricular ejection fraction (LVEF) by an average of 10.6% 12 months after placement. == Complications == Key complications include: Dissection or perforation of coronary sinus which can in turn cause pericardial effusion Inability to cannulate coronary sinus (approximately 5% of patients) Bleeding and pocket haematoma, each of which with an incidence of less than 1% Myocardial perforation, pneumothorax and infection, all of which have an incidence of less than 1% == Technology == Several research papers have proposed software platforms for planning and guiding the implantation of CRT devices. This research proposes using pre-operative images to characterize tissue and left ventricle activation to identify potential target regions for deploying the CRT leads. == References ==	Wikipedia/Cardiac_resynchronization_therapy
Impedance cardiography (ICG) is a non-invasive technology measuring total electrical conductivity of the thorax and its changes in time to process continuously a number of cardiodynamic parameters, such as stroke volume (SV), heart rate (HR), cardiac output (CO), ventricular ejection time (VET), pre-ejection period and used to detect the impedance changes caused by a high-frequency, low magnitude current flowing through the thorax between additional two pairs of electrodes located outside of the measured segment. The sensing electrodes also detect the ECG signal, which is used as a timing clock of the system. == Introduction == Impedance cardiography (ICG), also referred to as electrical impedance plethysmography (EIP) or Thoracic Electrical Bioimpedance (TEB) has been researched since the 1940s. NASA helped develop the technology in the 1960s. The use of impedance cardiography in psychophysiological research was pioneered by the publication of an article by Miller and Horvath in 1978. Subsequently, the recommendations of Miller and Horvath were confirmed by a standards group in 1990. A comprehensive list of references is available at ICG Publications. With ICG, the placement of four dual disposable sensors on the neck and chest are used to transmit and detect electrical and impedance changes in the thorax, which are used to measure and calculate cardiodynamic parameters. == Process == Four pairs of electrodes are placed at the neck and the diaphragm level, delineating the thorax High frequency, low magnitude current is transmitted through the chest in a direction parallel with the spine from the set of outside pairs Current seeks path of least resistance: the blood filled aorta (the systolic phase signal) and both vena cava superior and inferior (the diastolic phase signal, mostly related to respiration) The inside pairs, placed at the anatomic landmarks delineating thorax, sense the impedance signals and the ECG signal ICG measures the baseline impedance (resistance) to this current With each heartbeat, blood volume and velocity in the aorta change ICG measures the corresponding change in impedance and its timing ICG attributes the changes in impedance to (a) the volumetric expansion of the aorta (this is the main difference between ICG and electrical cardiometry) and (b) to the blood velocity-caused alignment of erythrocytes as a function of blood velocity ICG uses the baseline and changes in impedance to measure and calculate hemodynamic parameters == Hemodynamics == Hemodynamics is a subchapter of cardiovascular physiology, which is concerned with the forces generated by the heart and the resulting motion of blood through the cardiovascular system. These forces demonstrate themselves to the clinician as paired values of blood flow and blood pressure measured simultaneously at the output node of the left heart. Hemodynamics is a fluidic counterpart to the Ohm's law in electronics: pressure is equivalent to voltage, flow to current, vascular resistance to electrical resistance and myocardial work to power. The relationship between the instantaneous values of aortic blood pressure and blood flow through the aortic valve over one heartbeat interval and their mean values are depicted in Fig.1. Their instantaneous values may be used in research; in clinical practice, their mean values, MAP and SV, are adequate. === Blood flow parameters === Systemic (global) blood flow parameters are (a) the blood flow per heartbeat, the Stroke Volume, SV [ml/beat], and (b) the blood flow per minute, the Cardiac Output, CO [l/min]. There is clear relationship between these blood flow parameters: CO[l/min] = (SV[ml] × HR[bpm])/1000 {Eq.1} where HR is the Heart Rate frequency (beats per minute, bpm). Since the normal value of CO is proportional to body mass it has to perfuse, one "normal" value of SV and CO for all adults cannot exist. All blood flow parameters have to be indexed. The accepted convention is to index them by the Body Surface Area, BSA [m2], by DuBois & DuBois Formula, a function of height and weight: BSA[m2] = W0.425[kg] × H0.725[cm] × 0.007184 {Eq.2} The resulting indexed parameters are Stroke Index, SI (ml/beat/m2) defined as SI[ml/beat/m2] = SV[ml]/BSA[m2] {Eq.3} and Cardiac Index, CI (l/min/m2), defined as CI[l/min/m2] = CO[l/min]/BSA[m2] {Eq.4} These indexed blood flow parameters exhibit typical ranges: For the Stroke Index: 35 < SItypical < 65 ml/beat/m2; for the Cardiac Index: 2.8 < CItypical < 4.2 l/min/m2. Eq.1 for indexed parameters then changes to CI[l/min/m2] = (SI[ml/beat/m2] × HR[bpm])/1000 {Eq.1a} === Oxygen transport === The primary function of the cardiovascular system is transport of oxygen: blood is the vehicle, oxygen is the cargo. The task of the healthy cardiovascular system is to provide adequate perfusion to all organs and to maintain a dynamic equilibrium between oxygen demand and oxygen delivery. In a healthy person, the cardiovascular system always increases blood flow in response to increased oxygen demand. In a hemodynamically compromised person, when the system is unable to satisfy increased oxygen demand, the blood flow to organs lower on the oxygen delivery priority list is reduced and these organs may, eventually, fail. Digestive disorders, male impotence, tiredness, sleepwalking, environmental temperature intolerance, are classic examples of a low-flow-state, resulting in reduced blood flow. === Modulators === SI variability and MAP variability are accomplished through activity of hemodynamic modulators. The conventional cardiovascular physiology terms for the hemodynamic modulators are preload, contractility and afterload. They deal with (a) the inertial filling forces of blood return into the atrium (preload), which stretch the myocardial fibers, thus storing energy in them, (b) the force by which the heart muscle fibers shorten thus releasing the energy stored in them in order to expel part of blood in the ventricle into the vasculature (contractility), and (c) the forces the pump has to overcome in order to deliver a bolus of blood into the aorta per each contraction (afterload). The level of preload is currently assessed either from the PAOP (pulmonary artery occluded pressure) in a catheterized patient, or from EDI (end-diastolic index) by use of ultrasound. Contractility is not routinely assessed; quite often inotropy and contractility are interchanged as equal terms. Afterload is assessed from the SVRI value. Rather than using the terms preload, contractility and afterload, the preferential terminology and methodology in per-beat hemodynamics is to use the terms for actual hemodynamic modulating tools, which either the body utilizes or the clinician has in his toolbox to control the hemodynamic state: The preload and the Frank-Starling (mechanically)-induced level of contractility is modulated by variation of intravascular volume (volume expansion or volume reduction/diuresis). Pharmacological modulation of contractility is performed with cardioactive inotropic agents (positive or negative inotropes) being present in the blood stream and affecting the rate of contraction of myocardial fibers. The afterload is modulated by varying the caliber of sphincters at the input and output of each organ, thus the vascular resistance, with the vasoactive pharmacological agents (vasoconstrictors or vasodilators and/or ACE Inhibitors and/or ARBs)(ACE = Angiotensin-converting-enzyme; ARB = Angiotensin-receptor-blocker). Afterload also increases with increasing blood viscosity, however, with the exception of extremely hemodiluted or hemoconcentrated patients, this parameter is not routinely considered in clinical practice. With the exception of volume expansion, which can be accomplished only by physical means (intravenous or oral intake of fluids), all other hemodynamic modulating tools are pharmacological, cardioactive or vasoactive agents. The measurement of CI and its derivatives allow clinicians to make timely patient assessment, diagnosis, prognosis, and treatment decisions. It has been well established that both trained and untrained physicians alike are unable to estimate cardiac output through physical assessment alone. === Invasive monitoring === Clinical measurement of cardiac output has been available since the 1970s. However, this blood flow measurement is highly invasive, utilizing a flow-directed, thermodilution catheter (also known as the Swan-Ganz catheter), which represents significant risks to the patient. In addition, this technique is costly (several hundred dollars per procedure) and requires a skilled physician and a sterile environment for catheter insertion. As a result, it has been used only in very narrow strata (less than 2%) of critically ill and high-risk patients in whom the knowledge of blood flow and oxygen transport outweighed the risks of the method. In the United States, it is estimated that at least two million pulmonary artery catheter monitoring procedures are performed annually, most often in peri-operative cardiac and vascular surgical patients, decompensated heart failure, multi-organ failure, and trauma. === Noninvasive monitoring === In theory, a noninvasive way to monitor hemodynamics would provide exceptional clinical value because data similar to invasive hemodynamic monitoring methods could be obtained with much lower cost and no risk. While noninvasive hemodynamic monitoring can be used in patients who previously required an invasive procedure, the largest impact can be made in patients and care environments where invasive hemodynamic monitoring was neither possible nor worth the risk or cost. Because of its safety and low cost, the applicability of vital hemodynamic measurements could be extended to significantly more patients, including outpatients with chronic diseases. ICG has even been used in extreme conditions such as outer space and a Mt. Everest expedition. Heart failure, hypertension, pacemaker, and dyspnea patients are four conditions in which outpatient noninvasive hemodynamic monitoring can play an important role in the assessment, diagnosis, prognosis, and treatment. Some studies have shown ICG cardiac output is accurate, while other studies have shown it is inaccurate. Use of ICG has been shown to improve blood pressure control in resistant hypertension when used by both specialists and general practitioners. ICG has also been shown to predict worsening status in heart failure. == ICG Parameters == The electrical and impedance signals are processed to determine fiducial points, which are then utilized to measure and calculate hemodynamic parameters, such as cardiac output, stroke volume, systemic vascular resistance, thoracic fluid content, acceleration index, and systolic time ratio. == References == == External links == http://bomed.us/teb.html Archived 2016-07-03 at the Wayback Machine	Wikipedia/Impedance_cardiography
The Annals of Thoracic Surgery is a peer-reviewed medical journal that was established in 1965. It covers the fields of thoracic diseases and surgery. It is the official journal of the Society of Thoracic Surgeons and the Southern Thoracic Surgical Association. == Article retraction practice == In 2004, The Annals of Thoracic Surgery published a study comparing two heart drugs. In January 2011, the journal retracted the study. The journal's editor-in-chief, L. Henry Edmunds, was contacted by Retraction Watch to get details about the cause of the article retraction. Edmunds replied that journalists and bloggers need not discuss article retraction and that it was sufficient for the public to know that the article had been retracted. Edmunds went on to say that the reasons why a journal might retract an article are personal in the same way that the reasons for a marital divorce are. In 2012, the journal retracted a paper by Paolo Macchiarini, the senior author, for scientific misconduct after it was found that a table had been copied from another paper without citation. == Editorial board == === Editor-in-chief === Joanna Chikwe, MD, FRCS, Cedars-Sinai Medical Center, Los Angeles, CA === Past editors === L. Henry Edmunds Jr, MD, 2000–2015 Thomas B. Ferguson MD, 1984–2000 Herbert Sloan MD, 1969–1984 John D. Steele MD, 1964-1969 == References == == External links == Official website The Society of Thoracic Surgeons	Wikipedia/Annals_of_Thoracic_Surgery
A drug-eluting stent (DES) is a tube made of a mesh-like material used to treat narrowed arteries in medical procedures both mechanically (by providing a supporting scaffold inside the artery) and pharmacologically (by slowly releasing a pharmaceutical compound). A DES is inserted into a narrowed artery using a delivery catheter usually inserted through a larger artery in the groin or wrist. The stent assembly has the DES mechanism attached towards the front of the stent, and usually is composed of the collapsed stent over a collapsed polymeric balloon mechanism, the balloon mechanism is inflated and used to expand the meshed stent once in position. The stent expands, embedding into the occluded artery wall, keeping the artery open, thereby improving blood flow. The mesh design allows for stent expansion and also for new healthy vessel endothelial cells to grow through and around it, securing it in place. A DES is different from other types of stents in that it has a coating that delivers medication directly into the blood vessel wall. The stent slowly releases a drug to prevent the growth of scar tissue and new obstructive plaque material which caused the original blood vessel stenosis, this clogging of a stent is termed restenosis. A DES is fully integrated with a catheter delivery system and is viewed as one integrated medical device. DESs are commonly used in the treatment of narrowed arteries in the heart (coronary artery disease), but also elsewhere in the body, especially the legs (peripheral artery disease). Over the last three decades, coronary stenting has matured into a primary minimally invasive treatment tool in managing CAD. Coronary artery stenting is inherently tied to percutaneous coronary intervention (PCI) procedures. PCI is a minimally invasive procedure performed via a catheter (not by open-chest surgery), it is the medical procedure used to place a DES in narrowed coronary arteries. PCI procedures are performed by an interventional cardiologist using fluoroscopic imaging techniques to see the location of the required DES placement. PCI uses larger peripheral arteries in the arms or the legs to thread a catheter/DES device through the arterial system and place the DES in the narrowed coronary artery or arteries. Multiple stents are often used depending on the degree of blockage and the number of diseased coronary arteries that are being treated. == Design == A drug-eluting stent (DES) is a small mesh tube that is placed in the arteries to keep them open in the treatment of vascular disease. The stent slowly releases a drug to block cell proliferation (a biological process of cell growth and division), thus preventing the arterial narrowing (stenosis) that can occur after stent implantation. While such stents can be used in various arteries throughout the body, they are commonly placed in the coronary arteries to treat coronary heart disease. DES products are integrated medical devices and are part of a percutaneous coronary intervention (PCI) delivery system. DES is a medical device with several key properties: it functions as a structural scaffold, physically keeping an artery open to ensure blood flow; the device has specific drug delivery features, and the chosen drug is critical for its effectiveness. The drug, the hallmark compenent of the device, is selected for its suitability in inhibiting restenosis and its pharmacokinetics. Apart from the drug, the materials used in the fabrication of the device are also essential and are carefully chosen for their biocompatibility and durability in a biological environment, such as human blood; these materials must also withstand the constant motion of the heart's beat and be suitable for future patient imaging using magnetic resonance imaging (MRI) technologies, which employ high magnetic fields. Other components, such as the catheter design, also play significant roles in the device's overall functionality and effectiveness. DES are typically composed of metal alloys, most commonly stainless steel or cobalt-chromium, but can also be made of other materials such as platinum-chromium or nickel-titanium. The stent is often coated with a polymer to control the release of drugs. The role of polymers in drug delivery is significant as they regulate the rate at which the drug is released into the surrounding tissue. There are also polymer-free stents where the drug is directly coated on the stent or contained in reservoirs within the stent. The design of the stent includes struts, which are thin wire structures that make up the stent frame. The strut thickness can influence the stent's performance, with thinner struts generally being associated with lower restenosis rates and reduced thrombosis risk. Most DES are balloon-expandable, meaning they are mounted on a balloon catheter and expand when the balloon is inflated. There are also self-expanding stents, which automatically expand when deployed. The very first stent, introduced in 1986, was of this type. The stent tube mesh is initially collapsed onto the catheter—in this collapsed state, it is small enough to be passed though relatively narrow arteries and then expanded in its destination place, pushing firmly to the diseased artery wall. The pharmaceutical compounds that DES emit are antiproliferative agents such as sirolimus, everolimus, zotarolimus, paclitaxel and biolimus. These drugs help prevent the arterial narrowing that can occur after stent implantation. These drugs are also used for other purposes, that involve moderating the immune system or treating cancer. They work by inhibiting cell growth. In DES, they are used in very small amounts and for a short time, and only in the area where the stent is placed. There is a distinction between coronary stents and peripheral stents. While both are used to prevent the narrowing of arteries, coronary stents are specifically for the coronary arteries, while peripheral stents are for any other arteries in the body. Peripheral stents are mostly bare metal ones; some peripheral DES, of the self-expanding type, are used in arteries of the legs. Bioresorbable DES are made of materials that can be absorbed by the body over time, potentially reducing potential long-term complications associated with permanent stents. == Uses == === Atherosclerosis: a general background === Atherosclerosis is a chronic disease that affects the large and medium-sized arteries. It is characterized by the accumulation of calcium, fats (such as cholesterol) and other substances in the innermost layer of the endothelium, a layer of cells that line the interior surface of blood vessels. Atherosclerosis is considered to be the most common form of arteriosclerosis, which refers to the loss of arterial elasticity caused by thickening and stiffening of blood vessels. Atherosclerosis can begin as early as childhood with the development of small "fatty streaks" within arteries. These streaks are essentially deposits of fat. Over time, these initial lesions grow larger and become thicker, forming atheromas (atherosclerotic plaques). Drug-eluting stents (DESs) are used in the treatment of atherosclerosis in both coronary interventions and peripheral arterial interventions: In coronary interventions, DESs are used to treat coronary artery disease, which is primarily caused by atherosclerosis. The stents are inserted into narrowed coronary arteries and then expanded to open up the narrowed artery. The drug compound released by the stents suppresses cellular growth in the newly stented area, reducing the potential for blockage within the stent area itself. In peripheral arterial interventions, DESs have established themselves as the go-to choice for addressing symptomatic peripheral arterial disease (PAD). These highly effective stents are deployed in the treatment of peripheral arterial occlusive disease (PAOD), a condition that shares resemblances with coronary artery disease but specifically affects the peripheral arteries. By employing DESs, healthcare professionals can provide optimal care and intervention to manage PAOD, ultimately improving patient outcomes and mitigating associated complications. DESs are used in the management of atherosclerosis in both coronary and peripheral arterial interventions. They help improve blood flow and reduce the risk of restenosis, thereby improving patient outcomes. The use of DESs is accompanied by appropriate medical therapy and lifestyle modifications to manage atherosclerosis effectively. === Stenosis and restenosis of blood vessels === Stenosis of blood vessels refers to the narrowing of the blood vessels, which can restrict blood flow to the organs and tissues. This condition is often caused by the buildup of fatty deposits in the arteries, a process also called atherosclerosis. In the context of stents, stenosis is a significant concern. Stents are inserted into a narrowed artery during a procedure known as angioplasty. The stents help to open up the narrowed artery and improve blood flow. However, over time, the treated artery can close up again, a condition known as restenosis. Restenosis, or in-stent restenosis, is a blockage or narrowing that comes back in the portion of the artery previously treated with a stent. Restenosis tends to happen three to six months after the procedure. Restenosis is even more likely to occur if a stent would not have been used. When restenosis occurs, another procedure may be needed to correct the problem, such as the placement of a DES that gradually release a drug compound that suppresses cellular growth, thereby reducing the potential for blockage within the stent area itself. This therapy significantly reduces the occurrence of adverse events post-stenting. Technically, a DES in a mesh tube implant devices that is used in angioplasty procedures to treat stenosis of blood vessels and prevent restinosis: the stent, which elutes drugs, is implanted into the blood vessel to help keep the vessel open and improve blood flow. Specifically, drug-eluting stents are used in the treatment of various medical conditions usually at the site of stenotic or occlusive arterial lesions, but one of the primary medical uses is in the treatment of coronary artery disease. Stents are inserted into narrowed coronary arteries, where the narrowing is primarily caused by atherosclerosis. Stents are then expanded to open up the narrowed artery. Such stents gradually release a drug compound that suppresses cellular growth, into the newly stented area, thereby reducing the potential for blockage within the stent area itself. Such blockage is termed in-stent restenosis (ISR). This in-stent blockage is most often caused by excessive cell proliferation or thrombi (blood clots). Anticoagulation therapy (blood thinners), has become a standard treatment following the placement of DES. This therapy significantly reduces the occurrence of adverse events post-stenting. === Coronary interventions === DESs have played a transformative role in the management of coronary artery disease. These stents are tiny, flexible mesh tubes employed during percutaneous coronary intervention (PCI) to address narrowed coronary arteries. What sets them apart is their special coating, which incorporates a drug delivery system that enables controlled release of medication over a specific period, typically within the first 30 to 45 days following implantation. This medication aids in inhibiting the formation of scar tissue within the stent and subsequent re-narrowing of the blood vessel. PCI is a minimally invasive procedure. It involves the placement of a drug-eluting stent (DES) in a coronary artery. This procedure, previously known as angioplasty with a stent, is considered non-surgical as it is performed through a small puncture in a peripheral artery, avoiding the need to open the chest wall. While bleeding from the puncture site was once a concern, advancements in PCI practices have mitigated this issue through the use of pressure bands and arterial closure systems. Modern DES/PCI procedures are generally painless, although some mild discomfort may be experienced. In PCI, multiple DES are sometimes implanted within a single patient; the decision to use multiple stents is typically contingent on the extent of the coronary artery disease present and the number of diseased coronary arteries that require treatment. === Peripheral arterial interventions === DESs have emerged as the primary therapeutic approach for managing symptomatic peripheral arterial disease (PAD). These specialized stents are now widely utilized in the treatment of peripheral arterial occlusive disease (PAOD), a condition that shares similarities with coronary artery disease but affects the peripheral arteries. By deploying DESs, healthcare professionals can effectively address and alleviate the complications associated with PAOD, enhancing patient outcomes and quality of life. The use of DESs in peripheral arterial interventions has shown encouraging results in terms of primary patency (PP) and target lesion revascularization (TLR) compared with bare-metal stents (BMSs). Different types of DESs are available on the market, each with different concentrations of drugs and showing varying efficacy. Among the different DESs, sirolimus-eluting stents and everolimus-eluting stents were found to be more effective than paclitaxel-eluting stents. === Clinical indications === PCI and stent placement are considered when someone shows signs of reduced blood flow in the arteries that supply the heart or when tests, such as different types of coronary artery imaging, show a blockage in those arteries. Symptoms can include: severe, pressure-like chest pain unrelieved by rest; shortness of breath, fatigue, lightheadedness; palpitations; atypical symptoms: nausea, vomiting, indigestion, confusion, back pain. In a medical setting, it's not very useful for doctors to rely solely on what people say about where their pain comes from or how it feels, because the way people describe chest pain caused by reduced blood flow to the heart can vary greatly and may not match what is typically taught in medical education or described in books and articles. === Contraindications === DES is not recommended in some cases as it may do more harm than good. DES is not suitable: when individuals have a bleeding tendency; when a coronary artery has no clear and identifiable narrowing; when only one diseased coronary artery supplies oxygenated blood to the heart muscle. During stent placement, there is a short period of blood flow blockage by the balloon inflation. This blockage time is often longer than twenty seconds to allow the DES to expand and embed into the arterial wall. In this case, this time may be too long and cause serious events due to lack of blood to the heart muscle. Bleeding disorders make DES unsuitable because of the need for anticoagulation drugs (blood thinners) during the procedure and in post-stenting aftercare. Other factors that could rule out the use of stents include a history of in-stent blockage, bleeding problems, complex or unsuitable coronary anatomy, or a short life expectancy due to other serious medical conditions. === Risks and complications === ==== Risks from the procedure ==== Stent placement risks include bleeding, allergic reactions to the contrast agents used to visualize the coronary arteries, and myocardial infarction. With percutaneous coronary intervention (PCI), the requirement for emergency coronary artery bypass graft (CABG) surgery has decreased as better practices have been introduced. In some situations, coronary stenting is permitted in hospitals without cardiac surgery facilities, but such permission remains controversial because of the rare but unpredictable risk of coronary artery perforation. ==== Stent thrombosis risks ==== A complication of coronary stenting is stent thrombosis (blood clots). This occurs when a new clot forms within the stent and occludes blood flow, causing a heart attack. ==== In-stent restenosis risks (ISR) ==== DES were designed to specifically combat issues of restenosis that occurred with older bare-metal stents (BMS). Though less frequent with drug-eluting stents, restenosis can still occur. Since the advent of DES technology, the incidence of ISR has significantly decreased. === Usage outside the scope of typical regulatory approval === DES have been shown to be superior to BMS in reducing short-term complications of stenting in saphenous vein grafts. However, the use of DESs in bypass grafts was not their originally intended use nor within the scope of originally regulatory approval (US FDA, European Medicines Agency, etc.). The practice of using a medical device or drug in a way not specified in the original or current approved labeling is often referred to as "off-label" use. In regions were cardiac stenting has become commonplace, think tanks and advocacy groups express concern about the overzealous use of stents, because patients who received stents for unapproved reasons often have worse outcomes compared to patients who received stents for approved uses. == Clinical procedure == === DES placement === People who receive a coronary stent have different needs depending on their medical condition. Some patients are actually having a heart attack and need immediate life-saving emergency care. Other patients are at high risk of having a heart attack in the very near future. For people from each of these groups, PCI procedures may vary slightly, with particular modifications as to how they are sedated, pain management, and broader intensive care issues such as breathing support. Many people who are not in critical care situations are usually fully awake during the PCI procedure and DES placement, but they receive local anesthetic at the site of catheter entry, to ensure there is no pain. Different sedation and pain management practices are used by different medical institutions and practitioners, but patient comfort is always a primary consideration. The catheter/stent system is inserted into the body by piercing a peripheral artery (an artery in the arm or leg) and moved through the arterial system to deliver the DES into the blocked coronary artery. The stent is then expanded to widen (open) blocked or narrowed coronary arteries (narrowed by plaque buildup), caused by a condition called atherosclerosis. Peripheral arterial access is usually through the femoral (upper leg) or the radial artery (arm/wrist) and less often done through the brachial or ulnar artery (wrist/arm). In the past, controlling bleeding at the point of arterial access after the procedure was a problem. Modern arterial pressure bands and arterial closure systems now exist, which have helped control bleeding after the procedure, but it is still a concern. Modern catheter/stent systems are integrated medical devices, made of a guidewire, catheter, balloon, and stent. The stent tube mesh is initially collapsed onto the balloon of the device, and it is small enough to be passed through relatively narrow peripheral arteries. When in position, the balloon is inflated by introducing physiological saline, and this pushes the overlaying stent firmly into the diseased artery wall, inflation time and pressure are recorded during this placement procedure. After placement, the balloon is deflated, and the device is removed from the body, leaving the expanded stent in place and opening up the artery. The interventional cardiologist decides how to treat the blockage in the best way during the PCI/DES placement, based on real-time data. The cardiologist uses imaging data provided by both intravascular ultrasound (IVUS), and fluoroscopic imaging (combined with a radiopaque dye). During the procedure, the information obtained from these two sources enables the cardiologist to track the path of the catheter-DES device as it moves through the arterial blood vessels. This information also helps determine both the location and characteristics of any plaque causing narrowing in the arteries. Data from these two techniques is used to correctly position the stent and to obtain detailed information relating to the coronary arterial anatomy. Given that this anatomy varies greatly among individuals, having this information becomes a prerequisite for effective treatment. The obtained data is recorded on video and may be used in cases when further treatment is needed. === Post-stenting recovery and rehabilitation === For many people the stenting procedure does not require staying in the hospital for any extended time period, most people leave the hospital the same day. Much of the time immediately after the stenting is spent in a recovery area to make sure the access site is not bleeding and to ensure vital signs are stable. In most hospital settings, the interventional cardiologist who performed the procedure will speak directly with the patient/family and give them information about how things went, and follow-up instructions. The nursing staff will keep an eye on the person's condition and use tools like ECG to monitor their heart. To prevent a blood clot from forming in the stent, medications are given right after the procedure. One common medication is plavix, which is a potent blood thinner that comes as a pill. Other medicines that thin the blood are also used, and it's typical to combine aspirin with plavix. For people who have had a heart attack, the length of hospitalization is dependent on the degree of heart muscle damage caused by the event. A catheter with DES is a medical device, so people who receive it are given a medical device card. This card has information on the implanted DES and a medical device serial number. This information is important for future medical procedures, because it helps the doctors to know what type of device is in the person's body. Some arterial closure systems, which are devices that help to seal the access site after the procedure, are also medical devices and have their own informational cards. The access site is the place where the catheter enters the artery in the arm or leg. There is usually soreness and bruising at this site. This bruising and soreness usually get better after a week or so. People are advised to rest for a week or two and not to lift heavy things. This is mainly to make sure the access site heals well. It is normal to have follow-up appointments with a cardiologist or a primary care provider/general practitioner within a week or two of the procedure. People who get a coronary stent usually have more check-ups every three to six months for the first year, but this can vary. They usually do not need to have another coronary angiography, which is a test that uses a special dye and X-rays to see the arteries of the heart. If the doctors suspect that the heart disease is getting worse, they can prescribe a stress test, which is a test that measures how the heart works during physical activity. People who have symptoms or show signs of reduced blood flow to the heart in a stress test may need to have a diagnostic cardiac re-catheterization. After PCI-stenting procedures, physical examinations are important. People who have a high risk of complications or more complex coronary problems may need to have angiography. This may be the case even if the results of non-invasive stress tests, which are tests that measure how the heart works during physical activity, appear normal. Cardiac rehabilitation activities depend on many factors, but mainly on how much the heart muscle was damaged before the PCI/DES procedure. Many people who have this procedure have not had a heart attack, and their hearts may be fine. Others may have had a heart attack and their hearts may have trouble pumping oxygen-rich blood to the body. Rehabilitation activities are tailored to each person's needs. == Efficacy == === Benefits === DES are an improvement over older BMS devices as they reduce the chances of in-stent blockages. This reduces the incidence of serious post-stenting events such as, angina occurrence or recurrence, heart attacks, and death. They also reduce the likelihood of requiring another PCI procedure to open a blockage caused by the actual stent. The major benefit of drug-eluting stents (DES) when compared to bare-metal stents (BMS) is the prevention of in-stent restenosis (ISR). Restenosis is a gradual re-narrowing of the stented segment that occurs most commonly between 3–12 months after stent placement. High rates of restenosis associated with BMS prompted the development of DES, which resulted in a reduction of ISR incidence to around 5-10%. Continued development of newer generation DES have resulted in the near-elimination of BMS from clinical practice. === Procedure outcomes === A key benefit of DES usage compared to BMS is a lower incidence of repeat revascularization procedures (re-stenting, invasive bypass surgeries etc.). Revascularization procedures are treatments that restore blood flow to parts of the heart that are not getting enough blood, a problem called ischemia. This can happen because of plaque buildup in the arteries of the heart, which can narrow or block them. Rates of repeat revascularizations and stent thrombosis (blood clots) are significantly lower in those who received DES compared to BMS. Newer generations of DES devices have substantially improved safety outcomes, specifically regarding stent thrombosis, recurrent myocardial infarctions, and death. == Considerations for regulatory submission, assessment and approval == There are a number of very detailed medical device design considerations for DES products, these considerations are included in submissions for approval to regulatory authorities such as the US FDA: Aspects of the design that relate to a DES as structural devices that keep an artery open by purely physical means. Choice of the construction materials, with a particular focus on biocompatibility, longevity in the human body, mechanical stress resistance and the suitability of the chosen material for future patient imaging using MRI technologies, due to the high magnetic fields used in such imaging. Choice of a mechanism of the drug release: how long the drug lasts, and how to make the stent release the drug in a manner that inhibits in-stent restenosis. Choice of chemical agent the stent will deliver. Choice of the stent delivery technology as an integrated system: catheter design, placement visualization and assessment of the success of artery reperfusion (is the treated artery actually supplying cardiac muscle with sufficient oxygenated blood). Quality assurance considerations such as those defined in ISO 13485. Quality control considerations: what testing can be performed on each manufactured unit prior to release for sale to demonstrate its usage suitability. Traceability issues, can a single stent be traced from the manufacturer to the patient it was implanted in. In the case of a recall of a product it is critical to be able to trace the stent from design, manufacture, and distribution to the patient. The drug choice is a critical design element and determining its true effectiveness in inhibiting neointimal growth due to the proliferation of smooth muscle cells that would cause restenosis can be a design challenge. Much of the neointimal hyperplasia seems to be caused by inflammation. Vascular stents are classified by the US as class III medical devices, meaning that they pose the highest risk to patients and are subject to both general and premarket approval, which requires clinical trials and scientific evidence of safety and effectiveness, as well as rigorous mechanical testing. During the mechanical testing process, universal testing machines induce bending, stretching, twisting, and putting pressure on vascular stents from various angles. The specific properties of each type of stent and its intended use depend on the results of testing, and vice versa: different types of stents may need different or additional tests based on where they will be placed in the body and what they will be used for. Some of these additional tests might include checking how well the stent can withstand being crushed or bent out of shape, its resistance to getting kinks in it, whether it resists corrosion or damage over time, as well as making sure any coatings on the device remain intact. == Alternatives to stenting procedures == Pharmacological therapy for coronary artery disease may be indicated instead of or in addition to invasive treatment. For those requiring percutaneous coronary intervention or surgery, medical therapy should be viewed as complementary to revascularization procedures, rather than an opposing strategy. Coronary artery bypass graft (CABG) surgery is an alternative to percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for patients with ischemic left ventricular systolic dysfunction (LVSD). CABG is associated with lower risks of all-cause mortality, repeat revascularization, and myocardial infarction compared to PCI. == History == The first procedure to treat blocked coronary arteries was coronary artery bypass graft surgery (CABG), wherein a section of vein or artery from elsewhere in the body is used to bypass the diseased segment of the coronary artery. In 1977, Andreas Grüntzig introduced percutaneous transluminal coronary angioplasty (PTCA), also called balloon angioplasty, in which a catheter was introduced through a peripheral artery and a balloon expanded to dilate the narrowed segment of the artery. As equipment and techniques improved, the use of PTCA rapidly increased, and by the mid-1980s, PTCA and CABG were being performed at equivalent rates. Balloon angioplasty was generally effective and safe, but restenosis was frequent, occurring in about 30–40% of cases, usually within the first year after dilation. In about 3% of balloon angioplasty cases, failure of the dilation and acute or threatened closure of the coronary artery (often because of dissection) prompted emergency CABGs. Charles Theodore Dotter and Melvin Judkins had proposed using prosthetic devices inside arteries in the leg to maintain blood flow after dilation as early as 1964. In 1986, Puel and Sigwart implanted the first coronary stent in a human patient. Several trials in the 1990s showed the superiority of stent placement over balloon angioplasty. Restenosis was reduced because the stent acted as a scaffold to hold open the dilated segment of the artery. Acute closure of the coronary artery (and the requirement for emergency CABG) was reduced, because the stent repaired dissections of the arterial wall. By 1999, stents were used in 84% of percutaneous coronary interventions (i.e., those done via a catheter, and not by open-chest surgery). Early difficulties with coronary stents included a risk of early thrombosis (clotting) resulting in occlusion of the stent. Coating stainless steel stents with other substances such as platinum or gold did not eliminate this problem. High-pressure balloon expansion of the stent to ensure its full apposition to the arterial wall, combined with drug therapy using aspirin and another inhibitor of platelet aggregation (usually ticlopidine or clopidogrel) nearly eliminated this risk of early stent thrombosis. Though it occurred less frequently than with balloon angioplasty or other techniques, stents nonetheless remained vulnerable to restenosis, caused almost exclusively by neointimal tissue growth (tissue formation in the inner 'tube' structure of the artery). To address this issue, developers of drug-eluting stents used the devices themselves as a tool for delivering medication directly to the arterial wall. While initial efforts were unsuccessful, the release (elution) of drugs with certain specific physicochemical properties from the stent was shown in 2001 to achieve high concentrations of the drug locally, directly at the target lesion, with minimal systemic side effects. As currently used in clinical practice, "drug-eluting" stents refers to metal stents that elute a drug designed to limit the growth of neointimal scar tissue, thus reducing the likelihood of stent restenosis. The first type of DES to be approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) were sirolimus-eluting stents (SES), which release a natural product called sirolimus, an immunosuppressant drug. SES were shown to reduce the need for repeat procedures and improve the outcomes of patients with coronary artery disease. The sirolimus-eluting Cypher stent received CE mark approval in Europe in 2002, and then underwent a larger trial to demonstrate its safety and effectiveness for the US market. The trial, published in 2003, enrolled 1058 patients with more complex lesions and confirmed the superiority of SES over bare metal stents in terms of angiographic and clinical outcomes. Based on these results, the Cypher stent received FDA approval and was released in the US in 2003. The FDA approval process for DES involves submitting an investigational device exemption (IDE) application to conduct clinical trials under 21 CFR Part 812, and then a premarket approval (PMA) application to obtain marketing authorization under 21 CFR Part 8144. The FDA assigns the primary review responsibility to the Center for Devices and Radiological Health (CDRH), but also consults with the Center for Drug Evaluation and Research (CDER) for the drug component of the combination product. The second type of DES to be approved by the EMA and the FDA were paclitaxel-eluting stents (PES), which release another natural product called paclitaxel. PES also reduced the need for repeat procedures and improved the outcomes of patients with different types of lesions and risk factors. The paclitaxel-eluting Taxus stent received FDA approval and was launched in the US in 2004, after a series of trials that compared it with a bare metal stent in various settings. The trials showed a significant reduction in target lesion revascularization and major adverse cardiac events with the Taxus stent at 9 and 12 months. Both SES and PES use natural products as the active agents to prevent the recurrence of blockages in the arteries. These DES have changed the practice of interventional cardiology and have become the preferred treatment for many patients with coronary artery disease. The initial rapid acceptance of DES led to their peak usage in 2005, accounting for 90% of all stent implantations, but concerns about late stent thrombosis led to a decrease in DES usage in late 2006. Subsequent studies reassured the medical community about their safety, showing that while DES may have a slightly higher risk for very late stent thrombosis, they significantly reduce target vessel revascularization without increasing the incidence of death or myocardial infarction; these reassurances led to a resurgence in DES utilization, although it did not reach the peak usage rates seen in early 2006. The concept of using absorbable (also called biodegradable, bioabsorbable or bioresorbable) materials in stents was first reported in 1878 by Huse who used magnesium wires as ligatures to halt the bleeding in vessels of three patients. Despite extensive search, the full name of this pioneer in the field remains elusive. In 20th century, a resorbable stent tested in humans was developed by the Igaki Medical Planning Company in Japan and was constructed from poly-L-lactic acid (a form of polylactic acid); they published their initial results in 2000. The German company Biotronik developed a magnesium absorbable (bioresorbable) stent and published clinical results in 2007. The first company to bring a bioresorbable stent to market was Abbott Vascular which received European marketing approval in September 2012; the second was Elixir which received its CE mark in May 2013. Despite the initial promise, the first-generation bioresorbable stents, such as the Absorb bioresorbable stent by Abbott, faced significant challenges in their performance. In comparison to current-generation drug-eluting stents, numerous trials revealed that these first-generation bioresorbsble stents exhibited poor outcomes. Specifically, they showed high rates of stent thrombosis (cases where an implanted coronary stent caused a thrombotic occlusion), target-lesion myocardial infarction (heart attack occurring at the site of the treated lesion), and target vessel revascularization (the need for further procedures to restore blood flow in the treated artery). In 2017, Abbott pulled its bioabsorbable stent, Absorb, from the European market after negative press regarding the device. Boston Scientific also announced termination of its Renuvia bioresorbable coronary stent program as studies showed higher risk of serious adverse events. Currently, fully bioresorbable stents do not play a significant role in coronary interventions. While various manufacturers are proposing new stents and continuing their development, it remains uncertain whether they will have a substantial impact, unless there will be more data from their clinical trials. As of now, these stents are not widely utilized in practice. Due to challenges in developing resorbable stents, many manufacturers have focused efforts on targeting or reducing drug release through bioabsorbable-polymer coatings. Boston Scientific's Synergy bioabsorbable polymer stent has been shown potential to reduce the length of dual antiplatelet therapy post-implantation. MicroPort's Firehawk target eluting stent has been shown to be non-inferior to traditional drug-eluting stents while using one-third of the amount of equivalent drug. As for the materials used to make a DES, the first DES products available for treating patients were stainless steel alloys composed of iron, nickel, and chromium and were based on existing bare metal stents. These stents were hard to visualize with medical imaging, posed a risk of causing allergic responses, and were difficult to deliver. Subsequent new alloys were used, namely cobalt-chrome and platinum chrome, with improved performance. Bioresorbable stents have been developed in which the stent itself dissolves over time. Materials explored for use include magnesium, polylactic acid, polycarbonate polymers, and salicylic acid polymers. Resorbable stents have held the promise of providing an acute treatment that would eventually allow the vessel to function normally, without leaving a permanent device behind. For the coating of DES, one to three or more layers of polymer can be used: a base layer for adhesion, a main layer that holds and elutes (releases) the drug into the arterial wall by contact transfer, and sometimes a top coat to slow down the release of the drug and extend its effect. The first few drug-eluting stents to be licensed used durable coatings. The first generation of coatings appears to have caused immunological reactions at times, and some possibly led to thrombosis. This has driven experimentation and the development of new coating approaches. == Research directions == A research direction for a DES is to improve the material from which a device is made. The first-generation DES were made of stainless steel, while contemporary DES mainly consist of different kinds of alloys such as cobalt chromium and platinum chromium. In the current generation DES, thinner struts are employed than in the first-generation DES with preserved radial strength and radio-opacity. The lower strut thickness is believed to be associated with better stent-related outcomes including target lesion revascularization, myocardial infarction, and stent thrombosis. Another area of research for DES focuses on polymers. The current generation DES includes both durable polymer-coated stents and biodegradable polymer-coated stents. It has been reported that the presence of a durable polymer in the body over a long period can lead to chronic inflammation and neoatherosclerosis. To address this potential limitation, researchers have developed biodegradable polymer DES as an alternative solution. Scientists are also studying different drugs that could be used in DES to prevent restenosis. These drugs, which have immunosuppressive and anti-cancer properties, aim to inhibit the growth of smooth muscle cells. Additionally, there is a specific type of stent that features an extra layer of anti-CD4 antibodies on its struts. This additional layer is positioned on top of the polymer coating and aims to capture circulating endothelial progenitor cells. The goal behind this design is to promote improved healing of the blood vessel lining, known as the endothelium. A potential research focus for DES is the application of a polymer-free DES in clinical practice: moving away from polymer-based DES and instead using either a polymer-free DES or a drug-coated coronary stent. In the case of the polymer-free DES, it utilizes an abluminal coating of probucol to control the release of sirolimus. On the other hand, the drug-coated coronary stent has a micro-structured abluminal surface that allows for direct application of an anti-restenotic drug. == Society and culture == === Brand names and manufacturers === As of 2023 there are over 20 different types of drug-eluting stents available, with differences in features and characteristics. === Economics === The economic evaluation of DES has been a topic of extensive research. In 2007, the overall incremental cost-effectiveness ratio in Europe was €98,827 per quality-adjusted life-years gained. Avoiding one revascularization with DES would cost €4,794, when revascularization with BMS costs €3,2606. === Controversies === There were controversies related to the use of DES. In 2012, a meta-analysis of clinical trial data showed no benefit of the use of DES for people with stable coronary artery compared to treatment with drugs, yet, The New York Times interviewed David Brown, an author of the analysis, who said that more than half of patients with stable coronary artery disease were implanted with stents without even trying drug treatment and that he believed this happened because hospitals and doctors wanted to make more money. The interview sparked a debate among cardiologists, researchers, and patients about the appropriateness and effectiveness of DES for stable coronary artery disease: some agreed with the study's findings and questioned the overuse of stents, while others criticized the study's methods and limitations and defended the benefits of stents, arguing that the interviewee's statement was "outrageous and defamatory" and that he was "insulting the integrity of the entire profession. In 2013 the Times of India reported that DES were widely overused and that Indian distributors used profits from high markups on DES to bribe doctors to use them. In 2014 an investigation by the Maharashtra Food and Drug Administration found that high markups and bribery related to DES was still widespread. === Intellectual property disputes === There have been several patent disputes related to drug-eluting stents. In one of them, Boston Scientific Corporation (BSC) has been found guilty of infringing upon a patent awarded to the University of Texas at Arlington in 2003 and licensed to TissueGen. This patent involves technology developed by TissueGen founder Kevin Nelson, during his time as a faculty member at the university. The technology is designed to deliver drugs through an extruded fiber within an implanted vascular stent. As a result, BSC has been ordered to pay $42 million in lost royalties to both TissueGen and the university === Class action lawsuits === Drug-eluting stents have been associated with legal and ethical controversies, and there have been related class action lawsuits. In 2014, the former owners of St. Joseph Medical Center in Maryland settled a class action lawsuit for $37 million with hundreds of patients who received unnecessary DES implantation. The lawsuit alleged that Dr. Mark Midei, a cardiologist at the center, falsified the degree of coronary artery stenosis to justify the use of DES, exposing the patients to increased risks of thrombosis, bleeding, and infection. Another DES manufacturer, Cordis Corporation, a subsidiary of Johnson & Johnson, was involved in lawsuits from people who suffered adverse events from the Cypher Stent, a stainless-steel DES coated with sirolimus, an immunosuppressant drug. The Cypher Stent was approved by the FDA in 2003, but soon after, the FDA issued a Safety Warning following 290 reports of subacute thrombosis and at least 60 deaths related to the device. == See also == bioresorbable stent – medical stent that dissolves or is absorbed by the body; coronary stent – medical stent implanted into coronary arteries; drug-eluting implant – implant for delivering a drug. == References ==	Wikipedia/Drug-eluting_stent
Cardiac ventriculography is a medical imaging test used to determine a person's heart function in the right, or left ventricle. Cardiac ventriculography involves injecting contrast media into the heart's ventricle(s) to measure the volume of blood pumped. Cardiac ventriculography can be performed with a radionuclide in radionuclide ventriculography or with an iodine-based contrast in cardiac chamber catheterization. The 3 major measurements obtained by cardiac ventriculography are: Ejection Fraction Stroke Volume Cardiac Output These three measurements share a commonality of ratios between end systolic volume and end diastolic volume and all lend mathematical structure to the common medical term systole. == Radionuclide ventriculography == Radionuclide ventriculography is a form of nuclear imaging, where a gamma camera is used to create an image following injection of radioactive material, usually Technetium-99m (99mTc). == References == == Further reading == Topol, Eric J. (2000), Cleveland Clinic Heart Book, Hyperion, ISBN 0-7868-6495-8 http://healthguide.howstuffworks.com/nuclear-ventriculography-dictionary.htm	Wikipedia/Cardiac_ventriculography
Video-assisted thoracoscopic surgery (VATS) is a type of minimally invasive thoracic surgery performed using a small video camera mounted to a fiberoptic thoracoscope (either 5 mm or 10 mm caliber), with or without angulated visualization, which allows the surgeon to see inside the chest by viewing the video images relayed onto a television screen, and perform procedures using elongated surgical instruments. The camera and instruments are inserted into the patient's chest cavity through small incisions in the chest wall, usually via specially designed guiding tubes known as "ports". VATS procedures are done using either conventional surgical instruments or laparoscopic instruments. Unlike with laparoscopy, carbon dioxide insufflation is not generally required in VATS due to the inherent rigidity of the thoracic cage. However, lung deflation on the side of the operated chest is a must to be able to visualize and pass instruments into the thorax; this is usually effected with a double-lumen endotracheal tube that allows for single-lung ventilation, or a one-side bronchial occlusion delivered via a standard single-lumen tracheal tube. == History == VATS came into widespread use beginning in the early 1990s. Operations that traditionally were carried out with thoracotomy or sternotomy that today can be performed with VATS include: biopsy for diagnosis of pulmonary, pleural or mediastinal pathology; decortication for empyema; pleurodesis for recurrent pleural effusions or spontaneous pneumothorax; surgical stapler-assisted wedge resection of lung masses; resection of mediastinal or pleural masses; thoracic sympathectomy for hyperhidrosis; operations for diaphragmatic hernias or paralysis; esophageal resection or resection of esophageal masses or diverticula; and VATS lobectomy/mediastinal lymphadenectomy for lung cancer. Similarly to laparoscopy, VATS has enjoyed widespread use for technically straightforward operations such as pulmonary decortication, pleurodesis, and lung or pleural biopsies, while more technically demanding operations such as esophageal operations, mediastinal mass resections, or pulmonary lobectomy for early stage lung cancer, have been slower to catch on and have tended to remain confined to selected centers. It is expected that advanced VATS techniques will continue to grow in numbers spurred by patient demand and greater surgeon comfort and familiarity with the techniques. == Benefits == The main advantage of VATS is that the smaller postoperative wounds drastically reduce the risk for wound infection and dehiscence, which allows for a faster recovery by the patient and a greater chance for the wound to heal. Traditional thoracic surgery requires opening the chest through thoracotomy or sternotomy incisions, which are significantly traumatic to the body. Sternotomy requires the use of a sternal saw to split the sternum and a retractor to spread apart the divided sternum to allow visualization and access to the thoracic structures. Thoracotomy, as most commonly performed, requires division of one or more major muscles of the chest wall including the latissimus, pectoralis or serratus muscles, along with spreading of the ribs with a rib spreader. Because the costovertebral joints have only limited flexibility, the use of a rib spreader usually results in iatrogenic rib fractures, which can lead to complications like a flail chest or intercostal neuralgia. Because of this, thoracic surgeons generally intentionally use a bone cutter to remove section of one or more ribs in an effort to prevent jagged rib fractures. Although sternotomy and thoracotomy have been proven over decades to provide highly effective access to thoracic structures and in general are tolerated by patients, both incisions have the potential for causing significant pain that may last for extended periods and both prevent the patients from heavy lifting or strenuous activity for weeks in order to heal, and can still result in malunions and nonunions. The great advantage of VATS over sternotomy or thoracotomy is the avoidance of muscle division and bone-cutting, which allows for reduced postoperative pain, shorter duration of hospital stay and quicker return to full activity. == See also == Thoracic surgery VATS lobectomy == References == == Further reading == == External links == Media related to Video-assisted thoracoscopic surgery at Wikimedia Commons	Wikipedia/Video-assisted_thoracoscopic_surgery
The University of Texas Health Science Center at San Antonio (UTHSCSA, pronounced "U-tesk-uh"), doing business as UT Health San Antonio, is a public academic health science center in San Antonio, Texas. It is part of the University of Texas System. UT Health San Antonio is the largest health sciences university in South Texas. It is located in the South Texas Medical Center and serves San Antonio and all of the 50,000 square miles (130,000 km2) area of Central and South Texas. It extends to campuses in the Texas border communities of Laredo and the Lower Rio Grande Valley. UT Health San Antonio has produced more than 42,550 graduates; more than 4,700 students a year train in an environment that involves more than 100 affiliated hospitals, clinics and health care facilities in South Texas. The university offers more than 65 degrees, the large majority of them being graduate and professional degrees, in the biomedical and health sciences fields. UT Health San Antonio is home to the Mays Cancer Center, which is in partnership with the MD Anderson Cancer Center and is a designated a National Cancer Institute Cancer Center. The Mays Cancer Center's Institute for Drug Development (IDD) is internationally recognized for conducting one of the largest oncology Phase I clinical drug trials programs in the world. Fifteen of the cancer drugs most recently approved by the U.S. Food & Drug Administration underwent development or testing at the IDD. Other noted programs include: cellular and structural biology, urology, nephrology, transplantation biology, aging and longevity studies, cardiology and research imaging. UT Health San Antonio publishes a periodic magazine, Mission. In August 2024, the University of Texas Board of Regents announced that the University of Texas at San Antonio and UT Health Science Center at San Antonio would be amalgamated to form a "world class university in San Antonio." The integrated universities will retain the UTSA name. == History == 1959: South Texas Medical School is chartered. 1966: First class of 15 students is admitted to the Medical School; temporarily housed at Trinity University. 1969: Legislature authorizes creation of Dental School. 1970: Legislature authorizes School of Nursing. 1972: School of Allied Health Sciences and Graduate School of Biomedical Sciences created Institution is officially designated The University of Texas Health Science Center at San Antonio. Frank Harrison, M.D., Ph.D., appointed first president. 1976: Responsibility for the School of Nursing is transferred to the U. T. Health Science Center from the U. T. Nursing School at Austin. 1987: Gift of $15 million from H. Ross Perot finances creation of Institute of Biotechnology. 1992: National Institutes of Health funds HSC researchers' work on the Human Genome Project. 1998: State Legislature authorizes creation of a Regional Academic Health Center in the Lower Rio Grande Valley (RAHC), to be administered by the Health Science Center’s Medical School. 1999: Health Science Center is designated to receive a $200 million public endowment from the State of Texas to establish a Children’s Cancer Research Institute Construction begins on South Texas Centers for Biology in Medicine at the Texas Research Park. 2002: The Regional Academic Health Center in the Lower Rio Grande Valley (RAHC) opens its doors for medical students and residents. 2003: Health Science Center receives largest grant to date for a $37 million study of small subcortical strokes. Health Science Center and UT San Antonio establish the San Antonio Life Sciences Institute, a collaborative research and education partnership. A $300 million initiative announced to build a Research Tower in the South Texas Medical Center and recruit leading scientists for it. 2004: Health Science Center dedicates $50 million Children's Cancer Research Institute. 2006: The Regional Academic Health Center - Medical Research Division (E-RAHC) [1] was dedicated April 25, 2006 on the campus of UT Pan American in Edinburg. Also administered by the Health Science Center, this division provides laboratory space and equipment for research on critical health problems of the South Texas/Border Region. 2007: Health Science Center receives a $25 million donation from the Greehey Family Foundation. 2007: Valero Energy Corporation donates $5 million to the university. 2007: The Cancer Therapy & Research Center is acquired by the Health Science Center. 2007: Health Science Center receives a $25 million donation from Joe R. and Teresa Lozano Long. The central campus is renamed the Joe R. and Teresa Lozano Long Campus. 2007: The second facility was dedicated at The Regional Academic Health Center in the Lower Rio Grande Valley campus - the Academic and Clinical Research building. This facility houses the RAHC clinical research center and also the South Texas VA Health Care Center. 2008: University Hospital announces plans for a $1 billion expansion that includes a new trauma tower. 2011: The Liaison Committee on Medical Education (LCME) put the Medical School on probation. The LCME cited curricular issues as a central feature that prompted the probationary status 2013: The Liaison Committee on Medical Education (LCME) removed the Medical School from its probation list. === 2010 Failed merger with University of Texas at San Antonio === State Senator Leticia Van de Putte championed the creation of a special advisory group that would research the benefits of a possible merger between the Health Science Center and the University of Texas at San Antonio (UTSA), which is also located on the city's northwest side. In 2010, the special advisory group, headed by Peter T. Flawn, former president of both UTSA and the University of Texas at Austin, concluded that a merger would not be in the best interest of the two institutions. Among its key arguments were that both institutions had strong leadership already on a positive trajectory, the merger would be a short-term distraction for UTHSCSA, and the benefit to UTSA's national stature would be slight. The Health Science Center has a public–private partnership that is designed to promote research at the institution. The $300 million project, titled "The Campaign for the Future of Health", seeks to build new infrastructure with the South Texas Research Facility and the President's Excellence Fund. === Path to Merge with The University of Texas at San Antonio === On August 22, 2024, The University of Texas System Board of Regents Chairman Kevin P. Eltife and the board authorized Chancellor James B. Milliken and the UT System to work with UT San Antonio President Taylor Eighmy and UT Health San Antonio (UTHSA) Acting President Rob Hromas to integrate both institutions into one unified institution by 2025. [2] == Campuses == The university is one of four medical schools in the University of Texas System. UT Austin's Pharmacy School is also partially located on this campus. The school has eight campuses, spanning 250 acres (1.0 km2) in total: Joe R. and Teresa Lozano Long Campus Greehey Academic and Research Campus Center for Oral Health Care & Research (COHR) Multispecialty and Research Hospital Texas Research Park Campus Medical Arts & Research Center Cancer Therapy & Research Center at UT Health San Antonio Laredo Regional Academic Health Center (RAHC) Harlingen Regional Academic Health Center - Edinburg (ERAHC) Edinburg === Campus design === The campus has a postmodern architecture, with several notable architects contributing to the design of the campus buildings, namely: Rafael Vinoly: South Texas Research Facility HKS, Inc.: The Administration Building Overland Partners Architects: The Barshop Institute, and the downtown University Hospital expansion project. FKP Architects: Medical Arts and Research Center (MARC) Perkins + Will: The new annex of the University Hospital. Kell Muñoz Architects: Dolph Briscoe Jr. Library == Teaching hospitals and clinics == University Hospital (ranked as one of the Top 50 hospitals in the US for seven years in a row, in 2007) The Center for Oral Health Care & Research (COHR) UT Health San Antonio Multispecialty and Research Hospital Audie L. Murphy Memorial VA Hospital Christus Santa Rosa medical center San Antonio State Hospital Brooke Army Medical Center (Fort Sam Houston) Wilford Hall Medical Center (USAF) Faculty Practice Plan: UT Health Physicians == Rankings and research == === Rankings === The university was 51st in the world in the Academic Ranking of World Universities 2011 clinical medicine rankings. The University of Texas Health Science Center at San Antonio selected to Forbes Best-In-State Employers 2021 list. === Research === CTRC is one of four National Cancer Institute (NCI)-designated cancer centers in the state of Texas. The liver transplant program is ranked 9th largest and most successful in the nation. Named a National Center of Excellence in Women's Health, by the U.S. Secretary of Health & Human Services Selected as National Institute of Aging-designated Alzheimer’s Disease Research Center (ADRC). Developed the UT Diabetic Wound Classification and ranked 20th in the world for diabetic foot research. == Schools == School of Dentistry: Community Dentistry, Comprehensive Dentistry, Dental Diagnostic Science, Endodontics, General Dentistry, Oral and Maxillofacial Surgery, Orthodontics, Pediatric Dentistry, Periodontics, Prosthodontics, Restorative Dentistry. Graduate School of Biomedical Sciences: Biochemistry, Biomedical Engineering, Cellular and Structural Biology, Clinical Investigation, Clinical Lab Sciences, dental Hygiene, Dentistry, Microbiology and Immunology, Molecular Medicine, Pathology, Pharmacology, Pharmacy, Nursing, Physiology, Radiological Sciences. Medical School: Anesthesiology, Emergency Medicine, Family and Community Medicine, Medicine, Obstetrics and Gynecology, Ophthalmology, Orthopaedics, Pediatrics, Psychiatry, Radiation Oncology, Rehabilitation Medicine, Surgery, Urology. School of Health Professions: Clinical Laboratory Sciences, Dental Hygiene, Dental Laboratory Sciences, Dietetics, Emergency Health Sciences, Occupational Therapy, Physician Assistant Studies, Physical Therapy, Respiratory Care, Speech-Language Pathology. School of Nursing: Acute Nursing Care, Chronic Nursing Care, Family Nursing Care. College of Pharmacy (affiliated with University of Texas at Austin) School of Public Health == Centers and institutes == == Notable alumni == Kyle Altman (born 1986) - ex-professional soccer player, orthopedist Sharon Bannister - dentist, director of medical ops in the Office of the Surgeon General of the United States Air Force Heidi Chumley - physician, academic, dean of Ross University School of Medicine Ivan Edwards - flight surgeon, community activist, humanitarian Lawrence B. Harkless - podiatrist, academic, retired department head Mariannette Miller-Meeks (born 1955) - physician, politician Anita Thigpen Perry (born 1952) - nurse, ex-First Lady of Texas (longest serving) George M. Rapier III - physician executive, entrepreneur Susan Weintraub - scientist, academic, director of mass spectrometry == See also == University of Texas System San Antonio South Texas Medical Center == References ==	Wikipedia/University_of_Texas_Health_Science_Center_at_San_Antonio
Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the alveoli (air sacs) of the lungs. It concerns alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues. It may occur when an injury to the lungs triggers an abnormal healing response. Ordinarily, the body generates just the right amount of tissue to repair damage, but in interstitial lung disease, the repair process is disrupted, and the tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream. The disease presents itself with the following symptoms: shortness of breath, nonproductive coughing, fatigue, and weight loss, which tend to develop slowly, over several months. The average rate of survival for someone with this disease is between three and five years. The term ILD is used to distinguish these diseases from obstructive airways diseases. There are specific types in children, known as children's interstitial lung diseases. The acronym ChILD is sometimes used for this group of diseases. In children, the pathophysiology involves a genetic component, exposure-related injury, autoimmune dysregulation, or all of the components. Thirty to 40% of those with interstitial lung disease eventually develop pulmonary fibrosis which has a median survival of 2.5-3.5 years. Idiopathic pulmonary fibrosis is interstitial lung disease for which no obvious cause can be identified (idiopathic) and is associated with typical findings both radiographic (basal and pleural-based fibrosis with honeycombing) and pathologic (temporally and spatially heterogeneous fibrosis, histopathologic honeycombing, and fibroblastic foci). In 2015, interstitial lung disease, together with pulmonary sarcoidosis, affected 1.9 million people. They resulted in 122,000 deaths. == Causes == ILD may be classified as to whether its cause is not known (idiopathic) or known (secondary). === Idiopathic === Idiopathic interstitial pneumonia is the term given to ILDs with an unknown cause. They represent the majority of cases of interstitial lung diseases (up to two-thirds of cases). They were subclassified by the American Thoracic Society in 2002 into 7 subgroups: Idiopathic pulmonary fibrosis (IPF): the most common subgroup, representing more than 30% of ILD Desquamative interstitial pneumonia (DIP) Acute interstitial pneumonia (AIP): also known as Hamman-Rich syndrome Nonspecific interstitial pneumonia (NSIP) Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) Cryptogenic organizing pneumonia (COP): also known by the older name bronchiolitis obliterans organizing pneumonia (BOOP) Lymphoid interstitial pneumonia (LIP) === Secondary === Secondary ILDs are those diseases with a known etiology, including: ==== Connective tissue and autoimmune diseases ==== Connective tissue related disease represents approximately 25% of all cases of ILD. Sarcoidosis Rheumatoid arthritis Systemic lupus erythematosus Systemic sclerosis Polymyositis Dermatomyositis Antisynthetase syndrome ==== Inhaled substances (pneumoconiosis) ==== Inorganic Silicosis Asbestosis Berylliosis Industrial printing chemicals (e.g. carbon black, ink mist) Organic Hypersensitivity pneumonitis (extrinsic allergic alveolitis), representing approximately 15% of cases of ILD. ==== Drug-induced ==== Antibiotics (e.g., nitrofurantoin and sulfa drugs) Chemotherapeutic drugs Antiarrhythmic agents Cigarette smoking Smoking-related interstitial fibrosis (SRIF) is an example of a type of interstitial lung disease known to be caused by smoking. ==== Infection ==== Coronavirus disease 2019 (COVID-19) Atypical pneumonia Pneumocystis pneumonia (PCP) Tuberculosis Chlamydia trachomatis Respiratory syncytial virus ==== Malignancy ==== Lymphangitic carcinomatosis ==== Childhood interstitial lung disease and ILD predominately in children ==== Diffuse developmental disorders Growth abnormalities and deficient alveolarisation Infant conditions of undefined cause ILD related to alveolar surfactant region == Diagnosis == Diagnosis of ILD involves assessing the signs and symptoms as well as a detailed history investigating occupational exposures. ILD usually presents with dyspnea, worsening exercise intolerance and 30-50% of those with ILD have a chronic cough. On examination, velcro crackles, in which the crackles compare to the sound of velcro being unfastened, are common in ILD. Pulmonary function tests usually show a restrictive defect with decreased diffusion capacity of carbon monoxide (DLCO) indicating reduced alveolar to blood capillary transport. Pulmonary function testing is indicated for all people with ILD and the FVC loss and DLCO is prognostic, with an FVC loss of greater than 5% per year associated with a poor prognosis in fibrosis subtypes of ILD. A chest x-ray is 63% sensitive and 93% specific for ILD. With advances in computed tomography, CT scans of the chest have supplanted lung biopsy as the preferred diagnostic test for ILD. A thoracic CT scan is 91% sensitive and 71% specific for ILD. In higher income countries, less than 10% of people with ILD undergo a lung biopsy as part of the diagnostic evaluation. A lung biopsy may be required if the clinical history and imaging are not clearly suggestive of a specific diagnosis or malignancy cannot otherwise be ruled out. Surgical lung biopsy or via a video-assisted thoracoscopic surgery (VATS) biopsy is associated with a mortality rate up to 1-2%. A bronchoscopic transbronchial cryobiopsy, in which a camera is introduced into the airways followed by rapid freezing of an area of lung tissue prior to biopsy is associated a lower complication rate and a much lower mortality rate compared to VATS or surgical biopsy with near comparable diagnostic accuracy. There are four types of histopathologic patterns seen in ILD: usual interstitial pneumonia, non-specific interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage. There is significant overlap of the histopathological and radiologic features of each ILD type making diagnosis challenging; even with lung biopsy, 15% of cases of ILD cannot be classified. === Pulmonary function testing === Most patients with suspected ILD are likely to undergo complete pulmonary function testing. These tests are useful in diagnosis and determining severity of the disease. Although there is large diversity in interstitial lung disease, most follow a restrictive pattern. Restrictive defects are defined by decreased TLC (total lung capacity), RV (residual volume), FVC (forced vital capacity) and FEV1 (forced expiratory volume in one second). As both FVC and FEV1 are reduced, the FVC to FEV1 ratio remains normal or is increased. As disease progression increases and the lungs become stiffer lung volumes will continue to decrease; lower TLC, RV, FVC and FEV1 scores are associated with a more severe disease progression and poorer prognosis. === X-ray and CT (computed tomography) === Chest radiography is usually the first test to detect interstitial lung diseases, but the chest radiograph can be normal in up to 10% of patients, especially early in the disease process. High-resolution CT of the chest is the preferred modality and differs from routine CT of the chest. Conventional (regular) CT chest examines 7–10 mm slices obtained at 10 mm intervals; high resolution CT examines 1–1.5 mm slices at 10 mm intervals using a high-spatial-frequency reconstruction algorithm. The HRCT therefore provides approximately 10 times more resolution than the conventional CT chest, allowing the HRCT to elicit details that cannot otherwise be visualized. Radiologic appearance alone, however, is not adequate and should be interpreted in the clinical context, keeping in mind the temporal profile of the disease process. Interstitial lung diseases can be classified according to radiologic patterns. ==== Pattern of opacities ==== Consolidation Acute: Alveolar hemorrhage syndromes Acute eosinophilic pneumonia Acute interstitial pneumonia Cryptogenic organizing pneumonia Chronic: Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia Lymphoproliferative disorders Pulmonary alveolar proteinosis Sarcoidosis Linear or reticular opacities Acute: Pulmonary edema Chronic: Idiopathic pulmonary fibrosis Connective tissue-associated interstitial lung diseases Asbestosis Sarcoidosis Hypersensitivity pneumonitis Drug-induced lung disease Small nodules Acute: Hypersensitivity pneumonitis Chronic: Hypersensitivity pneumonitis Sarcoidosis Silicosis Coal workers pneumoconiosis Respiratory bronchiolitis Alveolar microlithiasis Cystic airspaces Chronic: Pulmonary Langerhans cell histiocytosis Pulmonary lymphangioleiomyomatosis Honeycomb lung caused by idiopathic pulmonary fibrosis (IPF) or other diseases Ground glass opacities Acute: Alveolar hemorrhage syndromes Pulmonary edema Hypersensitivity pneumonitis Acute inhalational exposures Drug-induced lung diseases Acute interstitial pneumonia Chronic: Nonspecific interstitial pneumonia Respiratory bronchiolitis-associated interstitial lung disease Desquamative interstitial pneumonia Drug-induced lung diseases Pulmonary alveolar proteinosis Thickened alveolar septa Acute: Pulmonary edema Chronic: Lymphangitic carcinomatosis Pulmonary alveolar proteinosis Sarcoidosis Pulmonary veno-occlusive disease ==== Distribution ==== Upper lung predominance Pulmonary Langerhans cell histiocytosis Silicosis Coal workers pneumoconiosis Carmustine-related pulmonary fibrosis Respiratory broncholitis associated with interstitial lung disease Lower lung predominance Idiopathic pulmonary fibrosis Pulmonary fibrosis associated with connective tissue diseases (ILD-CTD) Asbestosis Chronic aspiration Central predominance (perihilar) Sarcoidosis Berylliosis Peripheral predominance Idiopathic pulmonary fibrosis Chronic eosinophilic pneumonia Cryptogenic organizing pneumonia ==== Associated findings ==== Pleural effusion or thickening Pulmonary edema Connective tissue diseases Asbestosis Lymphangitic carcinomatosis Lymphoma Lymphangioleiomyomatosis Drug-induced lung diseases Lymphadenopathy Sarcoidosis Silicosis Berylliosis Lymphangitic carcinomatosis Lymphoma Lymphocytic interstitial pneumonia === Genetic testing === For some types of paediatric ILDs and few forms adult ILDs, genetic causes have been identified. These may be identified by blood tests. For a limited number of cases, this is a definite advantage, as a precise molecular diagnosis can be done; frequently then there is no need for a lung biopsy. Testing is available for ==== ILDs related to alveolar surfactant region ==== Surfactant protein B deficiency (mutations in SFTPB) Surfactant protein C deficiency (mutations in SFTPC) ABCA3 deficiency (mutations in ABCA3) Brain–lung–thyroid syndrome (Mutations in TTF1) Congenital pulmonary alveolar proteinosis (mutations in CSFR2A and/or CSFR2B) ==== Diffuse developmental disorder ==== Alveolar capillary dysplasia (mutations in FoxF1) ==== Idiopathic pulmonary fibrosis ==== Mutations in telomerase reverse transcriptase (TERT) Mutations in telomerase RNA component (TERC) Mutations in the regulator of telomere elongation helicase 1 (RTEL1) Mutations in poly(A)-specific ribonuclease (PARN) == Treatment == ILD is not a single disease but encompasses many different pathological processes, hence treatment is different for each disease. If a specific occupational exposure cause is found, the person should avoid that environment. If a drug cause is suspected, that drug should be discontinued. === Oxygen therapy === Oxygen therapy at home is recommended in those with significantly low oxygen levels. Oxygen therapy in ILD is associated with improvements in quality of life but reductions in mortality are uncertain. Long-term oxygen therapy can be beneficial to people with ILD and hypoxemia to enhance gas exchange, lessen dyspnea, and increase physical activity. === Pulmonary rehabilitation === Pulmonary rehabilitation appears to be useful with the benefits being sustainable longer term with improvements in exercise capacity (as measured by a six minute walking test), dyspnea, and quality of life. === Lung transplantation === Lung transplantation is an option if the ILD progresses despite therapy in appropriately selected patients with no other contraindications. Life expectancy after lung transplant is 5.2 years in those with idiopathic interstitial pneumonias (including idiopathic pulmonary fibrosis) and 6.7 years in those with other types of ILD. === Medications === The antifibrotics pirfenidone and nintedanib have been shown to slow the decline in lung function (as measured by forced vital capacity [FVC]) in those with ILD compared to placebo. Pirfenidone was associated with a 45% less decline in FVC at 52 weeks compared to placebo in a trial involving people with idiopathic pulmonary fibrosis, and was associated with a slower FVC decline in those with progressive pulmonary fibrosis. Nintedanib was also associated with a slower FVC decline and increased mean survival in people with ILD. The immunomodulator tocilizumab has a benefit in scleroderma associated ILD by helping to preserve lung function (as measured by FVC) at 48 weeks. The immunomodulators cyclophosphamide, mycophenolate mofetil and rituximab all showed improved lung function (as measured by % predicted FVC) compared to placebo in systemic sclerosis or scleroderma associated ILD. The inhaled vasodilator treprostinil (a synthetic prostacyclin which acts as a prostaglandin I2 analogue) is indicated in the treatment of pulmonary hypertension secondary to interstitial lung disease and is associated with improved exercise capacity as measured by a 6-minute walk test. === Supportive care === Those with ILD should stop smoking cigarettes if they smoke. Vaccinations against pneumococcus, Covid-19, RSV and influenza are indicated in all those with ILD. Short acting opiates are known to improve breathlessness symptoms in those with end stage lung disease. The opiate agonist-antagonist nalbuphine and morphine are also known to improve coughing in those with ILD and other end stage lung diseases. == Prognosis == The median survival in idiopathic pulmonary fibrosis is 3-3.5 years. In those who receive a lung transplant, the medial survival in idiopathic pulmonary fibrosis is 5.2 years, as compared to 6.7 years in those with other types of ILD. ILD is associated with a 3-fold increased risk of lung cancer. == References == == External links == 00736 at CHORUS	Wikipedia/Diffuse_parenchymal_lung_disease
Robot-assisted surgery or robotic surgery are any types of surgical procedures that are performed using robotic systems. Robotically assisted surgery was developed to try to overcome the limitations of pre-existing minimally-invasive surgical procedures and to enhance the capabilities of surgeons performing open surgery. In the case of robotically assisted minimally-invasive surgery, instead of the surgeon directly moving the instruments, the surgeon uses one of two methods to perform dissection, hemostasis and resection, using a direct telemanipulator, or through computer control. A telemanipulator (e.g. the da Vinci Surgical System) is a system of remotely controlled manipulators that allows the surgeon to operate real-time under stereoscopic vision from a control console separate from the operating table. The robot is docked next to the patient, and robotic arms carry out endoscopy-like maneuvers via end-effectors inserted through specially designed trocars. A surgical assistant and a scrub nurse are often still needed scrubbed at the tableside to help switch effector instruments or provide additional suction or temporary tissue retraction using endoscopic grasping instruments. In computer-controlled systems, the surgeon uses a computer system to relay control data and direct the robotic arms and its end-effectors, though these systems can also still use telemanipulators for their input. One advantage of using the computerized method is that the surgeon does not have to be present on campus to perform the procedure, leading to the possibility for remote surgery and even AI-assisted or automated procedures. Robotic surgery has been criticized for its expense, with the average costs in 2007 ranging from $5,607 to $45,914 per patient. This technique has not been approved for cancer surgery as of 2019 as the safety and usefulness is unclear. == History == The concept of using standard hand grips to control manipulators and cameras of various sizes down to sub-miniature was described in the Robert Heinlein story 'Waldo' in August 1942, which also mentioned brain surgery. The first robot to assist in surgery was the Arthrobot, which was developed and used for the first time in Vancouver in 1983. This robot assisted in being able to manipulate and position the patient's leg on voice command. Intimately involved were biomedical engineer James McEwen, Geof Auchinleck, a UBC engineering physics grad, and Dr. Brian Day as well as a team of engineering students. The robot was used in an orthopaedic surgical procedure on 12 March 1983, at the UBC Hospital in Vancouver. The next great step was in 1985. in brain biopsy under CT guidance with the assistance of a robotic arm—PUMA560. Over 60 arthroscopic surgical procedures were performed in the first 12 months, and a 1985. National Geographic video on industrial robots, The Robotics Revolution, featured the device. Other related robotic devices developed at the same time included a surgical scrub nurse robot, which handed operative instruments on voice command, and a medical laboratory robotic arm. A YouTube video entitled Arthrobot – the world's first surgical robot illustrates some of these in operation. In 1985 a robot, the Unimation Puma 200, was used to orient a needle for a brain biopsy while under CT guidance during a neurological procedure. In the late 1980s, Imperial College in London developed PROBOT, which was then used to perform prostatic surgery. The advantages to this robot was its small size, accuracy and lack of fatigue for the surgeon. In the 1990s, computer-controlled surgical devices began to emerge, enabling greater precision and control in surgical procedures. One of the most significant advancements in this period was the da Vinci Surgical System, which was approved by the FDA for use in surgical procedures in 2000 (Intuitive Surgical, 2021). The da Vinci system uses robotic arms to manipulate surgical instruments, allowing surgeons to perform complex procedures with greater accuracy and control. In 1992, the ROBODOC was introduced and revolutionized orthopedic surgery by being able to assist with hip replacement surgeries. The latter was the first surgical robot that was approved by the FDA in 2008. The ROBODOC from Integrated Surgical Systems (working closely with IBM) could mill out precise fittings in the femur for hip replacement. The purpose of the ROBODOC was to replace the previous method of carving out a femur for an implant, the use of a mallet and broach/rasp. Further development of robotic systems was carried out by SRI International and Intuitive Surgical with the introduction of the da Vinci Surgical System and Computer Motion with the AESOP and the ZEUS robotic surgical system. The first robotic surgery took place at The Ohio State University Medical Center in Columbus, Ohio under the direction of Robert E. Michler. AESOP was a breakthrough in robotic surgery when introduced in 1994, as it was the first laparoscopic camera holder to be approved by the FDA. NASA initially funded the company that produces AESOP, Computer Motion, due to its goal to create a robotic arm that can be used in space, but this project ended up becoming a camera used in laparoscopic procedures. Voice control was then added in 1996 with the AESOP 2000 and seven degrees of freedom to mimic a human hand was added in 1998 with the AESOP 3000. ZEUS was introduced commercially in 1998, and started the idea of telerobotics or telepresence surgery where the surgeon is at a distance from the robot on a console and operates on the patient. ZEUS was first used during a gynecological surgery in 1997 to reconnect Fallopian tubes in Cleveland Ohio, a beating heart coronary artery bypass graft in October 1999, and the Lindbergh Operation, which was a cholecystectomy performed remotely in September 2001. In 2003, ZEUS made its most prominent mark in cardiac surgery after successfully harvesting the left internal mammary arteries in 19 patients, all of which had very successful clinical outcomes. The original telesurgery robotic system that the da Vinci was based on was developed at Stanford Research Institute International in Menlo Park with grant support from DARPA and NASA. A demonstration of an open bowel anastomosis was given to the Association of Military Surgeons of the US. Although the telesurgical robot was originally intended to facilitate remotely performed surgery in the battlefield to reduce casualties and to be used in other remote environments, it turned out to be more useful for minimally invasive on-site surgery. The patents for the early prototype were sold to Intuitive Surgical in Mountain View, California. The da Vinci senses the surgeon's hand movements and translates them electronically into scaled-down micro-movements to manipulate the tiny proprietary instruments. It also detects and filters out any tremors in the surgeon's hand movements, so that they are not duplicated robotically. The camera used in the system provides a true stereoscopic picture transmitted to a surgeon's console. Compared to the ZEUS, the da Vinci robot is attached to trocars to the surgical table, and can imitate the human wrist. In 2000, the da Vinci obtained FDA approval for general laparoscopic procedures and became the first operative surgical robot in the US. Examples of using the da Vinci system include the first robotically assisted heart bypass (performed in Germany) in May 1998, and the first performed in the United States in September 1999; and the first all-robotic-assisted kidney transplant, performed in January 2009. The da Vinci Si was released in April 2009 and initially sold for $1.75 million. In 2005, a surgical technique was documented in canine and cadaveric models called the transoral robotic surgery (TORS) for the da Vinci robot surgical system as it was the only FDA-approved robot to perform head and neck surgery. In 2006, three patients underwent resection of the tongue using this technique. The results were more clear visualization of the cranial nerves, lingual nerves, and lingual artery, and the patients had a faster recovery to normally swallowing. In May 2006 the first artificial intelligence doctor-conducted unassisted robotic surgery was on a 34-year-old male to correct heart arrhythmia. The results were rated as better than an above-average human surgeon. The machine had a database of 10,000 similar operations, and so, in the words of its designers, was "more than qualified to operate on any patient". In August 2007, Dr. Sijo Parekattil of the Robotics Institute and Center for Urology (Winter Haven Hospital and University of Florida) performed the first robotic-assisted microsurgery procedure denervation of the spermatic cord for chronic testicular pain. In February 2008, Dr. Mohan S. Gundeti of the University of Chicago Comer Children's Hospital performed the first robotic pediatric neurogenic bladder reconstruction. On 12 May 2008, the first image-guided MR-compatible robotic neurosurgical procedure was performed at University of Calgary by Dr. Garnette Sutherland using the NeuroArm. In June 2008, the German Aerospace Centre (DLR) presented a robotic system for minimally invasive surgery, the MiroSurge. In September 2010, the Eindhoven University of Technology announced the development of the Sofie surgical system, the first surgical robot to employ force feedback. In September 2010, the first robotic operation at the femoral vasculature was performed at the University Medical Centre Ljubljana by a team led by Borut Geršak. In 2019 the Versius Surgical Robotic System was launched and is a rival of the Da Vinci surgical system and claims to be more flexible and versatile, having independent modular arms which are "quick and easy to set up". The small-scale design means that it is suitable for virtually any operating room and can be operated at either a standing or a sitting position. == Uses == === Ophthalmology === Ophthalmology is still part of the frontier for robotic-assisted surgeries. However, there are a couple of robotic systems that are capable of successfully performing surgeries. PRECEYES Surgical System is being used for vitreoretinal surgeries. This is a single arm robot, that is tele manipulated by a surgeon. This system attaches to the head of the operating room table and provides surgeons with increased precision with the help of the intuitive motion controller. Preceyes is the only robotic instrument to be CE certified. Some other companies like Forsight Robotics, Acusurgical that raised 5.75 M€ (France), and Horizon (US) are working in this field. The da Vinci Surgical System, though not specifically designed for ophthalmic procedures, uses telemanipulation to perform pterygium repairs and ex-vivo corneal surgeries. === Heart === Some examples of heart surgery being assisted by robotic surgery systems include: Atrial septal defect repair – the repair of a hole between the two upper chambers of the heart, Mitral valve repair – the repair of the valve that prevents blood from regurgitating back into the upper heart chambers during contractions of the heart, Coronary artery bypass – rerouting of blood supply by bypassing blocked arteries that provide blood to the heart. === Thoracic === Robotic surgery has become more widespread in thoracic surgery for mediastinal pathologies, pulmonary pathologies and more recently complex esophageal surgery. The da Vinci Xi system is used for lung and mediastinal mass resection. This minimally invasive approach as a comparable alternative to video-assisted thoracoscopic surgery (VATS) and the standard open thoracic surgery. Although VATS is the less expensive option, the robotic-assisted approach offers benefits such as 3D visualizations with seven degrees of freedom and improved dexterity while having equivalent perioperative outcomes. === ENT === The first successful robot-assisted cochlear implantation in a person took place in Bern, Switzerland in 2017. Surgical robots have been developed for use at various stages of cochlear implantation, including drilling through the mastoid bone, accessing the inner ear and inserting the electrode into the cochlea. Advantages of robot-assisted cochlear implantation include improved accuracy, resulting in fewer mistakes during electrode insertion and better hearing outcomes for patients. The surgeon uses image-guided surgical planning to program the robot based on the patient's individual anatomy. This helps the implant team to predict where the contacts of the electrode array will be located within the cochlea, which can assist with audio processor fitting post-surgery. The surgical robots also allow surgeons to reach the inner ear in a minimally invasive way. Challenges that still need to be addressed include safety, time, efficiency and cost. Surgical robots have also been shown to be useful for electrode insertion with pediatric patients. === Gastrointestinal === Multiple types of procedures have been performed with either the 'Zeus' or da Vinci robot systems, including bariatric surgery and gastrectomy for cancer. Surgeons at various universities initially published case series demonstrating different techniques and the feasibility of GI surgery using the robotic devices. Specific procedures have been more fully evaluated, specifically esophageal fundoplication for the treatment of gastroesophageal reflux and Heller myotomy for the treatment of achalasia. Robot-assisted pancreatectomies have been found to be associated with "longer operating time, lower estimated blood loss, a higher spleen-preservation rate, and shorter hospital stay[s]" than laparoscopic pancreatectomies; there was "no significant difference in transfusion, conversion to open surgery, overall complications, severe complications, pancreatic fistula, severe pancreatic fistula, ICU stay, total cost, and 30-day mortality between the two groups." === Gynecology === The first report of robotic surgery in gynecology was published in 1999 from the Cleveland Clinic. The adoption of robotic surgery has contributed to the increase in minimally invasive surgery for gynecologic disease. Gynecologic procedures may take longer with robot-assisted surgery and the rate of complications may be higher, but there are not enough high-quality studies to know at the present time. In the United States, robotic-assisted hysterectomy for benign conditions was shown to be more expensive than conventional laparoscopic hysterectomy in 2015, with no difference in overall rates of complications. This includes the use of the da Vinci surgical system in benign gynecology and gynecologic oncology. Robotic surgery can be used to treat fibroids, abnormal periods, endometriosis, ovarian tumors, uterine prolapse, and female cancers. Using the robotic system, gynecologists can perform hysterectomies, myomectomies, and lymph node biopsies. The Hominis robotic system developed by Momentis Surgical™ is aimed to provide a robotic platform for natural orifice transluminal endoscopic surgery (NOTES) for myomectomy through the vagina. A 2017 review of surgical removal of the uterus and cervix for early cervical cancer robotic and laparoscopic surgery resulted in similar outcomes with respect to the cancer. === Bone === Robots are used in orthopedic surgery. ROBODOC is the first active robotic system that performs some of the surgical actions in a total hip arthroplasty (THA). It is programmed preoperatively using data from computer tomography (CT) scans. This allows for the surgeon to choose the optimal size and design for the replacement hip. Acrobot and Rio are semi-active robotic systems that are used in THA. It consists of a drill bit that is controlled by the surgeon however the robotic system does not allow any movement outside the predetermined boundaries. Mazor X is used in spinal surgeries to assist surgeons with placing pedicle screw instrumentation. Inaccuracy when placing a pedicle screw can result in neurovascular injury or construct failure. Mazor X functions by using templating imaging to locate itself to the target location of where the pedicle screw is needed. === Spine === Robotic devices started to be used in minimally invasive spine surgery starting in the mid-2000s. As of 2014, there were too few randomized clinical trials to judge whether robotic spine surgery is more or less safe than other approaches. As of 2019, the application of robotics in spine surgery has mainly been limited to pedicle screw insertion for spinal fixation. In addition, the majority of studies on robot-assisted spine surgery have investigated lumbar or lumbosacral vertebrae only. Studies on use of robotics for placing screws in the cervical and thoracic vertebrae are limited. === Transplant surgery === The first fully robotic kidney transplantations were performed in the late 2000s. It may allow kidney transplantations in people who are obese who could not otherwise have the procedure. Weight loss however is the preferred initial effort. In 2021, the team at Cedars-Sinai in Los Angeles, California completed the world's first robotic lung transplant, allowing a minimally invasive approach to the procedure. === General surgery === With regards to robotic surgery, this type of procedure is currently best suited for single-quadrant procedures, in which the operations can be performed on any one of the four quadrants of the abdomen. Cost disadvantages are applied with procedures such as a cholecystectomy and fundoplication, but are suitable opportunities for surgeons to advance their robotic surgery skills. === Hernia and abdominal wall surgery === Over the past several decades, there have been great advances in the field of abdominal wall and hernia surgery especially when it comes to robotic-assisted surgery. Unlike laparoscopic surgery, the robotic platform allows for the correction of large hernia defects with specialized techniques that would traditionally only be performed via an open approach. Compared to open surgery, robotic surgery for hernia repair can reduce pain, length of hospital stay, and improve outcomes. As the robotic instruments have 6 degrees of articulation, freedom of movement and ergonomics are greatly improved compared to laparoscopy. The first robotic inguinal hernia repairs were done in conjunction with prostatectomies in 2007. The first ventral hernia repairs were performed robotically in 2009. Since then the field has rapidly expanded to include most types of reconstruction including anterior as well as posterior component separation. With newer techniques such as direct access into the abdominal wall, major reconstruction of large hernias can be done without even entering the abdominal cavity. Due to its complexity, however, major reconstruction done robotically should be undertaken at advanced hernia centers such as the Columbia Hernia Center in New York City, NY, USA. The American Hernia Society and the European Hernia Society are moving towards specialty designation for hernia centers who are credentialed for complex hernia surgery, including robotic surgery. === Urology === Robotic surgery in the field of urology has become common, especially in the United States. There is inconsistent evidence of benefits compared to standard surgery to justify the increased costs. Some have found tentative evidence of more complete removal of cancer and fewer side effects from surgery for prostatectomy. In 2000, the first robot-assisted laparoscopic radical prostatectomy was performed. Robotic surgery has also been utilized in radical cystectomies. A 2013 review found less complications and better short term outcomes when compared to open technique. === Pediatrics === Pediatric procedures are also benefiting from robotic surgical systems. The smaller abdominal size in pediatric patients limits the viewing field in most urology procedures. The robotic surgical systems help surgeons overcome these limitations. Robotic technology provides assistance in performing Pyeloplasty - alternative to the conventional open dismembered pyeloplasty (Anderson-Hynes). Pyeloplasty is the most common robotic-assisted procedures in children. Ureteral reimplantation - alternative to the open intravesical or extravesical surgery. Ureteroureterostomy - alternative to the transperitoneal approach. Nephrectomy and heminephrectomy - Traditionally done with laparoscopy, it is not likely that a robotic procedure offers significant advantage due to its high cost. == Comparison to traditional methods == Major advances aided by surgical robots have been remote surgery, minimally invasive surgery and unmanned surgery. Due to robotic use, the surgery is done with precision, miniaturization, smaller incisions; decreased blood loss, less pain, and quicker healing time. Articulation beyond normal manipulation and three-dimensional magnification help to result in improved ergonomics. Due to these techniques, there is a reduced duration of hospital stays, blood loss, transfusions, and use of pain medication. The existing open surgery technique has many flaws such as limited access to the surgical area, long recovery time, long hours of operation, blood loss, surgical scars, and marks. The robot's costs range from $1 million to $2.5 million for each unit, and while its disposable supply cost is normally $1,500 per procedure, the cost of the procedure is higher. Additional surgical training is needed to operate the system. Numerous feasibility studies have been done to determine whether the purchase of such systems are worthwhile. As it stands, opinions differ dramatically. Surgeons report that, although the manufacturers of such systems provide training on this new technology, the learning phase is intensive and surgeons must perform 150 to 250 procedures to become adept in their use. During the training phase, minimally invasive operations can take up to twice as long as traditional surgery, leading to operating room tie-ups and surgical staffs keeping patients under anesthesia for longer periods. Patient surveys indicate they chose the procedure based on expectations of decreased morbidity, improved outcomes, reduced blood loss and less pain. Higher expectations may explain higher rates of dissatisfaction and regret. Compared with other minimally invasive surgery approaches, robot-assisted surgery gives the surgeon better control over the surgical instruments and a better view of the surgical site. In addition, surgeons no longer have to stand throughout the surgery and do not get tired as quickly. Naturally occurring hand tremors are filtered out by the robot's computer software. Finally, the surgical robot can continuously be used by rotating surgery teams. Laparoscopic camera positioning is also significantly steadier with less inadvertent movements under robotic controls than compared to human assistance. The use of mixed reality to support robot-assisted surgery was developed at the Air Force Research Laboratory in 1992 through the creation of "virtual fixtures" that overlay virtual boundaries or guides that assist the human operator and has become a common method for increasing safety and precision. There are some issues in regards to current robotic surgery usage in clinical applications. There is a lack of haptics in some robotic systems currently in clinical use, which means there is no force feedback, or touch feedback. No interaction between the instrument and the patient is felt. However, recently the Senhance robotic system by Asensus Surgical was developed with haptic feedback in order to improve the interaction between the surgeon and the tissue. The robots can also be very large, have instrumentation limitations, and there may be issues with multi-quadrant surgery as current devices are solely used for single-quadrant application. Critics of the system, including the American Congress of Obstetricians and Gynecologists, say there is a steep learning curve for surgeons who adopt the use of the system and that there's a lack of studies that indicate long-term results are superior to results following traditional laparoscopic surgery. Articles in the newly created Journal of Robotic Surgery tend to report on one surgeon's experience. Complications related to robotic surgeries range from converting the surgery to open, re-operation, permanent injury, damage to viscera and nerve damage. From 2000 to 2011, out of 75 hysterectomies done with robotic surgery, 34 had permanent injury, and 49 had damage to the viscera. Prostatectomies were more prone to permanent injury, nerve damage and visceral damage as well. Very minimal surgeries in a variety of specialties had to actually be converted to open or be re-operated on, but most did sustain some kind of damage or injury. For example, out of seven coronary artery bypass grafting, one patient had to go under re-operation. It is important that complications are captured, reported and evaluated to ensure the medical community is better educated on the safety of this new technology. If something was to go wrong in a robot-assisted surgery, it is difficult to identify culpability, and the safety of the practice will influence how quickly and widespread these practices are used. One drawback of the use of robotic surgery is the risk of mechanical failure of the system and instruments. A study from July 2005 to December 2008 was conducted to analyze the mechanical failures of the da Vinci Surgical System at a single institute. During this period, a total of 1797 robotic surgeries were performed used 4 da Vinci surgical systems. There were 43 cases (2.4%) of mechanical failure, including 24 (1.3%) cases of mechanical failure or malfunction and 19 (1.1%) cases of instrument malfunction. Additionally, one open and two laparoscopic conversions (0.17%) were performed. Therefore, the chance of mechanical failure or malfunction was found to be rare, with the rate of converting to an open or laparoscopic procedure very low. There are also current methods of robotic surgery being marketed and advertised online. Removal of a cancerous prostate has been a popular treatment through internet marketing. Internet marketing of medical devices are more loosely regulated than pharmaceutical promotions. Many sites that claim the benefits of this type of procedure had failed to mention risks and also provided unsupported evidence. There is an issue with government and medical societies promotion a production of balanced educational material. In the US alone, many websites promotion robotic surgery fail to mention any risks associated with these types of procedures, and hospitals providing materials largely ignore risks, overestimate benefits and are strongly influenced by the manufacturer. == Use in popular media == Since April 2018, medical insurance coverage was expanding in Japan, so doctors were considering promoting the procedure for cardiac surgery, as it has the advantage of reducing the burden on the patient. Japanese drama Black Pean takes on this challenge, showing both sides' point of view. Two University Hospitals are competing to be the best in the Cardiac Surgery Department. One, Tojo, has the best traditional surgeons, while the other, Teika, is all about researching and implementing the most recent technology. With this, Teika sends its technical specialist to Tojo to try to convince them to update their techniques, including the use of the Da Vinci robot (named in the drama as Darwin). Newhart Watanabe International Hospital, a pioneer in da Vinci surgery for the heart in Japan, was used as background for the drama, with Dr. Gou Watanabe providing technical support. == See also == == References == == External links ==	Wikipedia/Robot-assisted_heart_surgery
The ballistocardiograph (BCG) is a measure of ballistic forces generated by the heart. The downward movement of blood through the descending aorta produces an upward recoil, moving the body upward with each heartbeat. As different parts of the aorta expand and contract, the body continues to move downward and upward in a repeating pattern. Ballistocardiography is a technique for producing a graphical representation of repetitive motions of the human body arising from the sudden ejection of blood into the great vessels with each heart beat. It is a vital sign in the 1–20 Hz frequency range which is caused by the mechanical movement of the heart and can be recorded by noninvasive methods from the surface of the body. It was shown for the first time, after extensive research work by Isaac Starr, that the effect of main heart malfunctions can be identified by observing and analyzing the BCG signal. Recent work also validates BCG could be monitored using camera in a non-contact manner. One example of the use of a BCG is a ballistocardiographic scale, which measures the recoil of the persons body who is on the scale. A BCG scale is able to show a person's heart rate as well as their weight. The term ballistocardiograph originated from the Roman ballista, which is derived from the Greek word ballein (to throw), a machine for launching missiles, plus the Greek words for heart and writing. == See also == Advanced cardiac life support (ACLS) Cardiac arrest Cardiac cycle EKG tech Cardiac monitoring Heart rate monitor Holter monitor SCP-ECG == References == Half a century of contributing to medical care and society James S. Walker, 2002, Physics, Prentice Hall, p. 243–244 Measuring the Heart's Kick Simultaneous Monitoring of Ballistocardiogram and Photoplethysmogram Using a Camera Dangdang Shao, "IEEE Transactions on Biomedical Engineering", Volume: 64, Issue: 5, May 2017, p. 1003–1010 == Further reading == David M. Harrison (July 2003). "The Ballistocardiogram". Archived from the original on 8 February 2007. Retrieved 2007-03-22. Eblen-Zajjur, Antonio (2003). "A Simple Ballistocardiographic System For A Medical Cardiovascular Physiology Course". Advances in Physiology Education. 27 (4): 224–229. doi:10.1152/advan.00025.2002. PMID 14627620. S2CID 6895831.	Wikipedia/Ballistocardiography
The Model for End-Stage Liver Disease, or MELD, is a scoring system for assessing the severity of chronic liver disease. It was initially developed to predict mortality within three months of surgery in patients who had undergone a transjugular intrahepatic portosystemic shunt (TIPS) procedure, and was subsequently found to be useful in determining prognosis and prioritizing for receipt of a liver transplant. This score is now used by the United Network for Organ Sharing (UNOS) and Eurotransplant for prioritizing allocation of liver transplants instead of the older Child-Pugh score. == Determination == MELD uses the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival. It is calculated according to the following formula: M E L D = d e f 3.78 × ln ⁡ ( serum bilirubin (mg/dL) ) + 11.2 × ln ⁡ ( INR ) + 9.57 × ln ⁡ ( serum creatinine (mg/dL) ) + 6.43 {\displaystyle \mathrm {MELD} {\overset {\mathrm {def} }{=}}3.78\times \ln \left({\text{serum bilirubin (mg/dL)}}\right)+11.2\times \ln({\text{INR}})+9.57\times \ln \left({\text{serum creatinine (mg/dL)}}\right)+6.43} MELD scores are reported as whole numbers, so the result of the equation above is rounded. UNOS has made the following modifications to the score: If the patient has been dialyzed twice within the last 7 days, then the value of serum creatinine should be 4.0 mg/dL Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8 a value of 1.0 is used) to prevent subtraction from any of the three factors, since the natural logarithm of a positive number below 1 (greater than 0 and less than 1) yields a negative value. The etiology of liver disease was subsequently removed from the model because it posed difficulties such as how to categorize patients with multiple causes of liver disease. Modification of the MELD score by excluding etiology of liver disease did not significantly affect the model's accuracy in predicting three-month survival. Patients with a diagnosis of liver cancer will be assigned a MELD score based on how advanced the cancer is. == Interpretation == In interpreting the MELD Score in hospitalized patients, the 3 month observed mortality (considering 3,437 adult liver transplant candidates with chronic liver disease who were added to the OPTN waiting list at 2A or 2B status between November, 1999, and December, 2001) is: Applications of MELD score include: The best outcomes with TIPS occur among patients with a MELD score less than 14. Patients with MELD scores greater than 24 who are reasonable liver transplant candidates are probably best served by forgoing TIPS placement. == History == MELD was originally developed at the Mayo Clinic by Dr. Patrick Kamath, and at that point was called the "Mayo End-stage Liver Disease" score. It was derived in a series of patients undergoing TIPS procedures. The original version also included a variable based on the underlying etiology (cause) of the liver disease. The score turned out to be predictive of prognosis in chronic liver disease in general, and—with some modifications—came to be applied as an objective tool in assigning need for a liver transplant. The etiology turned out to be relatively unimportant, and was also regarded as relatively subjective; it was therefore removed from the score. The successor of MELD, an advanced scoring system, made by collaboration between Massachusetts General Hospital and IBM, called MELD-Plus was introduced in 2017. == Potential of alternative scores to extend life expectancy == The United Network for Organ Sharing proposed that MELD-Na score (an extension of MELD) may better rank candidates based on their risk of pre-transplant mortality and is projected to save 50-60 lives total per year. Furthermore, a study published in the New England Journal of Medicine in 2008, estimated that using MELD-Na instead of MELD would save 90 lives for the period from 2005 to 2006. In his viewpoint published in June 2018, co-creator of MELD-Plus, Uri Kartoun, suggested that "...MELD-Plus, if incorporated into hospital systems, could save hundreds of patients every year in the United States alone." == See also == Pediatric End-Stage Liver Disease Milan criteria Child-Pugh score MELD-Plus MELD-Na MELD 3.0 == References == == External links == Model for End-Stage Liver Disease Calculator from MDCalc Online calculator for MELD score/UNOS modification	Wikipedia/Model_for_End-Stage_Liver_Disease
Gastric bypass surgery refers to a technique in which the stomach is divided into a small upper pouch and a much larger lower "remnant" pouch, where the small intestine is rearranged to connect to both. Surgeons have developed several different ways to reconnect the intestine, thus leading to several different gastric bypass procedures (GBP). Any GBP leads to a marked reduction in the functional volume of the stomach, accompanied by an altered physiological and physical response to food. The operation is prescribed to treat severe obesity (defined as a body mass index greater than 40), type 2 diabetes, hypertension, obstructive sleep apnea, and other comorbid conditions. Bariatric surgery is the term encompassing all of the surgical treatments for severe obesity, not just gastric bypasses, which make up only one class of such operations. The resulting weight loss, typically dramatic, markedly reduces comorbidities. The long-term mortality rate of gastric bypass patients has been shown to be reduced by up to 40%. As with all surgery, complications may occur. A study from 2005 to 2006 revealed that 15% of patients experienced complications as a result of gastric bypass, and 0.5% of patients died within six months of surgery due to complications. A meta-analysis of 174,772 participants published in The Lancet in 2021 found that bariatric surgery was associated with 59% and 30% reduction in all-cause mortality among obese adults with or without type 2 diabetes respectively. This meta-analysis also found that median life-expectancy was 9.3 years longer for obese adults with diabetes who received bariatric surgery as compared to routine (non-surgical) care, whereas the life expectancy gain was 5.1 years longer for obese adults without diabetes. == Uses == Gastric bypass is indicated for the surgical treatment of severe obesity, a diagnosis which is made when the patient is seriously obese, has been unable to achieve satisfactory and sustained weight loss by dietary efforts and has comorbid conditions that are either life-threatening or serious impairment to the quality of life. Before 1991, clinicians interpreted serious obesity as weighing at least 100 pounds (45 kg) more than the "ideal body weight", an actuarially determined body weight at which one was estimated to be likely to live the longest, as determined by the life-insurance industry. This criterion failed for persons of short stature. In 1991, the National Institutes of Health (NIH) sponsored a consensus panel whose recommendations have set the current standard for consideration of surgical treatment, the body mass index (BMI). The BMI is defined as the body weight (in kilograms), divided by the square of the height (in meters). The result is expressed as a number in kilograms per square meter. In healthy adults, BMI ranges from 18.5 to 24.9, with a BMI above 30 considered obese, and a BMI less than 18.5 considered underweight. The Consensus Panel of the National Institutes of Health (NIH) recommended the following criteria for consideration of bariatric surgery, including gastric bypass procedures: people who have a BMI of 40 or higher people with a BMI of 35 or higher with one or more related comorbid conditions The Consensus Panel also emphasized the necessity of multidisciplinary care of the bariatric surgical patient by a team of physicians and therapists to manage associated comorbidities and nutrition, physical activity, behavior, and psychological needs. The surgical procedure is best regarded as a tool that enables the patient to alter lifestyle and eating habits, and to achieve effective and permanent management of obesity and eating behavior. Since 1991, major developments in the field of bariatric surgery, particularly laparoscopy, have outdated some of the conclusions of the NIH panel. In 2004 the American Society for Bariatric Surgery (ASBS) sponsored a consensus conference which updated the evidence and the conclusions of the NIH panel. This conference, composed of physicians and scientists of both surgical and non-surgical disciplines, reached several conclusions, including: bariatric surgery is the most effective treatment for severe obesity gastric bypass is one of four types of operations for severe obesity laparoscopic surgery is equally effective and as safe as open surgery patients should undergo comprehensive preoperative evaluation and have multi-disciplinary support for optimum outcome In recent comparisons with sleeve gastrectomy, gastric bypass has shown slightly better outcomes in diabetes remission and weight maintenance. According to a 2021 evidence update, Roux-en-Y gastric bypass (RYGB) patients were more likely to maintain weight loss over five years, with a reduced relapse rate in Type 2 diabetes. However, RYGB was associated with a higher frequency of follow-up surgeries and hospitalizations due to complications. == Surgical techniques == The gastric bypass, in its various forms, accounts for a large majority of the bariatric surgical procedures performed. It is estimated that 200,000 such operations were performed in the United States in 2008. Laparoscopic surgery is performed using several small incisions, or ports: one to insert a surgical telescope connected to a video camera, and others to permit access to specialized operating instruments. The surgeon views the operation on a video screen. Laparoscopy is also called limited access surgery, reflecting the limitation on handling and feeling tissues and also the limited resolution and two-dimensionality of the video image. With experience, a skilled laparoscopic surgeon can perform most procedures as expeditiously as with an open incision—with the option of using an incision should the need arise. The Roux-en-Y laparoscopic gastric bypass, first performed and reported on in case studies between 1993 and 1994, is regarded as one of the most difficult procedures to perform by limited access techniques. The use of this method has greatly popularized the operation due to associated benefits such as a shortened hospital stay, reduced discomfort, shorter recovery time, less scarring, and minimal risk of incisional hernia. === Essential features === The gastric bypass procedure consists of: Creation of a small, 15–30 mL (1–2 tbsp) pouch from the upper stomach, accompanied by bypass of the remaining stomach (about 400 mL and variable). This restricts the volume of food that can be eaten. The stomach may simply be partitioned (like a wall between two rooms in a house or two office cubicles next to each other with a partition wall in between them—and typically by the use of surgical staples), or it may be divided into two separate/separated parts (also with staples). Total division (separate/separated parts) is usually advocated to reduce the possibility that the two parts of the stomach will heal back together ("fistulize") and negate the operation. Re-construction of the GI tract to enable drainage of both segments of the stomach. The particular technique used for this reconstruction produces several variants of the operation, differing in the lengths of the small intestine used, the degree to which food absorption is affected, and the likelihood of adverse nutritional effects. Usually, a segment of the small bowel (called the alimentary limb) is brought up to the proximal remains of the stomach. === Variations === ==== Gastric bypass, Roux-en-Y (RYGB, proximal) ==== This variant is the most commonly employed gastric bypass technique and is by far the most commonly performed bariatric procedure in the United States. The small intestine is divided approximately 45 cm (18 in) below the lower stomach outlet and is re-arranged into a Y-configuration, enabling outflow of food from the small upper stomach pouch via a "Roux limb". In the proximal version, the Y-intersection is formed near the upper (proximal) end of the small intestine. The Roux limb is constructed using 80–150 cm (31–59 in) of the small intestine, preserving the rest (and the majority) of it from absorbing nutrients. The patient will experience a very rapid onset of the stomach feeling full, followed by a growing satiety (or "indifference" to food) shortly after the start of a meal. ==== Gastric bypass, Roux-en-Y (RYGB, distal) ==== The small intestine is normally 20 - 22 ft (6 - 6.7 m) in length. As the Y-connection is moved further down the gastrointestinal tract, the amount available to fully absorb nutrients is progressively reduced, traded for greater effectiveness of the operation. The Y-connection is formed much closer to the lower (distal) end of the small intestine, usually 100–150 cm (39–59 in) from the lower end, causing reduced absorption (malabsorption) of food: primarily of fats and starches, but also of various minerals and the fat-soluble vitamins. The unabsorbed fats and starches pass into the large intestine, where bacterial actions may act on them to produce irritants and malodorous gases. These larger effects on nutrition are traded for a relatively modest increase in total weight loss. ==== Mini-gastric bypass (MGB) ==== The mini-gastric bypass procedure was first developed by Robert Rutledge from the US in 1997, as a modification of the standard Billroth II procedure. A mini gastric bypass creates a long narrow tube of the stomach along its right border (the lesser curvature). A loop of the small gut is brought up and hooked to this tube at about 180 cm from the start of the intestine. Numerous studies show that the loop reconstruction (Billroth II gastrojejunostomy) works more safely when placed low on the stomach, but can be a disaster when placed adjacent to the esophagus. Today thousands of "loops" are used for surgical procedures to treat gastric problems such as ulcers, stomach cancer, and injury to the stomach. The mini-gastric bypass uses the low set loop reconstruction and thus has rare chances of bile reflux. The MGB has been suggested as an alternative to the Roux-en-Y procedure due to the simplicity of its construction and is becoming more and more popular because of low risk of complications and good sustained weight loss. It has been estimated that 15.4% of weight loss surgery in Asia is now performed via the MGB technique. ==== Endoscopic duodenal-jejunal bypass ==== This technique has been clinically researched since the mid-2000s. It involves the implantation of a duodenal-jejunal bypass liner between the beginning of the duodenum (first portion of the small intestine from the stomach) and the mid-jejunum (the secondary stage of the small intestine). This prevents the partially digested food from entering the first and initial part of the secondary stage of the small intestine, mimicking the effects of the biliopancreatic portion of Roux-en-Y gastric bypass (RYGB) surgery. Despite a handful of serious adverse events such as gastrointestinal bleeding, abdominal pain, and device migration – all resolved with device removal – initial clinical trials have produced promising results in the treatment's ability to improve weight loss and glucose homeostasis outcomes. == Physiology == The gastric bypass reduces the size of the stomach by well over 90%. A normal stomach can stretch, sometimes to over 1000 mL, while the pouch of the gastric bypass may be 15 mL in size. The gastric bypass pouch is usually formed from the part of the stomach that is least susceptible to stretching. That, and its small original size, prevents any significant long-term change in pouch volume. What does change, over time, is the size of the connection between the stomach and intestine and the ability of the small intestine to hold a greater volume of food. Over time, the functional capacity of the pouch increases; by that time, weight loss has occurred, and the increased capacity should serve to allow maintenance of a lower body weight. When the patient ingests just a small amount of food, the first response is a stretching of the wall of the stomach pouch, stimulating nerves that tell the brain that the stomach is full. The patient feels a sensation of fullness as if they had just eaten a large meal—but with just a thimbleful of food. Most people do not stop eating simply in response to a feeling of fullness, but the patient rapidly learns that subsequent bites must be eaten very slowly and carefully, to avoid increasing discomfort or vomiting. Food is first churned in the stomach before passing into the small intestine. When the lumen of the small intestine comes into contact with nutrients, several hormones are released, including cholecystokinin from the duodenum and PYY and GLP-1 from the ileum. These hormones inhibit further food intake and have thus been dubbed "satiety factors". Ghrelin is a hormone that is released in the stomach that stimulates hunger and food intake. Changes in circulating hormone levels after gastric bypass have been hypothesized to produce reductions in food intake and body weight in obese patients. However, these findings remain controversial, and the exact mechanisms by which gastric bypass surgery reduces food intake and body weight have yet to be elucidated. For example, it is still widely perceived that gastric bypass works by mechanical means, i.e. food restriction and/or malabsorption. Recent clinical and animal studies, however, have indicated that these long-held inferences about the mechanisms of Roux-en-Y gastric bypass (RYGB) may not be correct. A growing body of evidence suggests that profound changes in body weight and metabolism resulting from RYGB cannot be explained by simple mechanical restriction or malabsorption. One study in rats found that RYGB induced a 19% increase in total and a 31% increase in resting energy expenditure, an effect not exhibited in vertical sleeve gastrectomy rats. In addition, pair-fed rats lost only 47% as much weight as their RYGB counterparts. Changes in food intake after RYGB only partially account for RYGB-induced weight loss, and there is no evidence of clinically significant malabsorption of calories contributing to weight loss. Thus, it appears RYGB affects weight loss by altering the physiology of weight regulation and eating behavior rather than by simple mechanical restriction or malabsorption. This hypothesis suggesting altered physiology is highly debated, and has no primary evidence supporting it. Anecdotal evidence is clear in that following gastric bypass surgery, eating after stomach distension causes nausea, discomfort, and vomiting, so patients very quickly learn to avoid overeating, which is agreed to be the main cause of weight loss following the surgery. To gain the maximum benefit from this physiology, it is important that the patient eat only at mealtimes, 5 to 6 small meals daily, and not graze between meals. Concentration on obtaining 80–100 g of daily protein is necessary. Meals after surgery are 1/4 cup (~60 mL) to 1/2 cup (~120 mL), slowly getting to 1 cup (~240 mL) by one year. This requires a change in eating behavior and an alteration of long-acquired habits for finding food. In almost every case where weight gain occurs late after surgery, the capacity for a meal has not greatly increased. Some assume the cause of regaining weight must be the patient's fault, e.g. eating between meals with high-caloric snack foods, though this has been debated. Others believe it is an unpredictable failure or limitation of the surgery for certain patients (e.g. reactive hypoglycemia). == Complications == Any major surgery involves the potential for complications—adverse events that increase risk, hospital stay, and mortality. Some complications are common to all abdominal operations, while some are specific to bariatric surgery. === Mortality and complication rates === The overall rate of complications during the 30 days following surgery ranges from 7% for laparoscopic procedures to 14.5% for operations through open incisions. One study on mortality revealed a 0% mortality rate out of 401 laparoscopic cases, and 0.6% out of 955 open procedures. Similar mortality rates—30-day mortality of 0.11%, and 90-day mortality of 0.3%—have been recorded in the U.S. Centers of Excellence program, the results being from 33,117 operations at 106 centers. Mortality and complications are affected by pre-existing risk factors such as degree of obesity, heart disease, obstructive sleep apnea, diabetes mellitus, and history of prior pulmonary embolism. It is also affected by the experience of the operating surgeon: the learning curve for laparoscopic bariatric surgery is estimated to be about 100 cases. Supervision and experience are important when selecting a surgeon, as the way a surgeon becomes experienced in dealing with problems is by encountering and solving them. === Complications of abdominal surgery === ==== Infection ==== Infection of the incisions or the inside of the abdomen (peritonitis, abscess) may occur due to the release of bacteria from the bowel during the operation. Nosocomial infections, such as pneumonia, bladder or kidney infections, and sepsis (blood-borne infection) are also possible. Effective short-term use of antibiotics, diligent respiratory therapy, and encouragement of activity within a few hours after surgery can reduce the risks of infections. ==== Venous thromboembolism ==== Any injury, such as a surgical operation, causes the body to increase the coagulation of the blood. Simultaneously, activity may be reduced. Gastric Bypass Surgery is done with minimally invasive techniques (laparoscopy). Due to insufflation of the abdominal cavity with CO2 for the surgery, the venous return is diminished and this will lead to deep vein thrombosis of the lower extremities. There is an increased probability of the formation of clots in the veins of the legs, or sometimes the pelvis, particularly in severely obese patients. A clot that breaks free and floats to the lungs is called a pulmonary embolus, a very dangerous occurrence. Blood thinners are commonly administered before surgery to reduce the probability of this type of complication. ==== Hemorrhage ==== Many blood vessels must be cut to divide the stomach and to move the bowel. Any of these may later begin bleeding, either into the abdomen (intra-abdominal hemorrhage) or into the bowel itself (gastrointestinal hemorrhage). Transfusions may be needed, and re-operation is sometimes necessary. The use of blood thinners to prevent venous thromboembolic disease may increase the risk of hemorrhage slightly. ==== Hernia ==== A hernia is an abnormal opening, either within the abdomen or through the abdominal wall muscles. An internal hernia may result from surgery and re-arrangement of the bowel and is a cause of bowel obstruction. Antecolic antegastric Roux-en-Y gastric bypass surgery has been estimated to result in internal hernia in 0.2% of cases, mainly through Petersen's defect. An incisional hernia occurs when a surgical incision does not heal well; the muscles of the abdomen separate and allow protrusion of a sac-like membrane, which may contain bowel or other abdominal contents, and which can be painful and unsightly. The risk of abdominal-wall hernia is markedly decreased in laparoscopic surgery. ==== Bowel obstruction ==== Abdominal surgery always results in some scarring of the bowel, called adhesions. A hernia, either internal or through the abdominal wall, may also result. When the bowel becomes trapped by adhesions or a hernia, it may become kinked and obstructed, sometimes many years after the original procedure. An operation is usually necessary to correct this problem. === Complications of gastric bypass === ==== Anastomotic leakage ==== An anastomosis is a surgical connection between the stomach and bowel, or between two parts of the bowel. The surgeon attempts to create a water-tight connection by connecting the two organs with either staples or sutures, either of which makes a hole in the bowel wall. The surgeon will rely on the body's natural healing abilities and its ability to create a seal, like a self-sealing tire, to succeed with the surgery. If that seal fails to form for any reason, fluid from within the gastrointestinal tract can leak into the sterile abdominal cavity and give rise to infection and abscess formation. Leakage of an anastomosis can occur in about 2% of Roux-en-Y gastric bypass and less than 1% in mini gastric bypass. Leaks usually occur at the stomach-intestine connection (gastro-jejunostomy). ==== Anastomotic stricture ==== As the anastomosis heals, it forms scar tissue, which naturally tends to shrink ("contract") over time, making the opening smaller. This is called a "stricture". Usually, the passage of food through an anastomosis will keep it stretched open, but if the inflammation and healing process outpaces the stretching process, scarring may make the opening so small that even liquids can no longer pass through it. The solution is a procedure called gastro endoscopy, and stretching of the connection by inflating a balloon inside it. Sometimes this manipulation may have to be performed more than once to achieve lasting correction. ==== Anastomotic ulcer ==== Ulceration of the anastomosis occurs in 1–16% of patients. Possible causes of such ulcers are: Restricted blood supply to the anastomosis (compared to the blood supply available to the original stomach) Anastomosis tension Gastric acid The bacteria Helicobacter pylori Smoking Use of non-steroidal anti-inflammatory drugs This condition can be treated with: Proton pump inhibitors, e.g. esomeprazole A cytoprotectant and acid buffering agent, e.g. sucralfate Temporary restriction of the consumption of solid foods ==== Dumping syndrome ==== Normally, the pyloric valve at the lower end of the stomach regulates the release of food into the bowel. When the gastric bypass patient eats a sugary food, the sugar passes rapidly into the intestine, where it gives rise to a physiological reaction called dumping syndrome. The body will flood the intestines with gastric content in an attempt to dilute the sugars. An affected person may feel their heart beating rapidly and forcefully, break into a cold sweat, get a feeling of butterflies in the stomach, and may have an anxiety attack. The person usually has to lie down and could be very uncomfortable for 30–45 minutes. Diarrhea may then follow. === Nutritional deficiencies === Nutritional deficiencies are common after gastric bypass surgery and are often not recognized. They include: Secondary hyperparathyroidism due to inadequate absorption of calcium may occur in GBP patients. Calcium is primarily absorbed in the duodenum, which is bypassed by the surgery. Most patients can achieve adequate calcium absorption by supplementation with vitamin D and calcium citrate (carbonate may not be absorbed—it requires an acidic stomach, which is bypassed). Iron frequently is seriously deficient, particularly in menstruating females, and must be supplemented. Again, it is normally absorbed in the duodenum. Ferrous sulfate can cause considerable GI distress in normal doses; alternatives include ferrous fumarate, or a chelated form of iron. Occasionally, a female patient develops severe anemia, even with supplements, and must be treated with parenteral iron. The signs of iron deficiency include: brittle nails, an inflamed tongue, constipation, depression, headaches, fatigue, and mouth lesions. Signs and symptoms of zinc deficiency may also occur such as acne, eczema, white spots on the nails, hair loss, depression, amnesia, and lethargy. Deficiency of thiamine (also known as vitamin B1) brings the risk of permanent neurological damage (i.e. Wernicke's encephalopathy or polyneuropathy). Signs of thiamin deficiency are heart failure, memory loss, numbness of the hands, constipation, and loss of appetite. Vitamin B12 requires intrinsic factor from the gastric mucosa to be absorbed. In patients with a small gastric pouch, it may not be absorbed, even if supplemented orally, and deficiencies can result in pernicious anemia and neuropathies. Vitamin B12 deficiency is quite common after gastric bypass surgery with reported rates of 30% in some clinical trials. Sublingual B12 (cyanocobalamin) appears to be adequately absorbed. In cases where sublingual B12 does not provide sufficient amounts, injections may be needed. Protein malnutrition is a real risk. Some patients experience troublesome vomiting after surgery, until their GI tract adjusts to the changes, and cannot eat adequate amounts even with 6 meals a day. Many patients require protein supplementation during the early phases of rapid weight loss to prevent excessive loss of muscle mass. Hair loss is also a risk of protein malnutrition. Vitamin A deficiencies generally occur as a result of fat-soluble vitamin deficiencies. This often comes after intestinal bypass procedures such as jejunoileal bypass (no longer performed) or biliopancreatic diversion/duodenal switch procedures. In these procedures, fat absorption is markedly impaired. There is also the possibility of a vitamin A deficiency with the use of the weight-loss medication orlistat (marketed as Xenical and Alli). Folate deficiency is also a common occurrence in gastric bypass surgery patients. ==== Nutritional effects ==== After surgery, patients feel fullness after ingesting only a small volume of food, followed soon thereafter by a sense of satiety and loss of appetite. Total food intake is markedly reduced. Due to the reduced size of the newly created stomach pouch, and reduced food intake, adequate nutrition demands that the patient follow the surgeon's instructions for food consumption, including the number of meals to be taken daily, adequate protein intake, and the use of vitamin and mineral supplements. Calcium supplements, iron supplements, protein supplements, multi-vitamins (sometimes prenatal vitamins are best), and vitamin B12 (cyanocobalamin) supplements are all very important to the post-operative bypass patient. Total food intake and absorbance rate of food will rapidly decline after gastric bypass surgery, and the number of acid-producing cells lining the stomach increases. Doctors often prescribe acid-lowering medications to counteract the high acidity levels. Many patients then experience a condition known as achlorhydria, where there is not enough acid in the stomach. As a result of the low acidity levels, patients can develop an overgrowth of bacteria. A study conducted on 43 post-operative patients revealed that almost all of the patients tested positive for a hydrogen breath test, which indicated an overgrowth of bacteria in the small intestine. Bacterial overgrowth causes the gut ecology to change and induces nausea and vomiting. Recurring nausea and vomiting eventually change the absorbance rate of food, contributing to the vitamin and nutrition deficiencies common in post-operative gastric bypass patients. ===== Protein nutrition ===== Proteins are essential food substances, contained in foods such as meat, fish, poultry, dairy products, eggs, vegetables, fruits, legumes, and nuts. With a reduced ability to eat a large volume of food, gastric bypass patients must focus on eating their protein requirements first, and with each meal. In some cases, surgeons may recommend the use of a liquid protein supplement. Powdered protein supplements added to smoothies or any food can be an important part of the post-op diet. ===== Calorie nutrition ===== The profound weight loss that occurs after bariatric surgery is due to taking in much less energy (calories) than the body needs to use every day. Fat tissue must be burned to offset the deficit, and weight loss results. Eventually, as the body becomes smaller, its energy requirements are decreased, while the patient simultaneously finds it possible to eat somewhat more food. When the energy consumed is equal to the calories eaten, weight loss will stop. Proximal GBP typically results in loss of 60–80% of excess body weight, and very rarely leads to excessive weight loss. The risk of excessive weight loss is slightly greater with distal GBP. ===== Vitamins ===== Vitamins are normally contained in foods and supplements. The amount of food eaten after GBP is severely reduced, and vitamin content is correspondingly lowered. Supplements should therefore be taken to complete minimum daily requirements of all vitamins and minerals. Pre-natal vitamins are sometimes suggested by doctors, as they contain more of certain vitamins than most multivitamins. Absorption of most vitamins is not seriously affected after proximal GBP, although vitamin B12 may not be well-absorbed in some persons: sublingual preparations of B12 provide adequate absorption. Some studies suggest that GBP patients who took probiotics after surgery can absorb and retain higher amounts of B12 than patients who did not take probiotics after surgery. After a distal GBP, fat-soluble vitamins A, D, and E may not be well-absorbed, particularly if fat intake is large. Water-dispersed forms of these vitamins may be indicated on specific physician recommendations. For some patients, sublingual B12 is not enough, and patients may require B12 injections. ===== Minerals ===== All versions of the GBP bypass the duodenum, which is the primary site of absorption of both iron and calcium. Iron replacement is essential in menstruating females, and supplementation of iron and calcium is preferable in all patients. Ferrous sulfate is poorly tolerated. Alternative forms of iron (fumarate, gluconate, chelates) are less irritating and probably better absorbed. Calcium carbonate preparations should also be avoided; calcium as citrate or gluconate (with 1200 mg as calcium) has greater bioavailability independent of acid in the stomach, and will likely be better absorbed. Chewable calcium supplements that include vitamin K are sometimes recommended by doctors as a good way to get calcium. ===== Alcohol metabolism ===== Post-operative gastric bypass patients develop a lowered tolerance for alcoholic beverages because their altered digestive tract absorbs alcohol at a faster rate than people who have not undergone the surgery. It also takes a post-operative patient longer to reach sober levels after consuming alcohol. In a study conducted on 36 post-operative patients and a control group of 36 subjects (who had not undergone surgery), each subject drank a 5 oz. glass of red wine and had the alcohol in their breath measured to evaluate alcohol metabolism. The gastric bypass group had an average peak alcohol breath level of 0.08%, whereas the control group had an average peak alcohol breath level of 0.05%. It took an average of 108 minutes for the gastric bypass patients group to return to an alcohol breath of zero, while it took the control group an average of 72 minutes. ===== Pica ===== There have been reported cases in which pica recurs after gastric bypass in patients with a pre-operative history of the disorder, which is possibly due to iron deficiency. Pica is a compulsive tendency to eat substances other than normal food. Some examples would be people eating paper, clay, plaster, ashes, or ice. Low levels of iron and hemoglobin are common in patients who have undergone gastric bypass. One study reported on a female post-operative gastric bypass patient who was consuming eight to ten 32 oz. glasses of ice a day. The patient's blood test revealed iron levels of 2.3 mmol/L and hemoglobin level of 5.83 mmol/L. Normal iron blood levels of adult women are 30 to 126 μg/dL and normal hemoglobin levels are 12.1 to 15.1 g/dL. This deficiency in the patient's iron levels may have led to an increase in Pica activity. The patient was then given iron supplements that brought her hemoglobin and iron blood levels to normal levels. After one month, the patient's eating diminished to two to three glasses of ice per day. After one year of taking iron supplements the patient's iron and hemoglobin levels remained in a normal range and the patient reported that she did not have any further cravings for ice. == Results and health benefits of gastric bypass == Weight loss of 65–80% of excess body weight is typical of most large series of gastric bypass operations reported. The medically more significant effects include a dramatic reduction in comorbid conditions: Hyperlipidemia is corrected in over 70% of patients. Essential hypertension is relieved in over 70% of patients, and medication requirements are usually reduced in the remainder. Obstructive sleep apnea improves markedly with weight loss and bariatric surgery may be curative for sleep apnea. Snoring is also reduced in most patients. Type 2 diabetes is reversed in up to 90% of patients usually leading to a normal blood-sugar level without medication, sometimes within days of surgery. Furthermore, Type 2 diabetes is prevented by more than 30-fold in patients with pre-diabetes. All these findings were first reported by Walter Pories and Jose F. Caro. Gastroesophageal reflux disease is relieved in almost all patients. Venous thromboembolic disease signs such as leg swelling are typically alleviated. Lower-back pain and joint pain are typically relieved or improved in nearly all patients. A study in a large prospective study of 2010 obese patients showed a 29% reduction in mortality up to 15 years following surgery (hazard ratio 0.71 when adjusted for sex, age, and risk factors), compared to a non-surgically treated group of 2037 patients. A meta-analysis of 174772 participants published in The Lancet in 2021 found that bariatric surgery was associated with 59% and 30% reduction in all-cause mortality among obese adults with or without type 2 diabetes respectively. This meta-analysis also found that median life expectancy was 9.3 years longer for obese adults with diabetes who received bariatric surgery as compared to routine (non-surgical) care, whereas the life expectancy gain was 5.1 years longer for obese adults without diabetes. Concurrently, most patients can enjoy greater participation in family and social activities. == Cost of gastric bypass == The patient's out-of-pocket cost for Roux-en-Y gastric bypass surgery varies widely depending on the method of payment, region, surgical practice, and hospital in which the procedure is performed. Methods of payment in the United States include private insurance, such as Individual & Family coverage, Small Group coverage through an employer (Under 50 full-time employees) and Large Group coverage through an employer (50 or more full-time employees), public insurance (Medicare and Medicaid), and self-pay. Out-of-pocket costs for a patient with private or public insurance that specifically lists bariatric surgery as a covered benefit include several insurance-policy-specific parameters such as deductible levels, coinsurance percentages, copay amounts, and out-of-pocket limits. Patients without insurance must pay for surgery directly (or through a third-party lender), and total out-of-pocket costs will depend on the surgical practice they choose and the hospital in which the surgical practice performs the procedure. On average, the total cost of gastric bypass surgery is about $24,000 in the United States, although on a state-specific level it ranges from an average of $15,000 (Arkansas) to an average of $57,000 (Alaska). In Germany a gastric bypass operation, if not covered by health insurance and therefore paid privately, costs up to €15,000; in Switzerland CHF 20,000–25,000, in Poland gastric bypass costs around £4,000, whereas in Turkey it costs £3,200. == Living with gastric bypass == Gastric bypass surgery has an emotional and physiological impact on the individual. Many who have undergone the surgery develop depression in the following months as a result of a change in the role food plays in their emotional well-being. Strict limitations on the diet can place great emotional strain on the patient. Energy levels in the period following the surgery can be low, both due to the restriction of food intake and negative changes in emotional state. It may take as long as three months for emotional levels to rebound. Muscular weakness in the months following surgery is also common. This is caused by many factors, including a restriction on protein intake, a resulting loss in muscle mass, and a decline in energy levels. Muscle weakness may result in balance problems, difficulty climbing stairs or lifting heavy objects, and increased fatigue following simple physical tasks. Many of these issues pass over time as food intake gradually increases. However, the first months following the surgery can be very difficult, an issue not often mentioned by physicians suggesting the surgery. The benefits and risks of this surgery are well established; however, the psychological effects are not well understood. Even if physical activity is increased, patients may still harbor long-term psychological effects due to excess skin and fat. Often bypass surgery is followed up with "body lifts" of skin and liposuction of fatty deposits. These extra surgeries have inherent risks but are even more dangerous when coupled with the typical nutritional deficiencies that accompany convalescing gastric bypass patients. == Surgeon accreditation == The American Society for Metabolic & Bariatric Surgery lists bariatric programs and surgeons in its "Centers of Excellence" network, while the American College of Surgeons accredits providers through its Bariatric Surgery Center Network. For listings of surgeons and centers in other countries, the International Federation for the Surgery of Obesity and Metabolic Disorders lists medical associations by country. == See also == Adjustable gastric band Duodenal switch surgery StomaphyX—Revisional, natural orifice procedure for patients that have regained weight after gastric bypass Vagotomy—Cutting of the vagus nerve to reduce the feeling of hunger == References == === Books === === Journal sources === === News sources === === Press releases === === Web sources === == Further reading == == External links == NIH – Gastrointestinal Surgery for Obesity Archived 30 March 2015 at the Wayback Machine NIH Medline Plus – Multiple Links to articles, videos about bariatric surgery Metabolic & Weight Loss Surgical Procedures Gallery – Including information on bariatric surgery	Wikipedia/Gastric_bypass_surgery
High-resolution manometry (HRM) is a gastrointestinal motility diagnostic system that measures intraluminal pressure activity in the gastrointestinal tract using a series of closely spaced pressure sensors. For a manometry system to be classified as "high-resolution" as opposed to "conventional", the pressure sensors need to be spaced at most 1 cm apart. Two dominant pressure transduction technologies are used: solid state pressure sensors and water perfused pressure sensors. Each pressure transduction technology has its own inherent advantages and disadvantages. HRM systems also require advanced computer hardware and software to store and analyze the manometry data. == See also == Functional Lumen Imaging Probe Anorectal manometry == References == == External links == HRM systems (from EBNeuro S.p.A.) HRM systems (from Sierra)	Wikipedia/High_resolution_manometry
Intravenous cholangiography is a form of cholangiography that was introduced in 1954. == Overview == The intravenous cholangiogram or IVC is a radiologic (x-ray) procedure that is used primarily to look at the larger bile ducts within the liver and the bile ducts outside the liver. The procedure can be used to locate gallstones within these bile ducts. IVC also can be used to identify other causes of obstruction to the flow of bile, for example, narrowings (strictures) of the bile ducts and cancers that may impair the normal flow of bile. == Procedure == To do an IVC, an iodine-containing dye (meglumine ioglycamate) is injected intravenously into the blood. The liver then removes the dye from the blood and excretes it into the bile. The iodine is sufficiently concentrated as it is secreted into the bile that it does not need to be further concentrated by the gallbladder to outline the bile ducts and any gallstones that may be there. The gallbladder is not always seen on an IVC, as the iodine-containing bile may bypass the gallbladder entirely and empty directly into the small intestine. == Risks == Occasional serious allergic reactions can occur to any iodine-containing dye. These reactions can usually be treated and rarely result in death. == Indications == The IVC is not used as much today as it was. Its use always was limited, because it did not work when there was more than a minimal amount of jaundice, and many of the conditions it was used to detect also caused substantial jaundice. The IVC has been largely replaced by other diagnostic procedures—by ERCP (endoscopic retrograde cholangiopancreatography), endoscopic ultrasound and, increasingly, by MRI cholangiography, none of which are affected by jaundice. It is sometimes used when ERCP is unsuccessful. == References ==	Wikipedia/Intravenous_cholangiography
Pediatric end-stage liver disease (PELD) is a disease severity scoring system for children under 12 years of age. It is calculated from the patient's albumin, bilirubin, and international normalized ratio (INR) together with the patient's age and degree of growth failure. This score is also used by the United Network for Organ Sharing (UNOS) for prioritizing allocation of liver transplants. == Determination == PELD uses the patient's values for serum bilirubin, serum albumin, the international normalized ratio for prothrombin time (INR), whether the patient is less than 1 year old, and whether the patient has growth failure (<-2 standard deviation) to predict survival. It is calculated according to the following formula: PELD = 4.80[Ln serum bilirubin (mg/dL)] + 18.57[Ln INR] - 6.87[Ln albumin (g/dL)] + 4.36(<1 year old) + 6.67(growth failure) == Usage == The PELD score calculated for any given patient is correlated to their prognosis and how likely they are to die within a certain time period. A higher score correlates with a more critical condition. Thus, liver donations are usually allocated by UNOS according to the PELD score to maximize the life-saving capability of each donated liver. == See also == Liver transplantation MELD MELD-Plus == References == == External links == PELD Calculator United Network for Organ Sharing	Wikipedia/Pediatric_end-stage_liver_disease
Partial ileal bypass surgery is a surgical procedure which involves shortening the ileum to shorten the total small intestinal length. First introduced in 1962 by Professor Henry Buchwald of the University of Minnesota, the procedure is used to treat a number of hyperlipidemias including familial hypercholesterolemia. The only randomized controlled trial comparing bypass surgery with standard management was the POSCH trial, which was conducted by Buchwald and his team. The trial ran between 1975 and 1983 and included 838 men who had survived a heart attack. This trial initially failed to show any benefit on mortality, but in 1998 follow-up results indicated that in addition to its known benefit on cholesterol levels and disease events it had also decreased mortality in the treatment group. Ileal bypass surgery was mainly performed prior to the introduction of effective oral medication for the most common hypercholesterolemias. It is occasionally used in the surgical treatment of obesity. As with any ileal resection, a possible complication is mild steatorrhea due to a reduced uptake of bile acids by the ileum. == See also == Familial hypercholesterolemia Ileojejunal bypass == References ==	Wikipedia/Partial_ileal_bypass_surgery
Percutaneous transhepatic cholangiography, percutaneous hepatic cholangiogram (PTHC) is a radiological technique used to visualize the anatomy of the biliary tract. A contrast medium is injected into a bile duct in the liver, after which X-rays are taken. It allows access to the biliary tree in cases where endoscopic retrograde cholangiopancreatography has been unsuccessful. Initially reported in 1937, the procedure became popular in 1952. == Uses == Some uses for this procedure includes: drainage of bile/infected bile to relieve obstructive jaundice, to place a stent to dilate a stricture in the biliary system, stone removal, and rendezvous technique where guidewire from the common bile duct (CBD) meets with duodenoscope (coming from the oesophagus into the stomach and then duodenum) at the major duodenal papilla. In this rendezvous technique, the guidewire is then pulled into duodenoscope and a small blade is slid over the guidewire into the CBD and perform surgeries on a specific bile duct in the biliary system. PTHC is frequently performed guide therapy of the biliary system. Rarely it is used for diagnostic purposes only. PTHC is also used in the drainage of unruptured or uncomplicated hydatid cysts. Rarely, PTHC is used in the drainage of ruptured hydatid cysts. == Contraindications == Among the contraindications are: increased bleeding tendency where platelets less than 100x109/litre and prothrombin time prolonged more than 2 seconds than the control. This procedure is also contraindicated in biliary tract sepsis, except to control the infection by drainage of the infected bile. == Technique == Low osmolar contrast medium is used in this procedure with concentration of 150 mg/ml with 20 to 60 ml volume. Those who undergoes the procedure needs to be fasted for four hours before the procedure. Besides, antibiotics such as ciprofloxacin 500 mg to 750 mg can be given as antibiotic prophylaxis to prevent infection during the procedure. Sedation (to reduce irritability and agitation of the subject during procedure) with analgesia (painkillers) and vital signs monitoring should be set up. Before the procedure, bedside ultrasound is done to confirm the position of the dilated bile ducts in the liver. The puncture site is then marked. Bile ducts of the right liver is located in the intercostal spaces between anterior and mid axillary lines. Meanwhile, the bile ducts in the left lobe of the liver is located to the left side of the xiphisternum on the epigastric region. The number of attempts made to pass Chiba needle into the biliary tract does not affect the rate of complication but the likehood of success is related to the degree of dilatation of the biliary tract (larger dilatation means needle is easier to find its way into the biliary tract) and total number of attempts made. Excessive contrast media injection into the liver should be avoided. When there is excessive injection into the liver, lymphatics within the liver will be opacified with contrast medium. Injection of the contrast medium into an artery or vein will cause the contrast to dispersed quickly due to blood flow. Cholangiography during a biliary drainage intervention is called perioperative or primary choloangiography, and when performed later in the same drain it is called secondary cholangiography. == Complications == Percutaneous transhepatic cholangiography may increase the incidence of metastasis, tube dislocation, and bleeding when compared to endoscopic biliary drainage. However, it has lower rate of cholangitis, pancreatitis when compared to endoscopic biliary drainage, probably because the latter has higher chance of incomplete drainage of infected bile, or accidental resection of papilla that causes the backflow of infected bile from the duodenum into the biliary system. == Percutaneous transhepatic biliary drainage == Percutaneous transhepatic biliary drainage (PTBD) is often performed if endoscopic retrograde biliary drainage (ERBD) is unsuccessful for biliary obstructions due to hepatocellular carcinoma. ERBD is the first line treatment because of its low bleeding risk. For biliary obstruction at the hilum (meeting point of right and hepatic hepatic ducts), both ERBD and PTBD can be done depending on subject's clinical circumstances and physician's preference. == Percutaneous extraction of retained biliary calculi == === Percutaneous transhepatic technique === This procedure is indicated when endoscopic retrograde cholangiopancreatography (ERCP), papillotomy (cutting through major duodenal papilla to relieve stenosis) or stone removal are unsuccessful. This procedure is also indicated when endoscopic access is difficult in case where there is major modification of the stomach and small intestine such as Billroth II stomach resection, and other conditions such as intradiverticular papilla (duodenal papilla located inside a duodenal outpouching), stenosis of the duodenal papilla, stone within the distal CBD, stenosis of ampulla of Vater, stone in the peripheral bile duct, or stone larger than 15 mm. Biliary calculi is seen on cholangiogram done on T-tube that was previously inserted into CBD. This happens in 3% of the cases post surgical management of biliary stones. This procedure is contraindicated if T-tube is too small (less than 12 French in size), tortous T tube in tissues, acute pancreatitis, and when there is another drain that is connected to the T-tube tract. PTBD is done one to two weeks before the procedure to reduce oedema of the biliary ducts and sphincter of Oddi oedema. Either high osmolar contrast medium or low osmolar contrast medium can be used (with concentration of 150 mg/ml). Low density contrast medium is used to prevent obscuring of the calculus. Antibiotic prophylaxis and pre-medication is given one hour before the procedure. Painkillers is given during the procedure. The subject lie down in supine position on the table. PTHC is performed if biliary drainage catheter is not in-situ. The drainage catheter is then removed over the guidewire and sheath is inserted into the ducts (7 to 8 French size). Contrast is then injected through the sheath to identify any stones or strictures. If a stricture is identified, put in biliary manipulation catheter with guidewire measuring 0.035 inches and commence balloon dilatation (with balloon sizes of 8, 10, and 12 mm). Using the balloon catheter, the stones are pushed into the duodenum. If the stones are difficult to push, Dormier basket is used to push them into the duodenum. The basket is removed and guidewire is inserted back into the sheath. The sheath is then removed and biliary drainage catheter is inserted back through the guidewire. Contrast is then injected intermittently through the drainage catheter to follow-up on the position of the stones. After the procedure, pulse and blood pressure are monitored half-hourly for six hours. The subject put on bed rest for a total of four to six hours. Possible complications include allergic reaction to the contrast and inflammation of the pancreas. There can also be perforation of the T-tube tract. === Trans T-tube technique === Post-operative T-tube cholangiography is performed on the 10th day post operation where either high osmolar or low osmolar contrast media with concentration of 150 mg/ml with volume of 20 to 30 ml is injected through the T-tube to determine if there is any leak from the biliary tract or remaining stones within the biliary system. Trans T-tube technique of stone extraction also known as Burhene technique. This procedure is done after 5 to 8 weeks post abdominal operation for the maturation of the T-tube tract when fibrous tissue is formed at its walls to support the tract and keep the tract open. Guidewire is then advanced through the T-tube before the T-tube is removed. Then a catheter is inserted over the guidewire and cholangiogram is performed to visualise the anatomy of the biliary tract and the positions of the stones. == References == == External links == MedlinePlus Encyclopedia: 003820 Medline page	Wikipedia/Percutaneous_transhepatic_cholangiography
Functional Lumen Imaging Probe (FLIP) is a test used to evaluate the function of the esophagus, by measuring the dimensions of the esophageal lumen using impedance planimetry. Typically performed with sedation during upper endoscopy, FLIP is used to evaluate for esophageal motility disorders, such as achalasia, diffuse esophageal spasm, etc. == Procedure == FLIP is most often performed immediately following upper endoscopy (EGD). EGD helps to rule out a mechanical obstruction as a cause for symptoms, and also provides an estimation on the distance from the incisors to the EGJ. FLIP uses impedance planimetry to measure the cross sectional area of the esophageal lumen. The FLIP device consists of a balloon that encases a catheter with multiple pairs of impedance electrodes. Two catheter configurations are available, which are 8 cm and 16 cm in length. The 8 cm catheter includes 16 sensors spaced 0.5 cm apart, and is used to evaluate esophagogastric junction (EGJ) distensibility and CSA. Alternatively, the 16 cm catheter has 16 sensors spaced 1 cm apart, and may be used to evaluate contractility via secondary peristalsis patterns, in addition to evaluating the esophagogastric junction (EGJ). Following upper endoscopy, the balloon is inserted into the esophagus and the balloon is distended with a fluid with known properties (e.g. conductivity and volume). Each electrode then measures impedance, and a single pressure sensor at the end of the device measures pressure within the balloon. == Results == The distensibility index (DI) is the most studied and most helpful result obtained with FLIP testing. The normal DI ranges from 3.1 to 9.0 mm2 per mmHg. As the balloon is distended, the results of secondary esophageal secondary contractions may be seen via FLIP panometry. Possible results may include: repetitive anterograde contractions (a normal finding), repetitive retrograde contractions (abnormal), absent contractility, and other abnormalities. == Indications == FLIP may be used for several indications to evaluate esophageal symptoms, such as dysphagia, chest pain, or regurgitation, or to assess response to treatment. FLIP is used to evaluate for esophageal motility disorders, such as achalasia, diffuse esophageal spasm, etc. FLIP may be used as a complementary or alternative to esophageal manometry for evaluating esophageal outflow obstructive disorders, including achalasia. FLIP may be used as a complementary test for barium esophagram for evaluating esophageal outflow obstructive disorders. FLIP may be used to assess the effect of treatment for achalasia. FLIP is recommended to further evaluate suspected esophagogastric junction outflow obstruction (EGJOO) where the manometry is normal or borderline. FLIP measurements may be used to guide intraoperative reflux surgery, or to assess the degree of fibrostenotic disease from eosinophilic esophagitis. FLIP may be used to guide endoscopic dilation of esophageal strictures. While recommendations exist for its use, the evidence supporting the use of FLIP is of very low quality and further research would be useful in more clearly defining its role. == History == Early development of impedance planimetry for evaluating the gastrointestinal tract began in the 1980s. FLIP was first developed with a short balloon catheter, which measures distension across the esophagogastric junction. A second generation device was later released, which measures secondary peristalsis proximal to the EGJ. == See also == Esophageal motility disorder Esophageal motility study == References ==	Wikipedia/Functional_Lumen_Imaging_Probe
Vertical banded gastroplasty (VBG), also known as stomach stapling, is a form of bariatric surgery for weight control. The VBG procedure involves using a band and staples to create a small stomach pouch. In the bottom of the pouch is an approximate one-centimeter hole through which the pouch contents can flow into the remainder of the stomach and hence on to the remainder of the gastrointestinal tract. Stomach stapling is a restrictive technique for managing obesity. The pouch limits the amount of food a patient can eat at one time and slows passage of the food. Stomach stapling is more effective when combined with a malabsorptive technique, in which part of the digestive tract is bypassed, reducing the absorption of calories and nutrients. Combined restrictive and malabsorptive techniques are called gastric bypass techniques, of which Roux-en-Y gastric bypass surgery (RGB) is the most common. In this technique, staples are used to form a pouch that is connected to the small intestine, bypassing the lower stomach, the duodenum, and the first portion of the jejunum. This type of weight loss surgery is losing favor as more doctors begin using the adjustable gastric band. The newer adjustable band does not require cutting into the stomach and does not use any staple lines, thus making it a much safer alternative. == Advantages and disadvantages == === Advantages === No dumping syndrome. No nutritional deficiencies/malabsorption. === Disadvantages === Needs strict patient compliance to diet. High-fiber foods and foods with a more dense, natural consistency can become very difficult to eat, while highly refined foods cause little discomfort. Many people who regain any weight lost after surgery do so because they begin to avoid the discomfort associated with consuming "healthier" foods, and start eating more easily passed "junk" foods. VBG is in no way a magic bullet or pill. It must be emphasized that lifestyle changes, e.g., diet and exercise, are absolutely imperative for weight loss to occur and be maintained. Realistic expectations are imperative. Reversal of a VBG requires a much more complex and intensive surgical process than getting the VBG. When removal of a polyurethane band is involved (polyurethane was predominantly used in the 1980s and 90s), it likely has built substantial scar tissue that must also be removed, depending on how long since the VBG took place. Removal of the staples involves stitching back together the previously separated parts of the stomach. For these reasons, a reversal should be considered only if there are serious medical complications. Vomiting and severe discomfort if food is not properly chewed or if food is eaten too quickly. Not adjustable (as with the adjustable gastric band, aka "lap band")). === Alternatives === Duodenal switch surgery Vertical sleeve gastrectomy Roux-en-Y gastric bypass Selective vagotomy (snipping the vagus nerve, effectively stopping hunger sensations). Mini gastric bypass == Long term == Although restrictive operations lead to weight loss in almost all patients, they are less successful than malabsorptive operations in achieving substantial, long-term weight loss. About 30% of those who undergo VBG achieve normal weight, and about 80% achieve some degree of weight loss. Most studies have suggested that 10 years after surgery, only 10% of patients maintain a minimum weight loss of at least 50% of their total excess weight at the time of their initial surgery. Some patients regain weight. Others are unable to adjust their eating habits and fail to lose the desired weight. Successful results depend on the patient's willingness to adopt a long-term plan of healthy eating and regular physical activity. According to an episode of Oprah Winfrey that aired on October 24, 2006, 30% of people who undergo weight-loss surgery such as VBG or gastric bypass develop addiction transference, which is transferring the previous addiction to food with a new addiction to alcoholism. The show stressed the importance of examining the root causes of addiction in order to avoid the phenomenon. == Complications == Staple-line disruption Stomal fibrosis Gastroesophageal reflux disease Incisional ventral hernia == History == Vertical banded gastroplasty was developed in 1980 by Dr. Edward E. Mason at the University of Iowa. Dr. Mason also developed the original gastric bypass for weight reduction in 1966 and is known for his pioneering work as the "father of obesity surgery". == See also == Endoscopic sleeve gastroplasty == References == == External links == Media related to Vertical banded gastroplasty at Wikimedia Commons	Wikipedia/Vertical_banded_gastroplasty_surgery
Defecography (also known as proctography, defecating/defecation proctography, evacuating/evacuation proctography or dynamic rectal examination) is a type of medical radiological imaging in which the mechanics of a patient's defecation are visualized in real time using a fluoroscope. The anatomy and function of the anorectum and pelvic floor can be dynamically studied at various stages during defecation. == History == Defecating proctography was pioneered in 1945, during World War II. The procedure gained popularity at this time in the midst of an outbreak of whipworm, which is known to cause rectal prolapse. It has since become used for diagnosis of various anorectal disorders, including anismus and other causes of obstructed defecation. It has fallen out of favor due to inadequate training in the technique. It is now only performed at a few institutions. Many radiology residents refer to the procedure as the "Def Proc", "Defogram", or "Stool Finale". == Indications == Defecography may be indicated for the following reasons: Evaluation of rectal outlet obstruction (obstructed defecation) symptoms Evaluation of all types of rectal (fecal) incontinence. Suspected conditions such as internal rectal intussusception, enterocele, anismus, rectocele or sigmoidocele. To compare pre- and post-surgical repair of rectal outlet obstruction (obstructed defecation). Specifically, defecography can differentiate between anterior and posterior rectocele. Also, in external rectal prolapse that was not directly visualized during examination, this radiographic projection will demonstrate its presence. == Technique == In females, pre-procedural preparation involves smearing a small amount of barium contrast agent in the vagina, which will help to identify if anterior rectocele, enterocele or sigmoidocele is present. The technique itself involves the insertion of a caulking gun device into the rectum with a subsequent manual infusion of barium paste until there is adequate distension. The patient is then transferred to a portable plastic commode which is situated next to a fluoroscope which records the defecation. Positioning of the X-ray camera is of paramount importance as visualization of the buttocks, rectal vault, and lower pelvis is critical. == Diagnostic yield and interpretation == Anatomical and physiological parameters that can be objectively measured by this investigation include: Anorectal angle: This is the "mid-axial longitudinal axis of the rectum and the anal canal", created by the anterior pull of the puborectalis sling at the level of the anorectal junction. At rest, it is held at 90 - 100°. This becomes more acute (70 - 90°) when the patient contracts the anal sphincters and pelvic floor muscles, and more obtuse (110 - 180°)during defecation. Perineal descent: This is "the caudad movement of the pelvic floor [during] straining". Defecation normally involves a relaxation of the pelvic floor (levator ani), leading to descent of the perineum. After straining, the opposite occurs, the perineum rises. From the proctogram, descent is calculated by drawing an imaginary line (the pubococcygeal line) between the most inferior point on the pubic bone and the tip of the coccyx. Normal perineal descent or elevation is less than 4 cm from the pubococcygeal line in either direction (superior or inferior). Efficiency of emptying/evacuation: Normally, there is 90-100% evacuation of rectal contents. Anal canal length: This is measured during maximal evacuation. Anal canal width: Again measured during maximal evacuation, this is usually less than 2.5 cm. Conditions which may be demonstrated include: Anismus (pelvic floor dyssynergia): It has been suggested that some patients may be embarrassed by this procedure, which give findings of abnormal defecation. For example, the patient may not be able to relax under the conditions, leading to relaxation failure of puborectalis and false positive diagnosis of anismus. It has also been reported that there is a high false positive rate of anismus diagnosis with anorectal manometry for similar reasons. Rectocele: This is the most common finding with this type of imaging. Almost always, this is an anterior rectocele where the anterior rectal wall bulges forward, into the vagina in females. In males, the prostate gland gives more support in this area compared to the vaginal cavity, so rectoceles, especially anterior rectoceles are uncommon in males. Less commonly and in males, there may be posterior rectoceles, where the rectum bulges posteriorly. Both the size and the efficiency of emptying can be assessed with proctography. Since many rectoceles are asymptomatic, this may only be a significant finding if there are symptoms of obstructed defecation. Usually rectoceles greater than 3 cm and those that do not empty are clinically significant. Enterocele and sigmoidocele: Enterocele is a prolapse of peritoneum that contains a section of small intestine. Sigmoidocele is a prolapse of peritoneum that contains a section of sigmoid colon. In females, these prolapses usually descend between the rectum and the vagina. They are most likely to be seen during straining. Rectal prolapse/Internal rectal intussusception: The rectum may be seen to prolapse, whether internally or externally. There can be difficulty differentiating between internal intussusception and a normal rectal fold. The thickness of the intussusception is half the width of the intussusception (the intussusception is a doubled over layer of rectal wall). This is most likely to be seen during straining. Megarectum: This is excessive width (>9 cm) of the rectum at the level of the distal sacrum and incomplete evacuation. Descending perineum syndrome: If the perineum descends >4 cm, descending perineum syndrome may be diagnosed. Fecal incontinence: If the barium paste does not stay in the rectum. == Cinedefecography and MRI defecography == Cinedefecography is a technique that is an evolution of defecography. The defecation cycle is recorded as a continuous series rather than individual still radiographs. More recent techniques involve the use of advanced, cross-sectional imaging modalities such as magnetic resonance imaging. This is known as dynamic pelvic MRI, or MRI proctography. The MRI proctography also called MRI defecography is not as efficient as conventional X-ray defecography for some problems. == See also == Anorectal manometry Obstructed defecation == References == == External links == Dynamic rectal examination on "the Radiology Assistant", many example defecating proctograms with interpretation.	Wikipedia/Defecography
Inguinal hernia surgery is an operation to repair a weakness in the abdominal wall that abnormally allows abdominal contents to slip into a narrow tube called the inguinal canal in the groin region. There are two different clusters of hernia: groin and ventral (abdominal) wall. Groin hernia includes femoral, obturator, and inguinal. Inguinal hernia is the most common type of hernia and consist of about 75% of all hernia surgery cases in the US. Inguinal hernia, which results from lower abdominal wall weakness or defect, is more common among men with about 90% of total cases. In the inguinal hernia, fatty tissue or a part of the small intestine gets inserted into the inguinal canal. Other structures that are uncommon but may get stuck in inguinal hernia can be the appendix, caecum, and transverse colon. Hernias can be asymptomatic, incarcerated, or strangled. Incarcerated hernia leads to impairment of intestinal flow, and strangled hernia obstructs blood flow in addition to intestinal flow. Inguinal hernia can make a small lump in the groin region which can be detected during a physical exam and verified by imaging techniques such as computed tomography (CT). This lump can disappear by lying down and reappear through physical activities, laughing, crying, or forceful bowel movement. Other symptoms can include pain around the groin, an increase in the size of the bulge over time, pain while lifting, and a dull aching sensation. In occult (hidden) hernia, the bulge cannot be detected by physical examination and magnetic resonance imaging (MRI) can be more helpful in this situation. Males who have asymptomatic inguinal hernia and pregnant women with uncomplicated inguinal hernia can be observed, but the definitive treatment is mostly surgery. Surgery remains the ultimate treatment for all types of hernias as they will not get better on their own, however not all require immediate repair. Elective surgery is offered to most patients taking into account their level of pain, discomfort, degree of disruption in normal activity, as well as their overall level of health. Emergency surgery is typically reserved for patients with life-threatening complications of inguinal hernias such as incarceration and strangulation. Incarceration occurs when intra-abdominal fat or small intestine becomes stuck within the canal and cannot slide back into the abdominal cavity either on its own or with manual maneuvers. Left untreated, incarceration may progress to bowel strangulation as a result of restricted blood supply to the trapped segment of small intestine causing that portion to die. Successful outcomes of repair are usually measured via rates of hernia recurrence, pain and subsequent quality of life. Surgical repair of inguinal hernias is one of the most commonly performed operations worldwide and the most commonly performed surgery within the United States. A combined 20 million cases of both inguinal and femoral hernia repair are performed every year around the world with 800,000 cases in the US as of 2003. The UK reports around 70,000 cases performed every year. Groin hernias account for almost 75% of all abdominal wall hernias with the lifetime risk of an inguinal hernia in men and women being 27% and 3% respectively. Men account for nearly 90% of all repairs performed and have a bimodal incidence of inguinal hernias peaking at 1 year of age and again in those over the age of 40. Although women account for roughly 70% of femoral hernia repairs, indirect inguinal hernias are still the most common subtype of groin hernia in both males and females. Inguinal hernia surgery is also one of the most common surgical procedures, with an estimated incidence of 0.8-2% and increasing up to 20% in preterm children. == Indications for surgery == Surgical intervention for hernias is guided by various factors, including the severity of symptoms, hernia type, medical history, hernia size, bowel incarceration (bowel can no longer return to the abdomen) and the overall general health of the person. === Non-urgent repair === Elective surgery is planned in order to help relieve symptoms, respect the person's preference, and prevent future complications that may require emergency surgery. Surgery is offered to the majority of people who: have symptoms that interfere with their normal level of activity. have hernias that become increasingly difficult to reduce. are female as it is often difficult to classify the subtype of hernia based on an exam alone. Symptomatic hernias tend to cause pain or discomfort within the groin region that may increase with exertion and improve with rest. A swollen scrotum within males may coincide with persistent feelings of heaviness or generalized lower abdominal discomfort. The sensation of groin pressure tends to be most prominent at the end of the day as well as after strenuous activities. Changes in sensation may be experienced along the scrotum and inner thigh. === Urgent repair === A hernia in which the small intestine has become incarcerated or strangulated constitutes a surgical emergency. Symptoms include: Fever Nausea and vomiting Extreme pain in the area of the hernia Warm hernia bulge with surrounding skin redness Can no longer pass gas or stool Surgical repair within 6 hours of the above symptoms may be able to save the strangulated portion of the intestine. Although pediatric inguinal hernias sometimes present asymptomatically, surgical repair is still the standard of care to prevent hernia incarceration, which for children who are born with hernias has a risk of 12% in full-term children and 39% in preterm children. In preterm neonates, the timing for intervention appears to be of utter importance as surgical hernia repair after neonatal intensive care unit (NICU) discharge might decrease recurrence and anesthesia-induced respiratory difficulties compared to surgery before NICU discharge. == Contraindications to surgery == The person with the hernia should be given an opportunity to participate in the shared decision-making with their physicians as almost all procedures carry significant risks. The benefits of inguinal hernia repair can become overshadowed by risks such that elective repair is no longer in a person's best interest. Such cases include: People with unstable medical conditions Repair using mesh is withheld if a person has an active infection within the groin or within the blood stream Elective repair is delayed in pregnant women until 4 weeks after delivery Additionally, certain medical conditions can prevent people from being candidates for laparoscopic approaches to repair. Examples of such include: People who are unable to undergo general anesthesia Prior major open abdominal surgery People who have ascites Previous radiation therapy to the pelvis A complex hernia == Surgical approaches == Techniques to repair inguinal hernias fall into two broad categories termed "open" and "laparoscopic". Surgeons tailor their approach by taking into account factors such as their own experience with either techniques, the features of the hernia itself, and the person's anesthetic needs. The cost associated with either approach varies widely across regions, but updated guidelines published by the International Endohernia Society (IES) cast doubt on the comprehensiveness of cost comparison studies due in part to the complexity inherent in calculating costs across institutions. The IES asserts that hospital and societal costs are lower for laparoscopic repairs as compared to open approaches. They recommend the routine use of reusable instruments as well as improving the proficiency of surgeons to help further decrease costs as well as time spent in the OR. However, as an example, the UK's National Health Service spends £56 million a year in repairing inguinal hernias, 96% of which were repaired via the open mesh approach while only 4% were done laparoscopically. === Open hernia repair === All techniques involve an approximate 10-cm incision in the groin. Once exposed, the hernia sac is returned to the abdominal cavity or excised and the abdominal wall is very often reinforced with mesh. There are many techniques that do not utilize mesh and have their own situations where they are preferable. Open repairs are classified via whether prosthetic mesh is utilized or whether the patient's own tissue is used to repair the weakness. Prosthetic repairs enable surgeons to repair a hernia without causing undue tension in the surrounding tissues while reinforcing the abdominal wall. Repairs with undue tension have been shown to increase the likelihood that the hernia will recur. Repairs not using prosthetic mesh are preferable options in patients with an above-average risk of infection such as cases where the bowel has become strangulated (blood supply lost due to constriction). One large benefit of this approach lies in its ability to tailor anesthesia to a person's needs. People can be administered local anesthesia, a spinal block, as well as general anesthesia. Local anesthesia has been shown to cause less pain after surgery, shorten operating times, shorten recovery times as well as decrease the need to return to the hospital. However, people who undergo general anesthesia tend to be able to go home faster and experience fewer complications. The European Hernia Society recommends the use of local anesthesia particularly for people with ongoing medical conditions. ==== Open mesh repairs ==== Repairs that utilize mesh are usually the first recommendation for the vast majority of patients including those that undergo laparoscopic repair. Procedures that employ mesh are the most commonly performed as they have been able to demonstrate better results compared to non-mesh repairs. Approaches utilizing mesh have been able to demonstrate faster return to usual activity, lower rates of persistent pain, shorter hospital stays, and a lower likelihood that the hernia will recur. Options for mesh include either synthetic or biologic. Synthetic mesh provides the option of using "heavyweight" as well as "lightweight" variations according to the diameter and number of mesh fibers. Lightweight mesh has been shown to have fewer complications related to the mesh itself than its heavyweight counterparts. It was additionally correlated with lower rates of chronic pain while sharing the same rates of hernia recurrence as compared to heavyweight options. This has led to the adoption of lightweight mesh for minimizing the chance of chronic pain after surgery. Biologic mesh is indicated in cases where the risk of infection is a major concern such as cases in which the bowel has become strangulated. They tend to have lower tensile strength than their synthetic counterparts lending them to higher rates of mesh rupture. Biomeshes are increasingly popular since their first use in 1999 and their subsequent introduction to the market in 2003. Some have a similar price to high end synthetic meshes. They can be produced from absorbable, animal-sourced extra cellular matrix, or by other means. Synthetic absorbable meshes are also available. Meshes made of mosquito net cloth, in copolymer of polyethylene and polypropylene have been used for low-income patients in rural India and Ghana. Each piece costs $0.01, 3700 times cheaper than an equivalent commercial mesh. They give results identical to commercial meshes in terms of infection and recurrence rate at 5 years. ===== Lichtenstein technique ===== The Lichtenstein tension-free repair has persisted as one of the most commonly performed procedures in the world. The European Hernia Society recommends that in cases where an open approach is indicated, the Lichtenstein technique be utilized as the preferred method. Recent studies have indicated that mesh attachment with the use of adhesive glue is faster and less likely to cause post-op pain as compared to attachment via suture material. ===== Plug and patch technique ===== The plug and patch tension-free technique has fallen out of favor due to higher rates of mesh shift along with its tendency to irritate surrounding tissue. This has led to the European Hernia Society recommending that the technique not be used in most cases. ===== Other open mesh repair techniques ===== A variety of other tension-free techniques have been developed and include: Prolene mesh system (PHS) Kugel (preperitoneal repair) Stoppa Trabucco (Hertra mesh) Wantz Rutkow/Robbins Modified APP ==== Open non-mesh repairs ==== Techniques in which mesh is not used are referred to as tissue repair technique, suture technique, and tension technique. All involve bringing together the tissue with sutures and are a viable alternative when mesh placement is contraindicated. Such situations are most commonly due to concerns of contamination in cases where there are infections of the groin, strangulation or perforation of the bowel. ===== Shouldice technique ===== The Shouldice technique is the most effective non-mesh repair thus making it one of the most commonly utilized methods. Numerous studies have been able to validate the conclusion that patients have lower rates of hernia recurrence with the Shouldice technique as compared to other non-mesh repair techniques. However this method frequently experiences longer procedure times and length of hospital stay. Despite being the superior non-mesh technique, the Shouldice method results much higher rates of hernia recurrence in patients when compared to repairs that utilize mesh. ===== Bassini technique ===== The Bassini technique, described by Edoardo Bassini in the 1880s, was the first efficient inguinal hernia repair. In this technique, the conjoint tendon (formed by the distal ends of the transversus abdominis and internal oblique muscles) is approximated to the inguinal ligament and closed. ===== Other open non-mesh techniques ===== The Shouldice technique was itself an evolution of prior techniques that had greatly advanced the field of inguinal hernia surgery. Such classic open non-mesh repairs include: McVay technique Halsted Maloney darn Plication darn Desarda technique A 1–2 cm strip of the external oblique aponeurosis is stitched below to the inguinal ligament and above to the muscle arch without disturbing its continuity at either end. This gives immediate protection, so no restrictions on activities are required. The procedures results in very low recurrence and complication rates. === Laparoscopic repair === There are two main methods of laparoscopic repair: transabdominal preperitoneal (TAPP) and totally extra-peritoneal (TEP) repair. When performed by a surgeon experienced in hernia repair, laparoscopic repair causes fewer complications than Lichtenstein, particularly less chronic pain. However, if the surgeon is experienced in general laparoscopic surgery but not in the specific subject of laparoscopic hernia surgery, laparoscopic repair is not advised as it causes more recurrence risk than Lichtenstein while also presenting risks of serious complications, as organ injury. All that said, many surgeons are shifting to using laparoscopic techniques as they require smaller incisions, and result in less bleeding, lower infection rates, faster recovery, shorter hospitalization periods, and reduced chronic pain. Recurrence rates are identical when laparoscopy is performed by an experienced surgeon. When performed by a surgeon less experienced in inguinal hernia lap repair, recurrence is larger than after Lichtenstein. ==== Robotic surgery ==== Robot assisted repair of inguinal hernias has demonstrated safety and efficacy in surgeries repairing inguinal hernias that present on both sides of the pubic bone (bilateral) as well as inguinal hernias that present on one side (unilateral). In comparing robot assisted repair of inguinal hernias to traditional laparoscopic techniques, robot assisted surgeries repairing inguinal hernias have longer operating times and can be more costly. However, measures of safety, complication rates, and readmission rates did not significantly differ between robot assisted repair and traditional laparoscopic repair. == Non-surgical management == Studies have demonstrated that men whose hernias cause little to no symptoms can safely continue to delay surgery until a time that is most convenient for patients and their healthcare team. Research shows that the risk of inguinal hernia complications remains under 1% within the population. Watchful waiting requires that patients maintain a close follow-up schedule with providers to monitor the course of their hernia for any changes in symptoms and can be safely offered for up to 2 years. Patients who do elect watchful waiting eventually undergo repair within five years as 25% will experience a progression of symptoms such as worsening of pain. Elective repair discussions should be revisited if patients begin to avoid aspects of their normal routine due to their hernia. After 1 year it is estimated that 16% of patients who initially opted for watchful waiting will eventually undergo surgery. Furthermore, 54% and 72% will undergo repair at 5-year and 7.5-year marks respectively. The use of a truss is an additional non-surgical option for men. It resembles a jock-strap that utilizes a pad to exert pressure at the site of the hernia in order prevent excursion of the hernia sack. It has little evidence to support its routine use and has not been shown to prevent complications such as incarceration (bowel can no longer slide back into abdomen) or strangulation of bowel (constriction causing loss of blood supply). However some patients do report a soothing of symptoms when utilized. == Complications and prognosis == Inguinal hernia repair complications are unusual, and the procedure as a whole proves to be relatively safe for the majority of patients. Risks inherent in almost all surgical procedures include: bleeding infection fluid collections damage to surrounding structures such as blood vessels, nerves, or the bladder urinary retention requiring a catheter risks of general anaesthetic (used for laparoscopic hernia repair and most open hernia repairs) Risks that are specific to inguinal hernia repairs include such things as: recurrence of the hernia impairment of sexual activity, such as genital or ejaculatory pain in males, injury to the tube that conveys sperm from the testicle to the penis in males, bruising and swelling of the scrotum chronic regional pain (also known as post-herniorrhaphy inguinodynia, or chronic postoperative inguinal pain) === Post-herniorraphy pain syndrome === Post-herniorrhaphy inguinodynia is a condition where 10-12% of patients experience severe pain after inguinal hernia repair, due to a complex combination of different forms of pain signals. It can occur with any inguinal hernia repair technique, and if unresponsive to pain medications, further surgical intervention is often required. Removal of the implanted mesh, in combination with bisection of regional nerves, is commonly performed to address such cases. There remains ongoing discussion amongst surgeons regarding the utility of planned resections of regional nerves as an attempt to prevent its occurrence. === Mortality rates === Mortality rates for non-urgent, elective procedures was demonstrated as 0.1%, and around 3% for procedures performed urgently. Other than urgent repair, risk factors that were also associated with increased mortality included being female, requiring a femoral hernia repair, and older age. == Follow-up == Upon awakening from anesthesia, patients are monitored for their ability to drink fluids, produce urine, as well as their ability to walk after surgery. Most patients are then able to return home once those conditions are met. It is not uncommon for patients to experience residual soreness for a couple of days after surgery. Patients are encouraged to make strong efforts in getting up and walking around the day after surgery. Most patients can resume their normal routine of daily living within the week such as driving, showering, light lifting, as well as sexual activity. Long work absences are rarely necessary and length of sick days tend to be dictated by respective employment policies. In general, it is not recommended to administer antibiotics as prophylaxis after elective inguinal hernia repair. However, the rate of wound infection determines the appropriate use of the antibiotics. Post-op development of any of the following should warrant timely reporting via phone: fever greater than 39C/101F progressive swelling of the surgical site severe pain recurring nausea or vomiting worsening redness around incisions drainage of pus from incisions difficulty or lack of producing urine new-onset shortness of breath == Prevention and screening == Most indirect inguinal hernias in the abdominal wall are not preventable. Direct inguinal hernias may be prevented by maintaining a healthy weight, refraining from smoking, preventing straining during bowel movements, and maintaining proper lifting techniques when heavy lifting. There is no evidence that indicates physicians should routinely screen for asymptomatic inguinal hernias during patient visits. == References ==	Wikipedia/Inguinal_hernia_surgery
Endoscopic retrograde cholangiopancreatography (ERCP) is a technique that combines the use of endoscopy and fluoroscopy to diagnose and treat certain problems of the biliary or pancreatic ductal systems. It is primarily performed by highly skilled and specialty trained gastroenterologists. Through the endoscope, the physician can see the inside of the stomach and duodenum, and inject a contrast medium into the ducts in the biliary tree and/or pancreas so they can be seen on radiographs. ERCP is used primarily to diagnose and treat conditions of the bile ducts and main pancreatic duct, including gallstones, inflammatory strictures (scars), leaks (from trauma and surgery), and cancer. ERCP can be performed for diagnostic and therapeutic reasons, although the development of safer and relatively non-invasive investigations such as magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound has meant that ERCP is now rarely performed without therapeutic intent. == Medical uses == === Diagnostic === The following represent indications for ERCP, particularly if or when less invasive options are not adequate or definitive: Obstructive jaundice – This may be due to several causes Gallstones with dilated bile ducts on ultrasonography Indeterminate biliary strictures and suspected bile duct tumors Suspected injury to bile ducts either as a result of trauma or of iatrogenic origin Sphincter of Oddi dysfunction Chronic pancreatitis is currently a controversial indication due to widespread availability of safer diagnostic modalities including endoscopic ultrasound, CT, and MRI/MRCP Pancreatic tumors no longer represent a valid diagnostic indication for ERCP unless they cause bile duct obstruction and jaundice. Endoscopic ultrasound represents a safer and more accurate diagnostic alternative === Therapeutic === ERCP may be indicated in the above diagnostic scenarios when any of the following are needed: Endoscopic sphincterotomy of the sphincter of Oddi Extraction of gallstones or other biliary debris Insertion of a stent through the major duodenal papilla and ampulla of Vater into the common bile duct and/or the pancreatic duct Dilation of strictures (e.g. primary sclerosing cholangitis, anastomotic strictures after liver transplantation) Extraction of liver flukes from the biliary system (e.g., opisthorchiasis, clonorchiasis, fasciolosis) == Contraindications == Acute pancreatitis (unless persistently elevated or rising bilirubin suggests ongoing obstruction) (Irreversible) coagulation disorder if sphincterotomy planned Recent myocardial infarction or pulmonary embolism Severe cardiopulmonary disease or other serious morbidity Hypersensitivity to iodinated contrast medium or a history of iodinated contrast dye anaphylaxis is not a contraindication of ERCP, though it should be discussed with your health provider, and you should tell them you are allergic to iodine, as an alternative contrast iodine-free material ("dye") is then injected gently into the ducts (pancreatic or biliary) and x-rays are taken. == Procedure == The patient is sedated or anaesthetized. Then a flexible camera (endoscope) is inserted through the mouth, down the esophagus, into the stomach, through the pylorus into the duodenum where the ampulla of Vater (the union of the common bile duct and pancreatic duct) exists. The sphincter of Oddi is a muscular valve that controls the opening to the ampulla. The region can be directly visualized with the endoscopic camera while various procedures are performed. A plastic catheter or cannula is inserted through the ampulla, and radiocontrast is injected into the bile ducts and/or pancreatic duct. Fluoroscopy is used to look for blockages, or other lesions such as stones. When needed, the sphincters of the ampulla and bile ducts can be enlarged by a cut (sphincterotomy) with an electrified wire called a sphincterotome for access into either so that gallstones may be removed or other therapy performed. Other procedures associated with ERCP include the trawling of the common bile duct with a basket or balloon to remove gallstones and the insertion of a plastic stent to assist the drainage of bile. Also, the pancreatic duct can be cannulated and stents be inserted. The pancreatic duct requires visualisation in cases of pancreatitis. Ultrasound is frequently the first investigation performed on admission; although it has little value in the diagnosis of pancreatitis or its complications. contrast-enhanced computed tomography (MD-CECT) is the most used imaging technique. However, magnetic resonance imaging (MRI) offers diagnostic capabilities similar to those of CT, with additional intrinsic advantages including lack of ionizing radiation and exquisite soft tissue characterization. In specific cases, other specialized or ancillary endoscopes may be used for ERCP. These include mother-baby and SpyGlass cholangioscopes (to help in diagnosis by directly visualizing the duct as opposed to only obtaining X-ray images) as well as balloon enteroscopes (e.g. in patients that have previously undergone digestive system surgery with post-Whipple or Roux-en-Y surgical anatomy). == Risks == One of the most frequent and feared complications after endoscopic retrograde cholangiopancreatography (ERCP) is post-ERCP pancreatitis (PEP). In previous studies, the incidence of PEP has been estimated at 3.5 to 5%. According to Cotton et al., PEP is defined as a "clinical pancreatitis with amylase at least three times the upper limit of normal at more than 24 hours after the procedure requiring hospital admission or prolongation of planned admission". Grading of severity of PEP is mainly based on the length of hospital stay. Risk factors for developing PEP include technical matters related to the ERCP procedure and patient-specific ones. The technical factors include manipulation of and injection of contrast into the pancreatic duct, cannulation attempts lasting more than five minutes, and biliary balloon sphincter dilation; among patient-related factors are female gender, younger age, and Sphincter of Oddi dysfunction. A systematic review of clinical trials concluded that a previous history of PEP or pancreatitis significantly increases the risk for PEP to 17.8% and to 5.5% respectively. Intestinal perforation is a risk of any gastroenterologic endoscopic procedure, and is an additional risk if a sphincterotomy is performed. As the second part of the duodenum is anatomically in a retroperitoneal location (that is, behind the peritoneal structures of the abdomen), perforations due to sphincterotomies are retroperitoneal. Sphincterotomy is also associated with a risk of bleeding. ERCP may provoke hemobilia from trauma to friable hilar tumors or a guide-wire penetrating the bile duct wall, creating a biliary fistula. Delayed bleeding is a rare but potentially serious complication of sphincterotomy, particularly as many patients are discharged home within hours of ERCP. There is also a risk associated with the contrast dye in patients who are allergic to compounds containing iodine, which can be very severe, even if the anaphylactoid reactions occur while patients are in a hospital. Oversedation can result in dangerously low blood pressure, respiratory depression, nausea, and vomiting. Other complications (less than 1%) may include heart and lung problems, infection in the bile duct called cholangitis, that can be life-threatening, and is regarded as a medical emergency. Using antibiotics before the procedure shows some benefits to prevent cholangitis and septicaemia. In rare cases, ERCP can cause fatal complications. Cases of hospital-acquired (i.e., nosocomial) infections with carbapenem resistant enterobacteriaceae linked to incompletely disinfected duodenoscopes have occurred in the U.S. since at least 2009 per the Food and Drug Administration. Outbreaks were reported from Virginia Mason Hospital in Seattle in 2013, UCLA Health System Los Angeles in 2015, Chicago and Pittsburgh. The FDA issued a safety communication "Design of ERCP Duodenoscopes May Impede Effective Cleaning" in February 2015, which was updated in December 2015, and more recently in 2022 which recommended disposable components. Prevalence of vitamin K and vitamin D deficiency, as bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of fat-soluble vitamins. == See also == Percutaneous transhepatic cholangiography Reynolds' pentad Charcot's cholangitis triad Primary sclerosing cholangitis == References == == External links == MedlinePlus Encyclopedia: ERCP National Digestive Diseases Information Clearinghouse Endoscopy Campus, Archives and Videos	Wikipedia/Endoscopic_retrograde_cholangiopancreatography
Relative energy deficiency in sport (RED-S) is a syndrome in which disordered eating (or low energy availability), amenorrhoea/oligomenorrhoea (in women), and decreased bone mineral density (osteoporosis and osteopenia) are present. It is caused by eating too little food to support the amount of energy being expended by an athlete, often at the urging of a coach or other authority figure who believes that athletes are more likely to win competitions when they have an extremely lean body type. RED-S is a serious illness with lifelong health consequences and can potentially be fatal. RED-S is the broader, more comprehensive name for what was formerly known as the female athlete triad (or simply the triad), which was a condition seen in females participating in sports that emphasize leanness or low body weight. As the non-menstrual components are also seen in males, the name was changed to the comprehensive term RED-S. == Classification == Formerly known as the female athlete triad, RED-S is a syndrome of three interrelated conditions. Thus, if an athlete is suffering from one element of the triad, it is likely that they are suffering from the other two components of the triad as well. With the increase in female participation in sports, the incidence of a triad of disorders particular to women—the female athlete triad—has also increased. The female athlete triad and its relationship with athletics was identified in the 1980s as the prevalence increased during this period, and symptoms, risk factors, causes, and treatments were studied in depth and their relatedness evaluated. The condition is most common in sports that emphasize leanness, such as cross country running, gymnastics, and figure skating. Many of those who suffer from the triad are involved in some sort of athletics, in order to promote weight loss and leanness. The competitive sports that promote this physical leanness may result in disordered eating and be responsible for the origin of the female athlete triad. For some women, the disorder can have major health consequences. In addition, for some competitive female athletes, problems such as low self-esteem, a tendency toward perfectionism, and family stress place them at risk for disordered eating. == Signs and symptoms == Clinical symptoms of RED-S may include disordered eating, fatigue, hair loss, cold hands and feet, dry skin, noticeable weight loss, increased healing time from injuries (e.g., lingering bruises), increased incidence of bone fracture and cessation of menses. Affected athletes may also struggle with low self-esteem and depression. Upon physical examination, a physician may also note the following symptoms: elevated carotene in the blood, anemia, orthostatic hypotension, electrolyte irregularities, hypoestrogenism, vaginal atrophy, and bradycardia. An athlete may show signs of restrictive eating, but not meet the clinical criteria for an eating disorder. They may also display subtle menstrual disturbances, such as a change in menstrual cycle length, anovulation, or luteal phase defects, but not yet have developed complete amenorrhea. Likewise, an athlete's bone density may decrease, but may not yet have dropped below her age-matched normal range. These signs can be considered "occult," as no one symptom may be severe enough to seek medical attention, leaving the triad to go unnoticed or untreated. Although the larger scientific community has not agreed upon a clear recommendation for ideal energy intake, physicians may take note of female athletes consuming under 30 kcal per kilogram of fat free mass (FFM) per day. === Disordered eating === Energy availability is defined as energy intake minus energy expended. Energy is taken in through food consumption. Bodies expend energy through normal functioning as well as through exercise. In the case of RED-S, low energy availability may be due to eating disorders, but not necessarily so. Athletes may experience low energy availability by exercising more without a concomitant change in eating habits, or they may increase their energy expenditure while also eating less. Disordered eating is defined among this situation due to the low caloric intake or low energy availability. While most athletes do not meet the clinical criteria to be diagnosed with an eating disorder such as anorexia nervosa or bulimia nervosa, many still exhibit subclinical disordered eating, along with general psychopathology associated with eating disorders (anxiety, depression, obsessive-compulsive symptoms. Particularly, excessive fasting and avoidance of certain types of food (such as foods containing fat) arise commonly in athletes. Especially in weight-class sports, leanness-dependent sports, and aesthetic sports, the prevalence of eating disorders soar much higher than the average population. In athletes that engage in such sports, the pressure to perform promotes excessive dieting and other disordered eating habits, as athletes try to conform to expected weight patterns. More severe examples of disordered eating habits may include binge-eating; purging; and the use of diet-pills, laxatives, diuretics, and enemas. By restricting their diet, the athlete may worsen their problem of low energy availability. Having low dietary energy from excessive exercise or dietary restrictions leaves too little energy for the body to carry out normal functions such as maintaining a regular menstrual cycle or healthy bone density. === Amenorrhea === Amenorrhea, defined as the cessation of the menstrual cycle for more than three months, is the second disorder in the triad. Weight fluctuations from dietary restrictions and/or excessive exercise affect the hypothalamus' output of gonadotropic hormones. Gonadotropic hormones “stimulate growth of the gonads and the secretion of sex hormones”, (e.g. gonadotropin-releasing hormone, lutenizing hormone and follicle stimulating hormone). These gonadotropic hormones play a role in stimulating estrogen release from the ovaries. Without estrogen release, the menstrual cycle is disrupted. Exercising intensely and not eating enough calories can lead to decreases in estrogen, the hormone that helps to regulate the menstrual cycle. As a result, periods may become irregular or stop altogether. There are two types of amenorrhea. A person who has been having her period and then stops menstruating for ninety days or more is said to have secondary amenorrhea. In the case of RED-S, the majority of secondary amenorrhea cases are attributed to functional hypothalamic amenorrhea (FHA), an adaptive mechanism to preserve energy for survival and vital processes rather than reproduction when energy balance is low. Primary amenorrhea is characterized by delayed menarche (the onset of menses during puberty). Delayed menarche may be associated with delay of the development of secondary sexual characteristics. === Osteoporosis === Osteoporosis is defined by the National Institutes of Health as ‘‘a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture.’’ Low estrogen levels and poor nutrition, especially low calcium intake, can lead to osteoporosis, the third aspect of the triad. This condition can ruin an athlete's career because it may lead to stress fractures and other injuries. Patients with RED-S get osteoporosis due to hypoestrogenemia, or low estrogen levels. With estrogen deficiency, the osteoclasts live longer and are therefore able to resorb more bone. In response to the increased bone resorption, there is increased bone formation and a high-turnover state develops which leads to bone loss and perforation of the trabecular plates. As osteoclasts break down bone, patients see a loss of bone mineral density (BMD). Low BMD renders bones more brittle and hence susceptible to fracture. Because athletes are active and their bones must endure mechanical stress, the likelihood of experiencing bone fracture is particularly high. Additionally, because those suffering with RED-S are also restricting their diet, they may also not be consuming sufficient amounts vitamins and minerals which contribute to bone density; not getting enough calcium or vitamin D further exacerbates the problem of weak bones. Bone mass is now thought to peak between the ages of 18 and 25. Thus, behaviors which result in low bone density in youth could be detrimental to an athlete's bone health throughout their lifetime. In addition, ovulation is the primary way that females create the hormone progesterone. When an ovum is released from the ovary, the structure that remains develops into the corpus luteum. The corpus luteum emits the hormone progesterone during the 10–16 days of the luteal phase. Without experiencing regular, ovulatory menstrual cycles, the female is not secreting the hormone progesterone during the luteal phase of her cycle. Progesterone directly stimulates osteoblasts to make new bone. Therefore, if the woman is not ovulating, she is not creating progesterone, and misses out on this opportunity to stimulate new bone growth. == Causes == Gymnastics, figure skating, ballet, diving, swimming, and long-distance running are examples of sports which emphasize low body weight. The triad is seen more often in aesthetic sports such as these versus ball game sports. People taking part in these sports may be at an increased risk for developing RED-S. Athletes at greatest risk for low energy availability are those who restrict dietary energy intake, who exercise for prolonged periods, who are vegetarian, and who limit the types of food they will eat. Many factors appear to contribute to disordered eating behaviors and clinical eating disorders. Dieting is a common entry point and interest has focused on the contribution of environmental and social factors, psychological predisposition, low self-esteem, family dysfunction, abuse, biological factors, and genetics. In some cases, financial hardship and food insecurity produce disordered eating habits. Additional factors for athletes include early start of sport-specific training and dieting, injury, and a sudden increase in training volume. Surveys show more negative eating attitude scores in athletic disciplines favoring leanness. Disordered eating behaviors are risk factors for eating disorders. == Treatment == The underlying cause of the RED-S is an imbalance between energy taken into the body (through nutrition) and energy used by the body (through exercise). The treatment includes correcting this imbalance by either increasing calories in a diet or by decreasing calories burned by exercise for 12 months or longer. Typically, it is recommended that athletes increase their consumption of calories by 300–600 kcal per day in the early stages of treatment, but there is no standard when it comes to increasing calories over time. Part of the treatment includes an assessment that determines the cause of low energy availability, as treatment needs to be specialized based on the presence of disordered eating or an eating disorder. Persons with RED-S should get treatment from a multi-disciplinary team that includes a physician, dietitian, and mental health counselor, and seek support from family, friends, and their coach. It is important that physicians are aware of the signs of refeeding syndrome, as this can be life-threatening if not detected early. Because a symptom of the RED-S is menstrual dysfunction, some physicians may recommend oral contraceptives because those pills will regulate the menstrual cycle. However, the underlying cause of the menstrual disorder is an energy imbalance, and using pills to regulate the menstrual cycle without changes in diet and behavior is likely to mask the food deficiency and delay appropriate treatment. A menstruating person taking contraceptives to treat menstrual dysfunction without correcting this energy imbalance will continue to lose bone density. Bone density should be measured using dual-energy X-ray absorpitiometry (DEXA) to determine severity of bone loss, especially if there is an absence of menstruation. === Decreasing energy expenditure === Continued participation in training and competition depends on the physical and mental health of the athlete. Athletes who weigh less than 80 percent of their ideal body weight may not be able to safely participate. Persons with RED-S are often asked by health care providers to reduce the amount of time they spend exercising by 10–12 percent. === Increasing energy intake === Low energy availability with or without eating disorders, functional hypothalamic amenorrhea, and osteoporosis, alone or in combination, pose significant health risks to physically active girls and women. Prevention, recognition, and treatment of these clinical conditions should be a priority of those who work with female athletes to ensure that they maximize the benefits of regular exercise. Patients are recommended to work with a dietician who can monitor their nutritional status and help the patient work towards a healthy goal weight. Patients should also meet with a psychiatrist or psychologist to address the psychological aspects of the triad. Therefore, it is important that trainers and coaches are made aware of the athlete's condition and be part of her recovery. === Medicine === Patients are also sometimes treated pharmacologically. To both induce menses and improve bone density, doctors may prescribe cyclic estrogen or progesterone as is used to treat post-menopausal women. Patients may also be put on oral contraceptives to stimulate regular periods. In addition to hormone therapy, nutrition supplements may be recommended. Doctors may prescribe calcium supplements. Vitamin D supplements may be also used because this vitamin aids in calcium absorption. Bisphosphonates and calcitonin, used to treat adults with osteoporosis, may be prescribed, although their effectiveness in adolescents has not yet been established. Finally, if indicated by a psychiatric examination, the affected athlete may be prescribed anti-depressants and in some cases benzodiazepines to help in alleviating severe distress at mealtimes. === Psychological treatment === Although relative energy deficiency in sport is often regarded as a physiological issue, it can have psychological impacts in the process of treatment and psychological stress may contribute to the development of RED-S, as athletes may use excessive exercise and decreased energy consumption as a means to manage stress levels. Many athletes strive for perfection and this can exacerbate mental stress as well as put athletes at a greater risk for developing an eating disorder. The main reasons why athletes would be resistant to treatment for RED-S is due to psychological factors. A mental health counselor who is experienced in eating disorders should provide treatment. If there are other comorbid psychological disorders, such as depression and anxiety, a risk of self harm, medical complications and lack of progress in an outpatient level of care, the person struggling with RED-S may need more intensive care at an inpatient, residential, partial hospitalization or intensive outpatient level. At each level of care, treatment modalities include cognitive-behavioral therapy, dialectical behavioral therapy or family-based therapy. == Prognosis == Sustained low energy availability, with or without disordered eating, can impair health. Psychological problems associated with eating disorders include low self-esteem, depression, and anxiety disorders. Medical complications involve the cardiovascular, endocrine, reproductive, skeletal, gastrointestinal, renal, and central nervous systems. The prognosis for anorexia nervosa is grave with a six-fold increase in standard mortality rates compared to the general population. In one study, 5.4% of athletes with eating disorders reported suicide attempts. Although 83% of anorexia nervosa patients partially recover, the rate of sustained recovery of weight, menstrual function and eating behavior is only 33%. Amenorrheic women can be infertile, due to the absence of ovarian follicular development, ovulation, and luteal function. Consequences of hypoestrogenism seen in amenorrheic athletes include impaired endothelium-dependent arterial vasodilation, which reduces the perfusion of working muscle, impaired skeletal muscle oxidative metabolism, elevated low-density lipoprotein cholesterol levels, and vaginal dryness. Due to low bone mineral density that declines as the number of missed menstrual cycles accumulates, and the loss of BMD may not be fully reversible. Stress fractures occur more commonly in physically active women with menstrual irregularities and/or low BMD with a relative risk for stress fracture two to four times greater in amenorrheic than eumenorrheic athletes. Fractures also occur in the setting of nutritional deficits and low BMD. == Society and culture == The American Academy of Pediatrics and the AAFP contend that exercise is important and should be promoted in girls for health and enjoyment; however, pediatricians should be wary of health problems that may occur in female athletes. The health related issues concerning this topic are grave and can lead to numerous health issues as previously demonstrated. The treatment plan will depend on the severity of the disorder, however some form of treatment has been shown as helpful to produce successful progress towards a better health condition. Clearly, many health problems arise due to disordered eating. Coaches are discouraged from active participation in the treatment of eating disorders. In addition to conflicts of interest, coaches may be perceived to pressure athletes and potentially perpetuate components of RED-S. For example, in maintaining a place on the team or continued scholarship support, a female athlete may feel compelled to overtrain or restrict eating. === Male athletes === Relative energy deficiency in sport is also common among male athletes, especially those in sports that encourage weight-cycling and low weight. There is currently insufficient empirical data available on RED-S in this population. The risk of RED-S is heightened in "road cyclists, rowers (lightweight and open weight), athletes in combat sports, distance runners, and jockeys." Male athletes who undergo long periods of low energy availability experience decreased androgen levels, bone mineral density, and overall strength. They also experience increases in cardiovascular disease, prevalence of bone fractures and mood disorders. Both male and female athletes are recommended treatment plans that focus on decreasing energy expenditure, increasing energy intake in addition to pharmacological and psychological treatment. == See also == Body dysmorphic disorder Gonadotropin List of medical triads, tetrads, and pentads == References == == Further reading == Heywood, Leslie (1998). Pretty Good for a Girl. Free Press. ISBN 978-0-684-85070-2.	Wikipedia/Relative_energy_deficiency_in_sport
Remote diagnostics is the act of diagnosing a given symptom, issue or problem from a distance. Instead of the subject being co-located with the person or system done diagnostics, with remote diagnostics the subjects can be separated by physical distance (e.g., Earth-Moon). Important information is exchanged either through wire or wireless. When limiting to systems, a general accepted definition is: "To improve reliability of vital or capital-intensive installations and reduce the maintenance costs by avoiding unplanned maintenance, by monitoring the condition of the system remotely." == Process elements for remote diagnostics == Remotely monitor selected vital system parameters Analysis of data to detect trends Comparison with known or expected behavior data After detected performance degradation, predict the failure moment by extrapolation Order parts and/or plan maintenance, to be executed when really necessary, but in time to prevent a failure or stop == Typical uses == Medical use (see Remote guidance) Formula One racecars Space (Apollo project and others) Telephone systems like a PABX Connected cars == Reasons for use == Limit local personnel to a minimum (Gemini, Apollo capsules: too tight to fit all technicians) Limit workload of local personnel Limit risks (exposure to dangerous environments) Central expertise (locally solve small problems, remotely/centralized solve complex problems by experts) Efficiency: reduce travel time to get expert and system or subject together == Remote diagnostics and maintenance == Remote diagnostics and maintenance refers to both diagnoses of the fault or faults and taking corrective (maintenance) actions, like changing settings to improve performance or prevent problems like breakdown, wear and tear. RDM can replace manpower at location by experts on a central location, in order to save manpower or prevent hazardous situations (space for instance). Increasing globalisation and more and more complicated machinery and software, also creates the wish to remote engineering, so travel over growing distances of experienced and expensive engineering personnel is limited. == See also == Real-time computing == References ==	Wikipedia/Remote_diagnosis
Preimplantation genetic diagnosis (PGD or PIGD) is the genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal diagnosis. When used to screen for a specific genetic disease, its main advantage is that it avoids selective abortion, as the method makes it highly likely that the baby will be free of the disease under consideration. PGD thus is an adjunct to assisted reproductive technology, and requires in vitro fertilization (IVF) to obtain oocytes or embryos for evaluation. Embryos are generally obtained through blastomere or blastocyst biopsy. The latter technique has proved to be less deleterious for the embryo, therefore it is advisable to perform the biopsy around day 5 or 6 of development. The world's first PGD was performed by Handyside, Kontogianni and Winston at the Hammersmith Hospital in London. "Female embryos were selectively transferred in five couples at risk of X-linked disease, resulting in two twin and one singleton pregnancy." The term preimplantation genetic screening (PGS) refers to the set of techniques for testing whether embryos (obtained through IVF/ ICSI have an abnormal number of chromosomes (aneuploidy). PGS is also called aneuploidy screening. PGS was renamed preimplantation genetic diagnosis for aneuploidy (PGD-A) by the Preimplantation Genetic Diagnosis International Society (PGDIS) in 2016. The PGD allows studying the DNA of eggs or embryos to select those that carry certain mutations for genetic diseases. It is useful when there are previous chromosomal or genetic disorders in the family and within the context of in vitro fertilization programs. The procedures may also be called "preimplantation genetic profiling" to adapt to the fact that they are sometimes used on oocytes or embryos prior to implantation for other reasons than diagnosis or screening. Procedures performed on sex cells before fertilization may instead be referred to as methods of oocyte selection or sperm selection, although the methods and aims partly overlap with PGD. == History == In 1968, Robert Edwards and Richard Gardner reported the successful identification of the sex of rabbit blastocysts. It was not until the 1980s that human IVF was fully developed, which coincided with the breakthrough of the highly sensitive polymerase chain reaction (PCR) technology. Handyside, Kontogianni and Winston's first successful tests happened in October 1989, with the first births in 1990 though the preliminary experiments had been published some years earlier. In these first cases, PCR was used for sex determination of patients carrying X-linked diseases. A report in 2001 on worldwide use of PGD since 1990 reported that embryo or polar body biopsy had occurred in more than 3000 clinical cycles, with a 24% pregnancy rate, which was comparable with assisted reproductive practices which do not involve biopsy. === First clinical cases === Elena Kontogianni was studying for her PhD at the Hammersmith Hospital, on single-cell PCR for sexing, which she did by amplifying a repeated region of the Y chromosome. It was this approach that she used for the world's first PGD cases. Female embryos were selectively transferred in five couples at risk of X-linked disease, resulting in two twins and one singleton pregnancy. Because the Y chromosome region Kontogianni was amplifying contained many repeats, it was more efficient than trying to amplify a unique region. A band on the PCR gel indicated that the embryo was male and the absence of a band indicated that the embryo was female. However, amplification failure or an anucleate blastomere also resulted in absence of a band on the PCR gel. To reduce the risk of misdiagnosis, Kontogianni went on to co-amplify sequences on the X and Y (Kontogianni et al., 1991). At that time nothing was known about allele dropout, cumulus cell contamination, or amplification failure from single cells. During the 1980s, human IVF embryos were exclusively transferred on day two of development as the culture medium used was incapable of reliably growing embryos past this stage. Since the biopsy was to be performed on day three, the first diagnoses were all performed in one day, with transfer of the embryos late on day three. A comparison of day two and day three transfers indicated that this would not adversely affect pregnancy rates. The worry of embryos arresting was so high that some transfers took place in the early hours of day four so that the embryos were removed from culture as soon as possible. There were many evenings at the Hammersmith when a transfer was performed at 1 a.m. on day four and researchers returned to the laboratory at 7 a.m. to start the next case. Winston helped deliver most of the first PGD babies. PGD became increasingly popular during the 1990s when it was used to determine a handful of severe genetic disorders, such as sickle-cell anemia, Tay–Sachs disease, Duchenne's muscular dystrophy, and beta-thalassemia. == Indications and applications == PGD is used primarily for genetic disease prevention, by selecting only those embryos that do not have a known genetic disorder. PGD may also be used to increase chances of successful pregnancy, to match a sibling in HLA type in order to be a donor, to have less cancer predisposition, and for sex selection. PGD is frequently employed for the detection of autosomal dominant, autosomal recessive, and X-linked abnormalities. However, its utilization in screening for mitochondrial disorders is less common, primarily due to the unpredictable characteristics of mitochondrial heteroplasmy. In cases of mitochondrial heteroplasmy, some mitochondria within a cell bear the mutation, while others do not. The ratio of mutant mitochondria plays a crucial role in determining both the expression of the disease (its impact on offspring) and the severity of the disease. === Monogenic disorders === PGD is available for a large number of monogenic disorders—that is, disorders due to a single gene only (autosomal recessive, autosomal dominant or X-linked)—or of chromosomal structural aberrations (such as a balanced translocation). PGD helps these couples identify embryos carrying a genetic disease or a chromosome abnormality, thus avoiding diseased offspring. The most frequently diagnosed autosomal recessive disorders are cystic fibrosis, Beta-thalassemia, sickle cell disease and spinal muscular atrophy type 1. The most common dominant diseases are myotonic dystrophy, Huntington's disease and Charcot–Marie–Tooth disease; and in the case of the X-linked diseases, most of the cycles are performed for fragile X syndrome, haemophilia A and Duchenne muscular dystrophy. Though it is quite infrequent, some centers report PGD for mitochondrial disorders or two indications simultaneously. PGD is also now being performed in a disease called hereditary multiple exostoses (MHE/MO/HME). In addition, there are infertile couples who carry an inherited condition and who opt for PGD as it can be easily combined with their IVF treatment. === Pregnancy chances === Preimplantation genetic profiling (PGP) has been suggested as a method to determine embryo quality in in vitro fertilization, in order to select an embryo that appears to have the greatest chances for successful pregnancy. However, as the results of PGP rely on the assessment of a single cell, PGP has inherent limitations as the tested cell may not be representative of the embryo because of mosaicism. Furthermore, a study found that diagnoses of the biopsies from the same embryos at two separate laboratories matched up only 50% of the time. A systematic review and meta-analysis of existing randomized controlled trials came to the result that there is no evidence of a beneficial effect of PGP as measured by live birth rate. On the contrary, for women of advanced maternal age, PGP significantly lowers the live birth rate. Technical drawbacks, such as the invasiveness of the biopsy, and chromosomal mosaicism are the major underlying factors for inefficacy of PGP. Normal live births of healthy offspring after transfers of embryos deemed aneuploid by PGP have been reported worldwide. Alternative methods to determine embryo quality for prediction of pregnancy rates include microscopy as well as profiling of RNA and protein expression. === HLA matching === Human leukocyte antigen (HLA) typing of embryos, so that the child's HLA matches a sick sibling, availing for cord-blood stem cell donation. The child is in this sense a "savior sibling" for the recipient child. HLA typing has meanwhile become an important PGD indication in those countries where the law permits it. The HLA matching can be combined with the diagnosis for monogenic diseases such as Fanconi anaemia or beta thalassemia in those cases where the ailing sibling is affected with this disease, or it may be exceptionally performed on its own for cases such as children with leukaemia. The main ethical argument against is the possible exploitation of the child, although some authors maintain that the Kantian imperative is not breached since the future donor child will not only be a donor but also a loved individual within the family. === Cancer predisposition === A more recent application of PGD is to diagnose late-onset diseases and (cancer) predisposition syndromes. Since affected individuals remain healthy until the onset of the disease, frequently in the fourth decade of life, there is debate on whether or not PGD is appropriate in these cases. Considerations include the high probability of developing the disorders and the potential for cures. For example, in predisposition syndromes, such as BRCA mutations which predispose the individual to breast cancer, the outcomes are unclear. Although PGD is often regarded as an early form of prenatal diagnosis, the nature of the requests for PGD often differs from those of prenatal diagnosis requests made when the mother is already pregnant. Some of the widely accepted indications for PGD would not be acceptable for prenatal diagnosis. === For late-onset conditions === A woman carrying the gene for early-onset Alzheimer's disease used preimplantation genetic diagnosis (PGD) to ensure that her child would not inherit this condition. Ethical questions arise regarding the decision to allow an individual aware of their own susceptibility to a late-onset disease to have a child free of the gene, despite the risk that the child may lose a parent prematurely. Some argue that this decision is ethical, asserting that the desire for reproduction is as legitimate for these individuals as for others seeking infertility services. Comparisons are drawn with other medical situations, such as assisted reproduction for individuals with HIV or other serious illnesses. Although the child may face risks of early bereavement, the argument put forth is that the psychological trauma does not render the child's life devoid of clear benefits. Therefore, assisting parents in reproducing in these circumstances is not considered to cause undue or unnecessary suffering to the child. === Sex discernment === Preimplantation genetic diagnosis provides a method of prenatal sex discernment even before implantation, and may therefore be termed preimplantation sex discernment. Potential applications of preimplantation sex discernment include: A complement to specific gene testing for monogenic disorders, which can be very useful for genetic diseases whose presentation is linked to the sex, such as, for example, X-linked diseases. Ability to prepare for any sex-dependent aspects of parenting. Sex selection. A 2006 survey found that 42 per cent of clinics that offer PGD have provided it for sex selection for non-medical reasons. Nearly half of these clinics perform it only for "family balancing", which is where a couple with two or more children of one sex desire a child of the other, but half do not restrict sex selection to family balancing. In India, this practice has been used to select only male embryos although this practice is illegal. Opinions on whether sex selection for non-medical reasons is ethically acceptable differ widely, as exemplified by the fact that the ESHRE Task Force could not formulate a uniform recommendation. In the case of families at risk for X-linked diseases, patients are provided with a single PGD assay of gender identification. Gender selection offers a solution to individuals with X-linked diseases who are in the process of getting pregnant. The selection of a female embryo offspring is used in order to prevent the transmission of X-linked Mendelian recessive diseases. Such X-linked Mendelian diseases include Duchenne muscular dystrophy (DMD), and hemophilia A and B, which are rarely seen in females because the offspring is unlikely to inherit two copies of the recessive allele. Since two copies of the mutant X allele are required for the disease to be passed on to the female offspring, females will at worst be carriers for the disease but may not necessarily have a dominant gene for the disease. Males on the other hand only require one copy of the mutant X allele for the disease to occur in one's phenotype and therefore, the male offspring of a carrier mother has a 50% chance of having the disease. Reasons may include the rarity of the condition or because affected males are reproductively disadvantaged. Therefore, medical uses of PGD for selection of a female offspring to prevent the transmission of X-linked Mendelian recessive disorders are often applied. Preimplantation genetic diagnosis applied for gender selection can be used for non-Mendelian disorders that are significantly more prevalent in one sex. Three assessments are made prior to the initiation of the PGD process for the prevention of these inherited disorders. In order to validate the use of PGD, gender selection is based on the seriousness of the inherited condition, the risk ratio in either sex, or the options for disease treatment. === Minor disabilities === PGD has occasionally been used to select an embryo for the presence of a particular disease or disability, such as deafness, in order that the child would share that characteristic with the parents. === Non-medical traits === The potential controversial use of PGD could arise with genetic tests targeting non-medical traits such as hearing, sexual orientation, height, beauty, or intelligence. Some tests, like those for GJB2 mutations linked to hereditary deafness, might lead to requests for PGD to avoid or favor these traits. Ethical concerns include potential harm to affected communities, such as the deaf. Similar questions would arise with a genetic test for sexual orientation, raising concerns about discrimination. Some insist on a complete ban on selecting such traits, fearing more serious implications like genetic engineering of offspring. However, definitive judgments on these issues cannot be made until such tests are closer to practical reality. == Classification == There are three distinguished types of Preimplantation Genetic Testing (PGT) depending on the defects evaluated. PGT-A, also called preimplantational genetic screening (PGS), improves pregnancy rates by allowing the discard of aneuploids and the selection of euploid embryos for transfer. Euploid embryos are more likely to implant and develop into a healthy pregnancy. NGS and FISH are the most frequently techniques used for the diagnosis of monosomies, trisomies and poliploidies. Primary candidates for PGT-A can include the following: Women of advanced maternal age Couples with a history of recurrent pregnancy loss Couples with repeated IVF failure Male partner swith severe male factor infertility. PGT-A is particularly beneficial for women of advanced maternal age. As women age, especially beyond 35 years, the quality of their eggs declines due to an increased risk of errors during the meiotic division of oocytes. These errors lead to chromosomal abnormalities, such as aneuploidies (monosomies, trisomies, and polyploidies), which can impair embryo development and result in failed pregnancies or genetic disorders. Because of this, PGT-A has become an essential tool for identifying and selecting euploid embryos (embryos with the correct number of chromosomes) for transfer, significantly improving the chances of a successful pregnancy. Studies have shown that the probability of chromosomal abnormalities increases with maternal age, making PGT-A an important step in fertility treatments like in vitro fertilization (IVF) for older women. PGT-M evaluates monogenic diseases are being evaluated in the embryo. Monogenic disorders are caused by single-gene mutations (autosomal recessive, autosomal dominant, X-linked). Previously, PCR was used for PGT-M. Recently, array and NGS technology are used. PGT-SR takes every structural abnormality in the chromosome into account (translocations, inversions, duplications, insertions, deletions). Techniques used include PCR, FISH and NGS. == Technical aspects == PGD is a form of genetic diagnosis performed prior to implantation. This implies that the patient's oocytes should be fertilized in vitro and the embryos kept in culture until the diagnosis is established. It is also necessary to perform a biopsy on these embryos in order to obtain material on which to perform the diagnosis. The diagnosis itself can be carried out using several techniques, depending on the nature of the studied condition. Generally, PCR-based methods are used for monogenic disorders and FISH for chromosomal abnormalities and for sexing those cases in which no PCR protocol is available for an X-linked disease. These techniques need to be adapted to be performed on blastomeres and need to be thoroughly tested on single-cell models prior to clinical use. Finally, after embryo replacement, surplus good quality unaffected embryos can be cryopreserved, to be thawed and transferred back in a next cycle. === Obtaining embryos === Currently, all PGD embryos are obtained by assisted reproductive technology, although the use of natural cycles and in vivo fertilization followed by uterine lavage was attempted in the past and is now largely abandoned. In order to obtain a large group of oocytes, the patients undergo controlled ovarian stimulation (COH). COH is carried out either in an agonist protocol, using gonadotrophin-releasing hormone (GnRH) analogues for pituitary desensitisation, combined with human menopausal gonadotrophins (hMG) or recombinant follicle-stimulating hormone (FSH), or an antagonist protocol using recombinant FSH combined with a GnRH antagonist according to clinical assessment of the patient's profile (age, body mass index (BMI), endocrine parameters). hCG is administered when at least three follicles of more than 17 mm mean diameter are seen at transvaginal ultrasound scan. Transvaginal ultrasound-guided oocyte retrieval is scheduled 36 hours after hCG administration. Luteal phase supplementation consists of daily intravaginal administration of 600 μg of natural micronized progesterone. Oocytes are carefully denudated from the cumulus cells, as these cells can be a source of contamination during the PGD if PCR-based technology is used. In the majority of the reported cycles, intracytoplasmic sperm injection (ICSI) is used instead of IVF. The main reasons are to prevent contamination with residual sperm adhered to the zona pellucida and to avoid unexpected fertilization failure. The ICSI procedure is carried out on mature metaphase-II oocytes and fertilization is assessed 16–18 hours after. The embryo development is further evaluated every day prior to biopsy and until transfer to the woman's uterus. During the cleavage stage, embryo evaluation is performed daily on the basis of the number, size, cell-shape and fragmentation rate of the blastomeres. On day 4, embryos were scored in function of their degree of compaction and blastocysts were evaluated according to the quality of the throphectoderm and inner cell mass, and their degree of expansion. === Biopsy procedures === As PGD can be performed on cells from different developmental stages, the biopsy procedures vary accordingly. Theoretically, the biopsy can be performed at all preimplantation stages, but only three have been suggested: on unfertilised and fertilised oocytes (for polar bodies, PBs), on day three cleavage-stage embryos (for blastomeres) and on blastocysts (for trophectoderm cells). The biopsy procedure always involves two steps: the opening of the zona pellucida and the removal of the cells. There are different approaches to both steps, including mechanical, chemical, and physical (Tyrode's acidic solution) and laser technology for the breaching of the zona pellucida, extrusion or aspiration for the removal of PBs and blastomeres, and herniation of the trophectoderm cells. ==== Polar body biopsy ==== A polar body biopsy is the sampling of a polar body, which is a small haploid cell that is formed concomitantly as an egg cell during oogenesis, but which generally does not have the ability to be fertilized. Compared to a blastocyst biopsy, a polar body biopsy can potentially be of lower costs, less harmful side-effects, and more sensitive in detecting abnormalities. The main advantage of the use of polar bodies in PGD is that they are not necessary for successful fertilisation or normal embryonic development, thus ensuring no deleterious effect for the embryo. One of the disadvantages of PB biopsy is that it only provides information about the maternal contribution to the embryo, which is why cases of maternally inherited autosomal dominant and X-linked disorders that are exclusively maternally transmitted can be diagnosed, and autosomal recessive disorders can only partially be diagnosed. Another drawback is the increased risk of diagnostic error, for instance due to the degradation of the genetic material or events of recombination that lead to heterozygous first polar bodies. ==== Cleavage-stage biopsy (blastomere biopsy) ==== Cleavage-stage biopsy is generally performed the morning of day three post-fertilization, when normally developing embryos reach the eight-cell stage. The biopsy is usually performed on embryos with less than 50% of anucleated fragments and at an eight-cell or later stage of development. A hole is made in the zona pellucida and one or two blastomeres containing a nucleus are gently aspirated or extruded through the opening. The main advantage of cleavage-stage biopsy over PB analysis is that the genetic input of both parents can be studied. On the other hand, cleavage-stage embryos are found to have a high rate of chromosomal mosaicism, putting into question whether the results obtained on one or two blastomeres will be representative for the rest of the embryo. It is for this reason that some programs utilize a combination of PB biopsy and blastomere biopsy. Furthermore, cleavage-stage biopsy, as in the case of PB biopsy, yields a very limited amount of tissue for diagnosis, necessitating the development of single-cell PCR and FISH techniques. Although theoretically PB biopsy and blastocyst biopsy are less harmful than cleavage-stage biopsy, this is still the prevalent method. It is used in approximately 94% of the PGD cycles reported to the ESHRE PGD Consortium. The main reasons are that it allows for a safer and more complete diagnosis than PB biopsy and still leaves enough time to finish the diagnosis before the embryos must be replaced in the patient's uterus, unlike blastocyst biopsy. Of all cleavage-stages, it is generally agreed that the optimal moment for biopsy is at the eight-cell stage. It is diagnostically safer than the PB biopsy and, unlike blastocyst biopsy, it allows for the diagnosis of the embryos before day 5. In this stage, the cells are still totipotent and the embryos are not yet compacting. Although it has been shown that up to a quarter of a human embryo can be removed without disrupting its development, it still remains to be studied whether the biopsy of one or two cells correlates with the ability of the embryo to further develop, implant, and grow into a full-term pregnancy. Not all methods of opening the zona pellucida have the same success rate because the well-being of the embryo and blastomere may be impacted by the procedure used for the biopsy. Zona drilling with acid Tyrode's solution (ZD) was looked at in comparison to partial zona dissection (PZD) to determine which technique would lead to more successful pregnancies and have less of an effect on the embryo and/or blastomere. ZD uses a digestive enzyme like pronase which makes it a chemical drilling method. The chemicals used in ZD may have a damaging effect on the embryo. PZD uses a glass microneedle to cut the zona pellucida which makes it a mechanical dissection method that typically needs skilled hands to perform the procedure. In a study that included 71 couples, ZD was performed in 26 cycles from 19 couples and PZD was performed in 59 cycles from 52 couples. In the single-cell analysis, there was a success rate of 87.5% in the PZD group and 85.4% in the ZD group. The maternal age, number of oocytes retrieved, fertilization rate, and other variables did not differ between the ZD and PZD groups. It was found that PZD led to a significantly higher rate of pregnancy (40.7% vs 15.4%), ongoing pregnancy (35.6% vs 11.5%), and implantation (18.1% vs 5.7%) than ZD. This suggests that using the mechanical method of PZD in blastomere biopsies for preimplantation genetic diagnosis may be more proficient than using the chemical method of ZD. The success of PZD over ZD could be attributed to the chemical agent in ZD having a harmful effect on the embryo and/or blastomere. Currently, zona drilling using a laser is the predominant method of opening the zona pellucida. Using a laser is an easier technique than using mechanical or chemical means. However, laser drilling could be harmful to the embryo and it is very expensive for in vitro fertilization laboratories to use especially when PGD is not a prevalent process as of modern times. PZD could be a viable alternative to these issues. ==== Blastocyst biopsy ==== In an attempt to overcome the difficulties related to single-cell techniques, it has been suggested to biopsy embryos at the blastocyst stage, providing a larger amount of starting material for diagnosis. It has been shown that if more than two cells are present in the same sample tube, the main technical problems of single-cell PCR or FISH would virtually disappear. On the other hand, as in the case of cleavage-stage biopsy, the chromosomal differences between the inner cell mass and the trophectoderm (TE) can reduce the accuracy of diagnosis, although this mosaicism has been reported to be lower than in cleavage-stage embryos. TE biopsy has been shown to be successful in animal models such as rabbits, mice and primates. These studies show that the removal of some TE cells is not detrimental to the further in vivo development of the embryo. Human blastocyst-stage biopsy for PGD is performed by making a hole in the ZP on day three of in vitro culture. This allows the developing TE to protrude after blastulation, facilitating the biopsy. On day five post-fertilization, approximately five cells are excised from the TE using a glass needle or laser energy, leaving the embryo largely intact and without loss of inner cell mass. After diagnosis, the embryos can be replaced during the same cycle, or cryopreserved and transferred in a subsequent cycle. There are two drawbacks to this approach, due to the stage at which it is performed. First, only approximately half of the preimplantation embryos reach the blastocyst stage. This can restrict the number of blastocysts available for biopsy, limiting in some cases the success of the PGD. McArthur and coworkers report that 21% of the started PGD cycles had no embryo suitable for TE biopsy. This figure is approximately four times higher than the average presented by the ESHRE PGD consortium data, where PB and cleavage-stage biopsy are the predominant reported methods. On the other hand, delaying the biopsy to this late stage of development limits the time to perform the genetic diagnosis, making it difficult to redo a second round of PCR or to rehybridize FISH probes before the embryos should be transferred back to the patient. ==== Cumulus cell sampling ==== Sampling of cumulus cells can be performed in addition to a sampling of polar bodies or cells from the embryo. Because of the molecular interactions between cumulus cells and the oocyte, gene expression profiling of cumulus cells can be performed to estimate oocyte quality and the efficiency of an ovarian hyperstimulation protocol, and may indirectly predict aneuploidy, embryo development and pregnancy outcomes. === Non-invasive methods === Traditional embryo biopsy can be invasive and costly. Therefore, researchers have an ongoing quest to find a less invasive methods for preimplantation genetic testing. Studies on new non-invasive preimplantation genetics screening methods such as blastocoel fluid and spent embryo media have recently been published as an alternative to traditional methods. ==== Using blastocoel fluid ==== During a normal IVF process, good practice to vitrify embryos increases the chance of a healthy pregnancy. During the process of vitrification a developed blast is dehydrated and it and its blastocoel cavity collapses for the freezing process. There are many methods that have been used to facilitate the collapse including laser-pulse, repeated micropipetting, microneedle puncture or microsuction. Normally this fluid would then be discarded, however with preimplantation genetic testing of BL, this fluid is saved and then tested for DNA. This DNA is thought to be from cells that have gone through apoptosis found in the developing embryo. ==== Using blastocyst culture conditioned medium ==== Another method for less invasive preimplantation genetic testing involves testing the culture media the embryo has developed in. It has been noted that the embryo releases DNA fragments from the cells that have died within the incubation period. With this knowledge, scientists have reasoned that they could isolate this DNA and use it for preimplantation genetic testing. ==== Benefits and consequences ==== While there is conflicting evidence as to whether or not the more traditional methods of preimplantation genetic testing are harmful to the embryo, there are newer methods for less invasive and equally effective testing methods using blastocoel fluid and spent embryo media. Two problems with these alternatives are the minimal amount of DNA there is to work with and whether or not this technology is accurate. Both of these concerns were recently addressed by Kuznyetsov, who decided to use both methods, combining the amount of DNA retrieved from both techniques. Once the DNA was isolated it was used for preimplantation genetic testing. The results showed that when both methods (blastocyst fluid and embryo spent media) were used in combination, they showed a cordance rate for the whole chromosome copy of 87.5% when compared to the trophectoderm, 96.4% when compared to the whole blastocyst (gold standard). Additionally after amplification using this new method they were able to produce 25.0–54.0 ng/ul of DNA per sample. With traditional methods such as trophectoderm they collected 10 to 44 ng/ul. === Genetic analysis techniques === Fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) are the two commonly used, first-generation technologies in PGD. PCR is generally used to diagnose monogenic disorders and FISH is used for the detection of chromosomal abnormalities (for instance, aneuploidy screening or chromosomal translocations). Over the past few years, various advancements in PGD testing have allowed for an improvement in the comprehensiveness and accuracy of results available depending on the technology used. Recently a method was developed allowing to fix metaphase plates from single blastomeres. This technique in conjunction with FISH, m-FISH can produce more reliable results, since analysis is done on whole metaphase plates In addition to FISH and PCR, single cell genome sequencing is being tested as a method of preimplantation genetic diagnosis. This characterizes the complete DNA sequence of the genome of the embryo. ==== FISH ==== FISH is the most commonly applied method to determine the chromosomal constitution of an embryo. In contrast to karyotyping, it can be used on interphase chromosomes, so that it can be used on PBs, blastomeres and TE samples. The cells are fixated on glass microscope slides and hybridised with DNA probes. Each of these probes are specific for part of a chromosome, and are labelled with a fluorochrome. Dual FISH was considered to be an efficient technique for determination of the sex of human preimplantation embryos and the additional ability to detect abnormal chromosome copy numbers, which is not possible via the polymerase chain reaction (PCR). Currently, a large panel of probes are available for different segments of all chromosomes, but the limited number of different fluorochromes confines the number of signals that can be analysed simultaneously. The type and number of probes that are used on a sample depends on the indication. For sex determination (used for instance when a PCR protocol for a given X-linked disorder is not available), probes for the X and Y chromosomes are applied along with probes for one or more of the autosomes as an internal FISH control. More probes can be added to check for aneuploidies, particularly those that could give rise to a viable pregnancy (such as a trisomy 21). The use of probes for chromosomes X, Y, 13, 14, 15, 16, 18, 21 and 22 has the potential of detecting 70% of the aneuploidies found in spontaneous abortions. In order to be able to analyse more chromosomes on the same sample, up to three consecutive rounds of FISH can be carried out. In the case of chromosome rearrangements, specific combinations of probes have to be chosen that flank the region of interest. The FISH technique is considered to have an error rate of 5–10%. The main problem of the use of FISH to study the chromosomal constitution of embryos is the elevated mosaicism rate observed at the human preimplantation stage. A meta-analysis of more than 800 embryos came to the result that approximately 75% of preimplantation embryos are mosaic, of which approximately 60% are diploid–aneuploid mosaic and approximately 15% aneuploid mosaic. Li and co-workers found that 40% of the embryos diagnosed as aneuploid on day 3 turned out to have a euploid inner cell mass at day 6. Staessen and collaborators found that 17.5% of the embryos diagnosed as abnormal during PGS, and subjected to post-PGD reanalysis, were found to also contain normal cells, and 8.4% were found grossly normal. As a consequence, it has been questioned whether the one or two cells studied from an embryo are actually representative of the complete embryo, and whether viable embryos are not being discarded due to the limitations of the technique. Nevertheless, mosaic embryos can be transferred but only if there are not euploids available, having previously informed patients about the risks and doing a prenatal diagnose preferably. ==== PCR ==== Kary Mullis conceived PCR in 1985 as an in vitro simplified reproduction of the in vivo process of DNA replication. Taking advantage of the chemical properties of DNA and the availability of thermostable DNA polymerases, PCR allows for the enrichment of a DNA sample for a certain sequence. PCR provides the possibility to obtain a large quantity of copies of a particular stretch of the genome, making further analysis possible. It is a highly sensitive and specific technology, which makes it suitable for all kinds of genetic diagnosis, including PGD. Currently, many different variations exist on the PCR itself, as well as on the different methods for the posterior analysis of the PCR products. When using PCR in PGD, one is faced with a problem that is nonexistent in routine genetic analysis: the minute amounts of available genomic DNA. As PGD is performed on single cells, PCR has to be adapted and pushed to its physical limits, and use the minimum amount of template possible: which is one strand. This implies a long process of fine-tuning of the PCR conditions and a susceptibility to all the problems of conventional PCR, but several degrees intensified. The high number of needed PCR cycles and the limited amount of template makes single-cell PCR very sensitive to contamination. Another problem specific to single-cell PCR is the allele drop out (ADO) phenomenon. It consists of the random non-amplification of one of the alleles present in a heterozygous sample. ADO seriously compromises the reliability of PGD as a heterozygous embryo could be diagnosed as affected or unaffected depending on which allele would fail to amplify. This is particularly concerning in PGD for autosomal dominant disorders, where ADO of the affected allele could lead to the transfer of an affected embryo. Several PCR-based assays have been developed for various diseases like the triplet repeat genes associated with myotonic dystrophy and fragile X in single human somatic cells, gametes and embryos. ==== Next-generation sequencing concept ==== The core philosophy of massive parallel sequencing used in NGS is adapted from shotgun sequencing developed to sequence longer sections of DNA. NGS technologies read the target DNA templates randomly. The target DNA or entire genome is broken into small pieces and then those DNA pieces are ligated to designated adapters for random reading during in-parallel DNA synthesis. The read length corresponds to the actual number of continuous sequenced bases. The read lengths are much shorter than with Sanger sequencing, which is why NGS results are called short reads. From 2014, next-generation sequencing (NGS) is being performed in the PGT. NGS is a group of techniques capable of sequencing great amounts of DNA at a reasonable cost and time. It can give us a general perspective of the complete embryo genome, including the mitochondrial one. Those techniques are based on sequencing short reads around 400 bases each and overlapping these reads with powerful alignment software. Likewise, NGS is used to detect aneuploidies in the 24 chromosomes and single-gene defects when there is an indication from the carrier parents. The main advantage is that NGS can combine the detection of both aneuploidies and monogenic diseases with a single biopsy and has reduced affordable costs, making it more accessible. Two examples of NGS are the pyrosequencing and the reversible dye terminator. === Pyrosequencing === Pyrosequencing technique is based on sequencing by-synthesis principle and on the detection of released pyrophosphate during DNA synthesis. It employs a series of four enzymes to accurately detect nucleic acid sequences during the synthesis. Cycles of four deoxynucleotide triphosphates (dNTPs) are separately added to the reaction mixture iteratively. The cascade starts with a nucleic acid polymerization reaction in which inorganic pyrophosphate is released as a result of nucleotide incorporation by polymerase. Each nucleotide incorporation event is followed by release of inorganic pyrophosphate in a quantity equimolar to the amount of incorporated nucleotide. The released pyrophosphate is quantitatively converted to ATP by ATP sulfurylase in the presence of APS. The generated ATP drives the luciferase-mediated conversion of luciferin to oxyluciferin, producing visible light in amounts that are proportional to the amount of ATPs. During this synthesis process, the DNA strand is extended by complementary nucleotides, and the DNA sequence is demonstrated by the pyrogram on a screen. The overall reaction from polymerization to light detection takes place within 3–4 seconds at room temperature. ATP sulfurylase converts pyrophosphate to ATP in approximately 1.5 seconds and the generation of light by luciferase takes place in less than 0.2 seconds. === Limits === Along with the benefits offered by these technologies, there are a number of challenges, both technical and ethical that must be addressed and solved before NGS technologies enter the clinical arena of embryo diagnosis. One limitation will be the interpretation of the massive sequence data generated by NGS technologies. Background polymorphisms must be distinguished from potentially disease-causing mutations and copy number variations. By selective recovery and subsequent sequencing of genomic loci of interest, generated data and efforts for analysis can be reduced significantly compared with a whole-genome sequencing approach. === Establishing a diagnosis === The establishment of a diagnosis in PGD is not always straightforward. The criteria used for choosing the embryos to be replaced after FISH or PCR results are not equal in all centres. In the case of FISH, in some centres only embryos are replaced that are found to be chromosomally normal (that is, showing two signals for the gonosomes and the analysed autosomes) after the analysis of one or two blastomeres, and when two blastomeres are analysed, the results should be concordant. Other centres argue that embryos diagnosed as monosomic could be transferred, because the false monosomy (i.e. loss of one FISH signal in a normal diploid cell) is the most frequently occurring misdiagnosis. In these cases, there is no risk for an aneuploid pregnancy, and normal diploid embryos are not lost for transfer because of a FISH error. Moreover, it has been shown that embryos diagnosed as monosomic on day 3 (except for chromosomes X and 21), never develop to blastocyst, which correlates with the fact that these monosomies are never observed in ongoing pregnancies. Diagnosis and misdiagnosis in PGD using PCR have been mathematically modelled in the work of Navidi and Arnheim and of Lewis and collaborators. The most important conclusion of these publications is that for the efficient and accurate diagnosis of an embryo, two genotypes are required. This can be based on a linked marker and disease genotypes from a single cell or on marker/disease genotypes of two cells. An interesting aspect explored in these papers is the detailed study of all possible combinations of alleles that may appear in the PCR results for a particular embryo. The authors indicate that some of the genotypes that can be obtained during diagnosis may not be concordant with the expected pattern of linked marker genotypes, but are still providing sufficient confidence about the unaffected genotype of the embryo. Although these models are reassuring, they are based on a theoretical model, and generally the diagnosis is established on a more conservative basis, aiming to avoid the possibility of misdiagnosis. When unexpected alleles appear during the analysis of a cell, depending on the genotype observed, it is considered that either an abnormal cell has been analysed or that contamination has occurred, and that no diagnosis can be established. A case in which the abnormality of the analysed cell can be clearly identified is when, using a multiplex PCR for linked markers, only the alleles of one of the parents are found in the sample. In this case, the cell can be considered as carrying a monosomy for the chromosome on which the markers are located, or, possibly, as haploid. The appearance of a single allele that indicates an affected genotype is considered sufficient to diagnose the embryo as affected, and embryos that have been diagnosed with a complete unaffected genotype are preferred for replacement. Although this policy may lead to a lower number of unaffected embryos suitable for transfer, it is considered preferable to the possibility of a misdiagnosis. === Preimplantation genetic haplotyping === Preimplantation genetic haplotyping (PGH) is a PGD technique wherein a haplotype of genetic markers that have statistical associations to a target disease are identified rather than the mutation causing the disease. Once a panel of associated genetic markers have been established for a particular disease it can be used for all carriers of that disease. In contrast, since even a monogenic disease can be caused by many different mutations within the affected gene, conventional PGD methods based on finding a specific mutation would require mutation-specific tests. Thus, PGH widens the availability of PGD to cases where mutation-specific tests are unavailable. PGH also has an advantage over FISH in that FISH is not usually able to make the differentiation between embryos that possess the balanced form of a chromosomal translocation and those carrying the homologous normal chromosomes. This inability can be seriously harmful to the diagnosis made. PGH can make the distinction that FISH often cannot. PGH does this by using polymorphic markers that are better suited at recognizing translocations. These polymorphic markers are able to distinguish between embryos that carried normal, balanced, and unbalanced translocations. FISH also requires more cell fixation for analysis whereas PGH requires only transfer of cells into polymerase chain reaction tubes. The cell transfer is a simpler method and leaves less room for analysis failure. === Embryo transfer and cryopreservation of surplus embryos === Embryo transfer is usually performed on day three or day five post-fertilization, the timing depending on the techniques used for PGD and the standard procedures of the IVF centre where it is performed. With the introduction in Europe of the single-embryo transfer policy, which aims at the reduction of the incidence of multiple pregnancies after ART, usually one embryo or early blastocyst is replaced in the uterus. Serum hCG is determined at day 12. If a pregnancy is established, an ultrasound examination at 7 weeks is performed to confirm the presence of a fetal heartbeat. Couples are generally advised to undergo PND because of the, albeit low, risk of misdiagnosis. It is not unusual that after the PGD, there are more embryos suitable for transferring back to the woman than necessary. For the couples undergoing PGD, those embryos are very valuable, as the couple's current cycle may not lead to an ongoing pregnancy. Embryo cryopreservation and later thawing and replacement can give them a second chance to pregnancy without having to redo the cumbersome and expensive ART and PGD procedures. == Side effects to embryo == PGD/PGS is an invasive procedure that requires a serious consideration, according to Michael Tucker, Ph.D., Scientific Director and Chief Embryologist at Georgia Reproductive Specialists in Atlanta. One of the risks of PGD includes damage to the embryo during the biopsy procedure (which in turn destroys the embryo as a whole), according to Serena H. Chen, M.D., a New Jersey reproductive endocrinologist with IRMS Reproductive Medicine at Saint Barnabas. Another risk is cryopreservation where the embryo is stored in a frozen state and thawed later for the procedure. About 20% of the thawed embryos do not survive. There has been a study indicating a biopsied embryo has a less rate of surviving cryopreservation. Another study suggests that PGS with cleavage-stage biopsy results in a significantly lower live birth rate for women of advanced maternal age. Also, another study recommends the caution and a long term follow-up as PGD/PGS increases the perinatal death rate in multiple pregnancies. In a mouse model study, PGD has been attributed to various long-term risks, including a weight gain and memory decline; a proteomic analysis of adult mouse brains showed significant differences between the biopsied and the control groups, of which many are closely associated with neurodegenerative disorders like Alzheimer's and Down syndrome. == Ethical issues == PGD has raised ethical issues, although this approach could reduce reliance on fetal deselection during pregnancy. The technique can be used for prenatal sex discernment of the embryo, and thus potentially can be used to select embryos of one sex in preference of the other in the context of "family balancing". The use of PGD for gender variety has been reported in India, where an IVF programme in Bombay is now providing PGD to select male offspring as the second child of couples who have already had a daughter. Because of the importance of a male heir in India, those couples might have resorted to abortion if pregnant with a female fetus (even though illegal for that purpose). In that setting PGD for sex selection for gender variety appears to be justified. It may be possible to make other "social selection" choices in the future that introduce socio-economic concerns. Only unaffected embryos are implanted in a woman's uterus; those that are affected are either discarded or donated to science. Objections to PGD based on its effect on embryos replay debates over abortion and embryo status that have occurred in many other contexts, from abortion to embryonic stem cell research. People who think that the embryo or fetus is a person will object to creating and destroying embryos, and oppose most uses of PGD. Others believe that preimplantation embryos are too rudimentary in development to have interests or rights, but that they deserve special respect as the first stage toward a new person. PGD has the potential to screen for genetic issues unrelated to medical necessity, such as intelligence and beauty, and against negative traits such as disabilities. The medical community has regarded this as a counterintuitive and controversial suggestion. The prospect of a "designer baby" is closely related to the PGD technique, creating a fear that increasing frequency of genetic screening will move toward a modern eugenics movement. On the other hand, a principle of procreative beneficence is proposed, which is a putative moral obligation of parents in a position to select their children to favor those expected to have the best life. An argument in favor of this principle is that traits (such as empathy, memory, etc.) are "all-purpose means" in the sense of being of instrumental value in realizing whatever life plans the child may come to have. Walter Veit has argued that there is no intrinsic moral difference between 'creating' and 'choosing' a life, thus making eugenics a natural consequence of accepting the principle of procreative beneficence. === Disabilities === In 2006, three percent of PGD clinics in the US reported having selected an embryo for the presence of a disability. Couples involved were accused of purposely harming a child. This practice is notable in dwarfism, where parents intentionally create a child who is a dwarf. In the selection of a saviour sibling to provide a matching bone marrow transplant for an already existing affected child, there are issues including the commodification and welfare of the donor child. By relying on the result of one cell from the multi-cell embryo, PGD operates under the assumption that this cell is representative of the remainder of the embryo. This may not be the case as the incidence of mosaicism is often relatively high. On occasion, PGD may result in a false negative result leading to the acceptance of an abnormal embryo, or in a false positive result leading to the deselection of a normal embryo. Another problematic case is the cases of desired non-disclosure of PGD results for some genetic disorders that may not yet be apparent in a parent, such as Huntington disease. It is applied when patients do not wish to know their carrier status but want to ensure that they have offspring free of the disease. This procedure can place practitioners in questionable ethical situations, e.g. when no healthy, unaffected embryos are available for transfer and a mock transfer has to be carried out so that such patients do not suspect that they are carriers. The European Society of Human Reproduction and Embryology (ESHRE) ethics task force currently recommends using exclusion testing instead. Exclusion testing is based on a linkage analysis with polymorphic markers, in which the parental and grandparental origin of the chromosomes can be established. This way, only embryos are replaced that do not contain the chromosome derived from the affected grandparent, avoiding the need to detect the mutation itself. ==== Criticisms of PGD ==== Because of the sensitivity of the issue, preimplantation genetic diagnosis has sparked a rich debate in academia and beyond. Those who are against the possibility of discarding an embryo to avoid the risk of disability (such as the possible adverse selection of embryos that might develop "disabilities" such as deafness) argue that if the only two possibilities are "existence and nonexistence" ("coming into the world" or "not coming into the world"), granting them the right to come into the world is better than the alternative of not existing. Another widely used argument for rejecting preimplantation genetic diagnosis involves the meaning of the term "disability" (Bickenach & Chatterji, 2003). The language of medicine describes disability as something whose functionalities deviate from a normal functioning. However, much of the disability community emphasizes that disability is often determined by the way society structures the world. Thus, the concepts of "normalcy" and "health" are relative and depend on time, place, and society. Opponents of PGD argue against avoiding the birth of people with disabilities through preimplantation genetic diagnosis, and that people must first determine how to define what disability is. ==== Support for PGD ==== The literature highlights three most common types of arguments in favor of preimplantation genetic diagnosis. The first type of argument is mainly made by a part of academia that believes that a disability or disorder likely implies a reduced quality of life for the unborn child. The second most common type of argument focuses primarily on the duties of parents in relation to the human flourishing of the individual. This argument feeds on the idea that parents have an obligation and responsibility to ensure minimum living conditions for the unborn child. A final category of argument is one that emphasizes the importance of bringing individuals with disabilities and disorders into the world with the consideration of how much they can contribute to the socioeconomic growth of society, suggesting these individuals would not be able to contribute to improving the status quo and well-being of society as a whole. ==== Legal status ==== In Japan, preimplantation genetic testing-monogenic (PGT-M) has been the topic of fierce debate by individuals suffering from genetic diseases on the one hand, and feminist groups and disability activist groups on the other. As Croydon notes, "prospective PGT-M patients, such as individuals of reproductive age impacted by a disability and their spouses...have wanted to take advantage of the technology," but they have faced opposition from "groups campaigning for women's and disabled people's rights [which] include individuals who see the genetic testing of embryos in one or all of the following ways: 1) it puts undue pressure on the women involved, conveying the message to them that they are only allowed to reproduce if they are bringing into the world a healthy offspring; 2) it reinforces existing discriminatory attitudes in society towards disabled people; and 3) the circumvention of disease through the reproductive process reduces the need in the scientific community to continue the pursuit of developing treatments/cures for people who currently live with disability." Ultimately, the use of PGT-M has remained restrictive in Japan and is informally regulated by the Japan Society of Obstetrics and Gynecology (JSOG). === Intersex traits === PGD allows discrimination against those with intersex traits. Georgiann Davis argues that such discrimination fails to recognize that many people with intersex traits led full and happy lives. Morgan Carpenter highlights the appearance of several intersex variations in a list by the Human Fertilisation and Embryology Authority of "serious" "genetic conditions" that may be de-selected in the UK, including 5-alpha reductase deficiency and androgen insensitivity syndrome, traits evident in elite women athletes and "the world's first openly intersex mayor". Organisation Intersex International Australia has called for the Australian National Health and Medical Research Council to prohibit such interventions, noting a "close entanglement of intersex status, gender identity and sexual orientation in social understandings of sex and gender norms, and in medical and medical sociology literature". In 2015, the Council of Europe published an Issue Paper on Human rights and intersex people, remarking: Intersex people's right to life can be violated in discriminatory "sex selection" and "preimplantation genetic diagnosis, other forms of testing, and selection for particular characteristics". Such de-selection or selective abortions are incompatible with ethics and human rights standards due to the discrimination perpetrated against intersex people on the basis of their sex characteristics. === Savior siblings === PGD combined with HLA (human leukocyte antigen) matching allows couples to select for embryos that are unaffected with a genetic disease in hopes of saving an existing, affected child. The "savior sibling" would conceivably donate life-saving tissue that is compatible to his/her brother or sister. Some ethicists argue that the "savior siblings" created from this procedure would be treated as commodities. Another argument against selecting for "savior siblings" is that it leads to genetically engineered "designer babies". This argument prompts a discussion between the moral distinction of enhancing traits and preventing disease. Finally, opponents of "savior siblings" are concerned with the welfare of the child, mainly that the procedure will cause emotional and psychological harm to the child. Currently in the United States, no formal regulation or guideline exists. The ethical decisions regarding this procedure is in the discretion of health care providers and their patients. In contrast, the UK's use of PGD is regulated by the Human Fertilization and Embryology Act (HFEA), which requires clinics performing this technique to attain a license and follow strict criteria. == Religious objections == Some religious organizations disapprove of this procedure. The Roman Catholic Church, for example, takes the position that it involves the destruction of human life. and besides that, opposes the necessary in vitro fertilization of eggs as contrary to Aristotelian principles of nature. Orthodox Judaism, by contrast, supports PGD. == Psychological factor == A meta-analysis that was performed indicates research studies conducted in PGD underscore future research. This is due to positive attitudinal survey results, postpartum follow-up studies demonstrating no significant differences between those who had used PGD and those who conceived naturally, and ethnographic studies which confirmed that those with a previous history of negative experiences found PGD as a relief. Firstly, in the attitudinal survey, women with a history of infertility, pregnancy termination, and repeated miscarriages reported having a more positive attitude towards preimplantation genetic diagnosis. They were more accepting towards pursuing PGD. Secondly, likewise to the first attitudinal study, an ethnographic study conducted in 2004 found similar results. Couples with a history of multiple miscarriages, infertility, and an ill child, felt that preimplantation genetic diagnosis was a viable option. They also felt more relief; "those using the technology were actually motivated to not repeat pregnancy loss". In summary, although some of these studies are limited due to their retrospective nature and limited samples, the study's results indicate an overall satisfaction of participants for the use of PGD. However, the authors of the studies do indicate that these studies emphasize the need for future research such as creating a prospective design with a valid psychological scale necessary to assess the levels of stress and mood during embryonic transfer and implantation. == Policy and legality == === Canada === Prior to implementing the Assisted Human Reproduction Act (AHR) in 2004, PGD was unregulated in Canada. The Act banned sex selection for non-medical purposes. Due to 2012's national budget cuts, the AHR was removed. The regulation of assisted reproduction was then delegated to each province. This delegation provides provinces with a lot of leeway to do as they please. As a result, provinces like Quebec, Alberta and Manitoba have put almost the full costs of IVF on the public healthcare bill. Dr. Santiago Munne, developer of the first PGD test for Down's syndrome and founder of Reprogenetics, saw these provincial decisions as an opportunity for his company to grow and open more Reprogenetics labs around Canada. He dismissed all controversies regarding catalogue babies and states that he had no problem with perfect babies. Ontario, however, has no concrete regulations regarding PGD. Since 2011, the Ministry of Children and Youth Services in Ontario advocates for the development government-funded 'safe fertility' education, embryo monitoring and assisted reproduction services for all Ontarians. This government report shows that Ontario not only has indefinite regulations regarding assisted reproduction services like IVF and PGD, but also does not fund any of these services. The reproductive clinics that exist are all private and located only in Brampton, Markham, Mississauga, Scarborough, Toronto, London and Ottawa. In contrast, provinces such as Alberta and Quebec not only have more clinics, but have also detailed laws regarding assisted reproduction and government funding for these practices. === Germany === Before 2010, the usage of PGD was in a legal grey area. In 2010, the Federal Court of Justice of Germany ruled that PGD can be used in exceptional cases. On 7 July 2011, the Bundestag passed a law that allows PGD in certain cases. The procedure may only be used when there is a strong likelihood that parents will pass on a genetic disease, or when there is a high genetic chance of a stillbirth or miscarriage. On 1 February 2013, the Bundesrat approved a rule regulating how PGD can be used in practice. === Hungary === In Hungary, PGD is allowed in case of severe hereditary diseases (when genetic risk is above 10%). The preimplantation genetic diagnosis for aneuploidy (PGS/PGD-A) is an accepted method as well. It is currently recommended in case of multiple miscarriages, and/or several failed IVF treatments, and/or when the mother is older than 35 years. Despite being an approved method, PGD-A is available at only one Fertility Clinic in Hungary. === India === In India, Ministry of Family Health and Welfare, regulates the concept under the Pre-Conception and Pre-Natal Diagnostic Techniques Act, 1994. The Act was further been revised after 1994 and necessary amendment were made are updated timely on the official website of the Indian Government dedicated for the cause. The use of PGD for sex identification/selection of child is illegal in India. === Mexico === As of 2006, clinics in Mexico legally provided PGD services. === South Africa === In South Africa, where the right to reproductive freedom is a constitutionally protected right, it has been proposed that the state can only limit PGD to the degree that parental choice can harm the prospective child or to the degree that parental choice will reinforce societal prejudice. === Ukraine === The preimplantation genetic diagnosis is allowed in Ukraine and from November 1, 2013, is regulated by the order of the Ministry of health of Ukraine "On approval of the application of assisted reproductive technologies in Ukraine" from 09.09.2013 No. 787. === United Kingdom === In the UK, assisted reproductive technologies are regulated under the Human Fertilization and Embryology Act (HFE) of 2008. However, the HFE Act does not address issues surrounding PGD. Thus, the HFE Authority (HFEA) was created in 2003 to act as a national regulatory agency that issues licenses and monitors clinics providing PGD. The HFEA only permits the use of PGD where the clinic concerned has a license from the HFEA and sets out the rules for this licensing in its Code of Practice. Each clinic, and each medical condition, requires a separate application where the HFEA check the suitability of the genetic test proposed and the staff skills and facilities of the clinic. Only then can PGD be used for a patient. The HFEA strictly prohibits sex selection for social or cultural reasons, but allows it to avoid sex-linked disorders. They state that PGD is not acceptable for, "social or psychological characteristics, normal physical variations, or any other conditions which are not associated with disability or a serious medical condition." It is however accessible to couples or individuals with a known family history of serious genetic diseases. Nevertheless, the HFEA regards intersex variations as a "serious genetic disease", such as 5-alpha-reductase deficiency, a trait associated with some elite women athletes. Intersex advocates argue that such decisions are based on social norms of sex gender, and cultural reasons. === United States === No uniform system for regulation of assisted reproductive technologies, including genetic testing, exists in the United States. The practice and regulation of PGD most often fall under state laws or professional guidelines as the federal government does not have direct jurisdiction over the practice of medicine. To date, no state has implemented laws directly pertaining to PGD, therefore leaving researchers and clinicians to abide by guidelines set by the professional associations. The Centers for Disease Control and Prevention (CDC) states that all clinics providing IVF must report pregnancy success rates annually to the federal government, but reporting of PGD use and outcomes is not required. Professional organizations, such as the American Society for Reproductive Medicine (ASRM), have provided limited guidance on the ethical uses of PGD. The American Society for Reproductive Medicine (ASRM) states that "PGD should be regarded as an established technique with specific and expanding applications for standard clinical practice." They also state, "While the use of PGD for the purpose of preventing sex-linked diseases is ethical, the use of PGD solely for sex selection is discouraged." In 2024, the Alabama Supreme Court ruled in an influential case that frozen embryos in test tubes should be considered children, thus raising complex legal questions with implications for reproductive care extending far beyond Alabama. === Spain === In Spain, preimplantation genetic diagnosis is not allowed to be carried out in an open and accessible way for everyone to avoid eugenics. That is why it is only legalized in high-risk cases. There are three essential requirements (except for the exceptions allowed by the Bioethics Committees) for a preimplantation genetic diagnosis to be carried out on the embryo. All three must be met: That the embryo may contain an early-onset disease. If it were a late-onset disease, such as Alzheimer's, it could not be prevented by preimplantation diagnosis. That the disease to be detected is not currently curable. If it were a serious but curable disease, it could not be prevented by this method. An example of a pathology with no current cure on which preimplantation diagnosis could be applied would be Retinoblastoma, which is an autosomal recessive monogenic disease. That the disease is life-threatening or seriously affects the mental or psychomotor development of the child. Any type of disease that does not meet these three requirements must go through a Bioethics Committee and be approved by it before PGD can be performed. Legislation began late, ten years after the birth in the United Kingdom of Louise Brown, the first person conceived by IVF. == References in popular culture == PGD features prominently in the 1997 film Gattaca. The movie is set in a near-future world where PGD/IVF is the most common form of reproduction. In the movie parents routinely use PGD to select desirable traits for their children such as height, eye color, and freedom from even the smallest of genetic predispositions to disease. The ethical consequences of PGD are explored through the story of the main character who faces discrimination because he was conceived without such methods. PGD is mentioned in the 2004 novel My Sister's Keeper by the characters as the main character, Anna Fitzgerald, was created through PGD to be a genetic match for her APL positive sister Kate so that she could donate bone marrow at her birth to help Kate fight the APL. It is also mentioned in the book that her parents received criticism for the act. == Information on clinic websites == In a study of 135 IVF clinics, 88% had websites, 70% mentioned PGD and 27% of the latter were university- or hospital-based and 63% were private clinics. Sites mentioning PGD also mentioned uses and benefits of PGD far more than the associated risks. Of the sites mentioning PGD, 76% described testing for single-gene diseases, but only 35% mentioned risks of missing target diagnoses, and only 18% mentioned risks for loss of the embryo. 14% described PGD as new or controversial. Private clinics were more likely than other programs to list certain PGD risks like for example diagnostic error, or note that PGD was new or controversial, reference sources of PGD information, provide accuracy rates of genetic testing of embryos, and offer gender selection for social reasons. == See also == Bioethics Designer baby Family-based QTL mapping Polygenic score Sperm sorting == Notes and references == == Further reading == Laurent Christian; Asker Melchior Tellier; Nathan Robert Treff; Stephen Hsu; Louis Lello; Erik Widen (2023). "Scientific refutation of ESHG statement on embryo selection." European Journal of Human Genetics 31, 278 https://doi.org/10.1038/s41431-022-01237-0 == External links == An Interview with Dr. Mark Hughes, a pioneer in PGD, discussing PGD Embryo Selection For Intelligence: A cost-benefit analysis of the marginal cost of IVF-based embryo selection for intelligence and other traits with 2016-2017 state-of-the-art Preimplantation genetic diagnosis and sex selection- How does it work in the UK? List of diseases screened in the UK licensed by the HFEA Screening Embryos for Disease by Joe Palca @ NPR.org Preimplantation Genetic Diagnosis images. Polar body and blastomere biopsy images. Normal and abnormal FISH images. Couzin-Frankel, Jennifer (22 March 2022). "Scientists say they can read nearly the whole genome of an IVF-created embryo". Science.	Wikipedia/Preimplantation_genetic_diagnosis
In health care, diagnosis codes are used as a tool to group and identify diseases, disorders, symptoms, poisonings, adverse effects of drugs and chemicals, injuries and other reasons for patient encounters. Diagnostic coding is the translation of written descriptions of diseases, illnesses and injuries into codes from a particular classification. In medical classification, diagnosis codes are used as part of the clinical coding process alongside intervention codes. Both diagnosis and intervention codes are assigned by a health professional trained in medical classification such as a clinical coder or Health Information Manager. Several diagnosis classification systems have been implemented to various degrees of success across the world. The various classifications have a focus towards a particular patient encounter type such as emergency, inpatient, outpatient, mental health as well as surgical care. The International Statistical Classification of Diseases and Related Health Problems (ICD) is one of the most widely used classification systems for diagnosis coding as it allows comparability and use of mortality and morbidity data. As the knowledge of health and medical advances arise, the diagnostic codes are generally revised and updated to match the most up to date current body of knowledge in the field of health. The codes may be quite frequently revised as new knowledge is attained. DSM (see below) changes some of its coding to correspond to the codes in ICD. In 2005, for example, DSM changed the diagnostic codes for circadian rhythm sleep disorders from the 307-group to the 327-group; the new codes reflect the moving of these disorders from the Mental Disorders section to the Neurological section in the ICD == Diagnostic coding systems == A number of diagnostic coding systems are implemented across the world to code the stay of patients within a typical health setting, such as a hospital. The following table provides a basic list of the coding systems in use as of approximately 2010: == Financial aspects of diagnostic coding == Diagnosis codes are generally used as a representation of admitted episodes in health care settings. The principal diagnosis, additional diagnoses alongside intervention codes essentially depict a patient's admission to a hospital. Diagnoses codes are subjected to ethical considerations as they contribute to the total coded medical record in health services areas such as a hospital. Hospitals that are based on Activity Based Funding and Diagnoses-Related Group Classification systems are often subjected to high end decision making that could affect the outcome of funding. It's important to look at the scope of diagnoses codes in terms of their application in finance. The diagnoses codes in particular the Principal Diagnoses and Additional Diagnoses can significantly affect the total funding that a hospital may receive for any patient admitted. Ethically, this highlights the fact that the assignment of the diagnoses code can be influenced by a decision to maximize reimbursement of funding. For example, when looking at the activity based funding model used in the public hospital system in Victoria the total coded medical record is responsible for its reflected funding. These decisions also affect clinical documentation by physicians as recommendations from a Health Information Service can directly affect how a clinician may document a condition that a patient may have. The difference between the codes assigned for confusion and delirium can alter a hospitals DRG assignment as delirium is considered a higher level code than confusion within the ICD-10 coding hierarchy in terms of severity. A clinical coder or Health Information Manager may feel obliged to maximize funding above the ethical requirement to be honest within their diagnostic coding; this highlights the ethical standpoint of diagnoses codes as they should be reflective of a patient's admission. == Factors affecting accuracy in diagnostic coding == Accuracy is a major component in diagnoses codes. The accurate assignment of diagnoses codes in clinical coding is essential in order to effectively depict a patient's stay within a typical health service area. A number of factors can contribute to the overall accuracy coding which includes medical record legibility, physician documentation, clinical coder experience, financial decision making, miscoding, as well as classification system limitations. Medical record legibility The legibility of a medical record is a contributing factor in the accuracy of diagnostic coding. The assigned proxy that is extracting information from the medical record is dependent on the quality of the medical record. Factors that contribute to a medical records quality are physician documentation, handwriting legibility, compilation of forms, duplication and inaccurate patient data. For example, if a clinical coder or Health Information Manager was extracting data from a medical record in which the principal diagnoses was unclear due to illegible handwriting, the health professional would have to contact the physician responsible for documenting the diagnoses in order to correctly assign the code. In Australia, the legibility of records has been sufficiently maintained due to the implementation of highly detailed standards and guidelines which aim to improve the legibility of medical records. In particular the paper medical record standard 'AS 2828' created by Standards Australia focuses on a few key areas that are critical to maintaining a legible paper medical record. The following criteria should be used as a guideline when creating a medical record specific to the aid of providing clear documentation for diagnostic coding. In particular the legibility of a medical record is dependent on — Durability: If a medical record wasn't durable, overtime if a coder was to revisit the record and it wasn't legible it wouldn't be feasible to code from that record. Ready Identification: A coder must be able to identify the exact record being coded in order to effectively extract diagnoses codes. Reproducible: A coder would need to make sure that the record is reproducible in that copies can be made to aid in effective coding. Clinical coder experience The experience of the health professional coding a medical record is an essential variable that must be accounted for when analysing the accuracy of coding. Generally a coder with years of experience is able to extract all the relevant information from a medical record whether it is paper, scanned or semi-electronic. The diagnoses codes selected from the extraction are generally compiled and sequenced in order to represent the admission. An experienced coder may incorrectly assign codes due a lack of application of a classification systems relevant standards. An example to highlight clinical coding experience would be the standard within the Australian Coding Standards 0010 General Abstraction Guidelines. These guidelines indicate that a coder must seek further detail within a record in order to correctly assign the correct diagnoses code. An inexperienced coder may simply just use the description from the discharge summary such as Infarction and may not use the correct detail which could be further found within the details of the medical record. This directly relates to the accuracy of diagnoses codes as the experience of the health professional coder is significant in its accuracy and contribution to finance. == Weaknesses in diagnostic coding == Generally, coding is a concept of modeling reality with reduced effort, but with physical copying. Hence, the result of coding is a reduction to the scope of representation as far as possible to be depicted with the chosen modeling technology. There will never be an escape, but choosing more than one model to serve more than one purpose. That led to various code derivatives, all of them using one basic reference code for ordering, as e.g., with ICD-10 coding. However, concurrent depiction of several models in one image remains principally impossible. Focusing a code on one purpose lets other purposes unsatisfied. This has to be taken into account when advertising for any coding concept. The operability of coding is generally bound to purpose. Inter-referring must be subject of evolutionary development, as code structures are subject of frequent change. Unambiguous coding requires strict restriction to hierarchical tree structures possibly enhanced with multiple links, but no parallel branching for contemporary coding whilst maintaining bijectivity. Spatial depictions of n-dimensional code spaces as coding scheme trees on flat screens may enhance imagination, but still leave the dimensionality of image limited to intelligibility of sketching, mostly as a 3D object on a 2D screen. Pivoting such image does not solve the intelligibility problem. Projections of code spaces as flattened graphs may ease the depiction of a code, but generally reduce the contained information with the flattening. There is no explanation given with many of the codes for transforming from one code system to another. That leads to specialized usage and to limitations in communication between codes. The escape is with code reference structures (as e.g., not existing with SNOMED3). Hierarchical ordering of more than one code system may be seen as appropriate, as the human body is principally invariant to coding. But the dependency implied with such hierarchies decrease the cross referencing between the code levels down to unintelligibility. The escape is with hyper maps that exceed planar views (as e.g. with SNOMED3) and their referring to other codes (as e.g., yet not existing with SNOMED3). Purpose of documenting will be seen as essential just for the validation of a code system in aspects of correctness. However this purpose is timely subordinate to the generating of the respective information. Hence some code system shall support the process of medical diagnosis and of medical treatment of any kind. Escape is with a specialised coding for the processes of working on diagnosis as on working with treatment (as e.g., not intended with SNOMED3). Intelligibility of results of coding is achieved by semantic design principles and with ontologies to support navigating in the codes. One major aspect despite the fuzziness of language is the bijectivity of coding. Escape is with explaining the code structure to avoid misinterpreting and various codes for the very same condition (as e.g., yet not served at all with SNOMED3). == See also == Systematized Nomenclature of Medicine Diagnosis-related group Medical classification Major Diagnostic Category MedDRA American Health Information Management Association == References ==	Wikipedia/Diagnosis_code
A review of systems (ROS), also called a systems enquiry or systems review, is a technique used by healthcare providers for eliciting a medical history from a patient. It is often structured as a component of an admission note covering the organ systems, with a focus upon the subjective symptoms perceived by the patient (as opposed to the objective signs perceived by the clinician). Along with the physical examination, it can be particularly useful in identifying conditions that do not have precise diagnostic tests. == Examples == Whatever system a specific condition may seem restricted to, it may be reasonable to review all the other systems in a comprehensive history. Different sources describe slightly different systems of organizing the organ systems. However, the following are examples of what can be included. Unspecified and other symptoms can't consider for both HPI and ROS: There are 14 systems recognized by the Centers for Medicare and Medicaid Services: The questions may be asked of the patient in a "head to toe" manner. == Relationship to history == For CMS, a "problem pertinent" ROS is limited to the problem(s) identified in the HPI; an "extended" ROS covers an additional 2 to 9 systems, and a "complete" ROS covers at least 10 additional systems. The chances of double dipping should be avoided while taking ROS from History. There are many rules and guidelines a coder must be aware of when it comes to appropriately selecting an Evaluation and Management (EM) code and avoiding doubling dipping is one of them.This established patient has had a fever with sore/scratchy throat and severe headache for the past three days. He has had a little nausea but no vomiting. He said his pain is relieved with cold drinks and ibuprofen.In the above example if you take throat as location in HPI, you can not take sore/scratchy throat in ROS as ENT element. Most of the double dipping will happen in ENT section since it is a combined system. Of note, some would say that the statement of "No known allergies" could be calculated as part of the review of systems (ROS). The statement suggests the patient is not allergic to any medications, which is commonly part of the "past medical history" element.The patient was brought up by an aunt; Patient having nasal problems for last 4 days, symptoms including runny nose / rhinorrhea. Denies cough, no fever, pneumonia, severe headache for the past three days.In the above example, if you take Nose as location, you can not take runny nose/rhinorrhea in ROS as an ENT element. Double dipping is against the rules. The common double dipping example (above) uses the elements of HPI (location and associated signs and symptoms) for both the HPI and the ROS. Double dipping may increase revenue by making it possible to qualify for a higher level of history and as such be considered fraud or abuse. There is a fine line between the signs and symptoms that patient shares in the HPI and those obtained via the ROS. The ROS is a distinct review of systems. For example: if the documentation reads "'patient states that her hip has been painful' credit is not given in both the HPI 'location' and to the MSK (musculoskeletal) review of systems." It goes on to explain that if the patient's complaint is followed by "no other MSK issues", then it can be counted in the ROS as well as the HPI. == References ==	Wikipedia/Review_of_systems
Overdiagnosis is the diagnosis of disease that will never cause symptoms or death during a patient's ordinarily expected lifetime and thus presents no practical threat regardless of being pathologic. Overdiagnosis is a side effect of screening for early forms of disease. Although screening saves lives in some cases, in others it may turn people into patients unnecessarily and may lead to treatments that do no good and perhaps do harm. Given the tremendous variability that is normal in biology, it is inherent that the more one screens, the more incidental findings will generally be found. For a large percentage of them, the most appropriate medical response is to recognize them as something that does not require intervention; but determining which action a particular finding warrants ("ignoring", watchful waiting, or intervention) can be very difficult, whether because the differential diagnosis is uncertain or because the risk ratio is uncertain (risks posed by intervention, namely, adverse events, versus risks posed by not intervening). Overdiagnosis occurs when a disease is diagnosed correctly, but the diagnosis is irrelevant. A correct diagnosis may be irrelevant because treatment for the disease is not available, not needed, or not wanted. Some people contend that the term "overdiagnosis" is inappropriate, and that "overtreatment" is more representative of the phenomenon. Because most people who are diagnosed are also treated, it is difficult to assess whether overdiagnosis has occurred in an individual. Overdiagnosis in an individual cannot be determined during life. Overdiagnosis is only certain when an individual remains untreated, never develops symptoms of the disease and dies of something else. The distinction of "died with disease" versus "died of disease" is then important and relevant. Thus most of the inferences about overdiagnosis comes from the study of populations. Rapidly rising rates of testing and disease diagnosis in the setting of stable rates of the feared outcome of the disease (e.g. death) are highly suggestive of overdiagnosis. Most compelling, however, is evidence from a randomized trial of a screening test intended to detect pre-clinical disease. A persistent excess of detected disease in the tested group years after the trial is completed constitutes the best evidence that overdiagnosis has occurred. Although overdiagnosis is potentially applicable to the diagnosis of any disease, the concept was first recognized and studied in cancer screening—the systematic evaluation of asymptomatic patients to detect early forms of cancer. The central harm of cancer screening is overdiagnosis—the detection of abnormalities that meet the pathologic definition of cancer (under the microscope) but will never progress to cause symptoms or death during a patient's ordinarily expected lifetime. In advanced age, such as 65 years or older, the concept of overdiagnosis takes on increasing importance as life expectancy decreases. There are various cancer types for which a standard contraindication to screening is life expectancy of less than 10 years, for the simple and logical reason that a person who already has medically complex health status (e.g., multiple comorbidities) and realistically can probably expect to live for less than 10 years is less likely to get a net benefit (balance of benefit versus harms) from diagnosing and treating that cancer, especially if it may be indolent anyway. Prostate cancer is a classic example, but the concept can apply to breast cancer and other types as well. == Overdiagnosis and the variability of cancer progression == Cancer screening is the effort to detect cancer early, during its pre-clinical phase—the time period that begins with an abnormal cell and ends when the patient notices symptoms from the cancer. It has long been known that some people have cancers with short pre-clinical phases (fast-growing, aggressive cancers), while others have cancers with long pre-clinical phases (slow-growing cancers). And this heterogeneity has an unfortunate implication: namely, screening tends to disproportionately detect slow-growing cancers (because they are accessible to be detected for a long period of time) and disproportionately miss the fast-growing cancers (because they are only accessible to be detected for a short period of time)—the very cancers we would most like to catch. For more information, see Screening (medicine)#Length time bias. This long-standing model has a hidden assumption: namely, that all cancers inevitably progress. But some pre-clinical cancers will not progress to cause problems for patients. And if screening (or testing for some other reason) detects these cancers, overdiagnosis has occurred. The figure below depicts the heterogeneity of cancer progression using 4 arrows to represent 4 categories of cancer progression. The arrow labeled "Fast" represents a fast-growing cancer, one that quickly leads to symptoms and to death. These are the worst forms of cancer and unfortunately often appear in the interval between screening tests. The arrow labeled "Slow" represents a slow-growing cancer, one that leads to symptoms and death but only after many years. These are the cancers for which screening has arguably the greatest beneficial impact. The arrow labeled "Very Slow" represents a cancer that never causes problems because it is growing very slowly. If a cancer grows slowly enough, then patients will die of some other cause before the cancer gets big enough to produce symptoms. The arrow labeled "Non-progressive" represents a cancer that never causes problems because it is not growing at all. In other words, there are cellular abnormalities that meet the pathologic definition of cancer but never grow to cause symptoms—alternatively, they may grow and then regress. Although the concept of non-progressive cancers may seem implausible, basic scientists have begun to uncover biologic mechanisms that halt the progression of cancer. Some cancers outgrow their blood supply (and are starved), others are recognized by the host's immune system (and are successfully contained), and some are not that aggressive in the first place. Cancer that grows too slowly to be likely to harm the patient is usually referred to as a benign tumor. Although some types of benign tumor may require intervention, they are often simply monitored for malignant transformation. == Evidence for overdiagnosis in cancer == The phenomenon of overdiagnosis is most widely understood in prostate cancer. A dramatic increase in the number of new cases of prostate cancer was observed following the introduction of the PSA (prostate specific antigen) screening test. Because of the problem of overdiagnosis, most organizations recommend against prostate cancer screening in men with limited life expectancy—generally defined as less than 10 years (see also prostate cancer screening). Overdiagnosis has been identified in mammographic screening for breast cancer. Long-term follow-up of the Malmo randomized trial of mammography found a persistent excess of 115 breast cancers in the screened group 15 years after the trial was completed (a 10% rate of overdiagnosis). In a letter to the editor, authors not associated with the original study of the data from the randomized clinical trial argued that one-quarter of mammographically detected breast cancers represent overdiagnosis. A systematic review of mammography screening programs reported an overdiagnosis rate of around 50%, which is the same of saying that a third of diagnosed cases of breast cancer are overdiagnosed. Overdiagnosis has also been identified in chest x-ray screening for lung cancer. Long-term follow-up of the Mayo Clinic randomized trial of screening with chest x-rays and sputum cytology found a persistent excess of 46 lung cancer cases in the screened group 13 years after the trial was completed, suggesting that 20–40% of lung cancers detected by conventional x-ray screening represent overdiagnosis. There is considerable evidence that the problem of overdiagnosis is much greater for lung cancer screening using spiral CT scans. Overdiagnosis has also been associated with early detection in a variety of other cancers, including neuroblastoma, melanoma, and thyroid cancer. In fact, some degree of overdiagnosis in cancer early detection is probably the rule, not the exception. == Evidence for overdiagnosis of infectious diseases == Issues with overdiagnosis of infectious diseases, such as malaria or typhoid fever, persist in many regions around the world. For example, malaria overdiagnosis is well-documented in African countries. and results in over-inflation of actual malaria rates reported at the local and national levels. Health facilities tend to over-diagnose malaria in patients presenting with symptoms such as fever, due to traditional perceptions (for example any fever being equivalent to malaria) and issues related to laboratory testing (see Diagnosis of malaria). Therefore, malaria overdiagnosis leads to under-management of other fever-inducing conditions, but also to over-prescription of antimalarial drugs. == Harms of overdiagnosis == Overdiagnosed patients cannot benefit from the detection and treatment of their "cancer" because the cancer was never destined to cause symptoms or death. They can only be harmed. There are three categories of harm associated with overdiagnosis: Physical effects of unnecessary diagnosis and treatment: All medical interventions have side effects. This is particularly true of cancer treatments. Surgery, radiation and chemotherapy all pose varying morbidity and mortality risks. Psychological effects: there is a burden for an individual simply being labeled as "diseased" (e.g. the burden of being labeled a "cancer patient") and an associated increased sense of vulnerability. Economic burden: Not only the associated cost of treatment (from which the patient cannot benefit, because the disease posed no threat), but also—at least, in the current health care system in the United States—a potential increase in the cost of health insurance or even an inability to procure it (e.g. the diagnosis creates a pre-existing condition that affects health insurance). Similar issues may arise with life insurance. Unlike health insurance, life insurance does not fall under the scope of the Affordable Care Act, thus insurers have even more leeway in denying or reducing coverage or inflating premiums due to the patient's condition. While many identify false positive results as the major downside to cancer screening, there are data to suggest that—when patients are informed about overdiagnosis—they are much more concerned about overdiagnosis than false positive results. == Distinction among overdiagnosis, misdiagnosis, and false positive results == Overdiagnosis is often confused with the term "false positive" test results and with misdiagnosis, but they are three distinct concepts. A false positive test result refers to a test that suggests the presence of disease, but is ultimately proved to be in error (usually by a second, more precise test). Patients with false positive test results may be told that they have a disease and erroneously treated; overdiagnosed patients are told they have disease and generally receive treatment. Misdiagnosed patients do not have the condition at all, or have a totally different condition, but are treated anyway. Overdiagnosis is also distinct from overtesting. Overtesting is the phenomenon where patients receive a medical test that they don't need; it will not benefit them. For instance, a patient that receives a lumbar spine x-ray when they have low back pain without any sinister signs or symptoms (weight loss, fever, lower limb paresthesia, etc.) and symptoms have been present for less than 4 weeks. Most tests are subject to overtesting, but echocardiograms (ultrasounds of the heart) have been shown to be particularly prone to overtesting. The detection of overtesting is difficult; recently, many population-level estimates have emerged to try to detect potential overtesting. The most common of these estimates is geographical variation in test use. These estimates detect regions, hospitals or general practices that order many more tests, compared to their peers, irrespective of differences in patient demographics between regions. Further methods that have been used include identifying general practices that order a higher proportion of tests that return a normal result, and the identification of tests with large temporal increases in their use, without a justifiable reason. == Solutions to overdiagnosis == The concept of undiagnosing is a strategy to review diagnostic labels and remove those that are unnecessary or no longer beneficial. It is important that the medical record is updated to reflect the removal of the diagnosis. === Removing cancer from names of low-risk diagnoses === It has been proposed that some conditions that are indolent (i.e., unlikely to cause appreciable harm during the patient's lifetime) should have the words "cancer" or "carcinoma" removed from their accepted/preferred medical name. Such a proposal is to name conditions as indolent lesions of epithelial origin or IDLE. == Medical complexity == If a person is medically complex (multiple comorbidities) and may expect to live for less than ten years, then there may be a net harm (benefit less harm) in diagnosing and treating one or more of their morbidities, eg prostate cancer. The principal, however, can apply to all cancers and other illnesses. == See also == Disease mongering – Pejorative term for expanding a disease's market for treatment False positive – Types of error in data reportingPages displaying short descriptions of redirect targets Medicalization – Categorization of human problems as medical Interventionism (medicine) – medical model in which patients are viewed as passive recipients receiving external treatments provided by the physician that have the effect of prolonging life, or at least of providing a subjective sense of doing everything possiblePages displaying wikidata descriptions as a fallback Patient education – teaching or training of patients concerning their own health needsPages displaying wikidata descriptions as a fallback Schooliosis – Misdiagnosis of scoliosis Screening (medicine) – Brief medical evaluation to detect unnoticed health problems == References == == Further reading == Welch, H. Gilbert, Schwartz, Lisa. Overdiagnosed: Making People Sick in the Pursuit of Health. Beacon Press; 2011-01-18. ISBN 9780807022009.	Wikipedia/Overdiagnosis
Dual diagnosis (also called co-occurring disorders (COD) or dual pathology) is the condition of having a mental illness and a comorbid substance use disorder. Several US based surveys suggest that about half of those with a mental illness will also experience a substance use disorder, and vice versa. There is considerable debate surrounding the appropriateness of using a single category for a heterogeneous group of individuals with complex needs and a varied range of problems. The concept can be used broadly, for example depression and alcohol use disorder, or it can be restricted to specify severe mental illness (e.g. psychosis, schizophrenia) and substance use disorder (e.g. cannabis use), or a person who has a milder mental illness and a drug dependency, such as panic disorder or generalized anxiety disorder and is dependent on opioids. Diagnosing a primary psychiatric illness in people who use substances is challenging as substance use disorder itself often induces psychiatric symptoms, thus making it necessary to differentiate between substance induced and pre-existing mental illness. Those with co-occurring disorders face complex challenges. They have increased rates of relapse, hospitalization, homelessness, and HIV and hepatitis C infection compared to those with either mental or substance use disorders alone. == Differentiating pre-existing and substance induced == The identification of substance-induced versus independent psychiatric symptoms or disorders has important treatment implications and often constitutes a challenge in daily clinical practice. Similar patterns of comorbidity and risk factors in individuals with substance induced disorder and those with independent non-substance induced psychiatric symptoms suggest that the two conditions may share underlying etiologic factors. Substance use disorders, including those of alcohol and prescription medications, can induce a set of symptoms which resembles mental illness, which can make it difficult to differentiate between substance induced psychiatric syndromes and pre-existing mental health problems. More often than not psychiatric disorders among people who use alcohol or illicit substances disappear with prolonged abstinence. Substance induced psychiatric symptoms can occur both in the intoxicated state and also during the withdrawal state. In some cases, these substance induced psychiatric disorders can persist long after detoxification, such as prolonged psychosis or depression after amphetamine or cocaine use. Use of hallucinogens can trigger delusional and other psychotic phenomena long after cessation of use and cannabis may trigger panic attacks during intoxication and with use it may cause a state similar to dysthymia. Severe anxiety and depression are commonly induced by sustained alcohol use which in most cases abates with prolonged abstinence. Even moderate sustained use of alcohol may increase anxiety and depression levels in some individuals. In most cases these drug induced psychiatric disorders fade away with prolonged abstinence. A protracted withdrawal syndrome can also occur with psychiatric and other symptoms persisting for months after cessation of use. Among the currently prevalent medications, benzodiazepines are the most notable drug for inducing prolonged withdrawal effects with symptoms sometimes persisting for years after cessation of use. Prospective epidemiological studies do not support the hypotheses that comorbidity of substance use disorders with other psychiatric illnesses is primarily a consequence of substance use or dependence or that increasing comorbidity is largely attributable to increasing use of substances. Yet emphasis is often on the effects of substances on the brain creating the impression that dual disorders are a natural consequence of these substances. However, addictive drugs or exposure to gambling will not lead to addictive behaviors or drug dependence in most individuals but only in vulnerable ones, although, according to some researchers, neuroadaptation or regulation of neuronal plasticity, and molecular changes, may alter gene expression in some cases and subsequently lead to substance use disorders. Research instruments are also often insufficiently sensitive to discriminate between independent, true dual pathology, and substance-induced symptoms. Structured instruments, as Global Appraisal of Individual Needs - Short Screener-GAIN-SS and Psychiatric Research Interview for Substance and Mental Disorders for DSM-IV-PRISM, have been developed to increase the diagnostic validity. While structured instruments can help organize diagnostic information, clinicians must still make judgments on the origin of symptoms. == Prevalence == Comorbidity of addictive disorders and other psychiatric disorders, i.e., dual disorders, is very common and a large body of literature has accumulated demonstrating that mental disorders are strongly associated with substance use disorders. Adolescents and young adults are particularly at risk for dual diagnosis, as early substance use can interfere with brain development and exacerbate emerging mental health conditions. The 2011 USA National Survey on Drug Use and Health found that 17.5% of adults with a mental illness had a co-occurring substance use disorder; this works out to 7.98 million people. Estimates of co-occurring disorders in Canada are even higher, with an estimated 40-60% of adults with a severe and persistent mental illness experiencing a substance use disorder in their lifetime. A study by Kessler et al. in the United States attempting to assess the prevalence of dual diagnosis found that 47% of clients with schizophrenia had a substance misuse disorder at some time in their life, and the chances of developing a substance misuse disorder was significantly higher among patients with a psychotic illness than in those without a psychotic illness. Another study looked at the extent of substance misuse in a group of 187 chronically mentally ill patients living in the community. According to the clinician's ratings, around a third of the sample used alcohol, street drugs, or both during the six months before evaluation. Further UK studies have shown slightly more moderate rates of substance misuse among mentally ill individuals. One study found that individuals with schizophrenia showed just a 7% prevalence of problematic drug use in the year prior to being interviewed and 21% reported problematic use some time before that. Wright and colleagues identified individuals with psychotic illnesses who had been in contact with services in the London borough of Croydon over the previous 6 months. Cases of alcohol or substance misuse and dependence were identified through standardized interviews with clients and keyworkers. Results showed that prevalence rates of dual diagnosis were 33% for the use of any substance, 20% for alcohol misuse only and 5% for drug misuse only. A lifetime history of any illicit drug use was observed in 35% of the sample. == Diagnosis == Substance use disorders can be confused with other psychiatric disorders. There are diagnoses for substance-induced mood disorders and substance-induced anxiety disorders and thus such overlap can be complicated. For this reason, the DSM-IV advises that diagnoses of primary psychiatric disorders not be made in the absence of sobriety (of a duration sufficient to allow for any substance-induced post-acute-withdrawal symptoms to dissipate) up to 1 year. == Treatment == Only a small proportion of those with co-occurring disorders actually receive treatment for both disorders. Therefore, it was argued that a new approach is needed to enable clinicians, researchers and managers to offer adequate assessment and evidence-based treatments to patients with dual pathology, who cannot be adequately and efficiently managed by cross-referral between psychiatric and addiction services as currently configured and resourced. In 2011, it was estimated that only 12.4% of American adults with co-occurring disorders were receiving both mental health and addictions treatment. Clients with co-occurring disorders face challenges accessing treatment, as they may be excluded from mental health services if they admit to a substance use problem and vice versa. There are multiple approaches to treat concurrent disorders. Partial treatment involves treating only the disorder that is considered primary. Sequential treatment involves treating the primary disorder first, and then treating the secondary disorder after the primary disorder has been stabilized. Parallel treatment involves the client receiving mental health services from one provider, and addictions services from another. Integrated treatment involves a seamless blending of interventions into a single coherent treatment package developed with a consistent philosophy and approach among care providers. With this approach, both disorders are considered primary. Integrated treatment can improve accessibility, service individualization, engagement in treatment, treatment compliance, mental health symptoms, and overall outcomes. The Substance Abuse and Mental Health Services Administration in the United States describes integrated treatment as being in the best interests or clients, programs, funders, and systems. Green suggested that treatment should be integrated, and a collaborative process between the treatment team and the patient. Furthermore, recovery should to be viewed as a marathon rather than a sprint, and methods and outcome goals should be explicit. A 2019 Cochrane meta-analysis that included 41 randomized controlled trials found no high-quality evidence in support of any one psycho-social intervention over standard care for outcomes such as remaining in treatment, reduction in substance use and/or improvement in global functioning and mental status. == Theories of dual diagnosis == There are a number of theories that explain the relationship between mental illness and substance use. === Causality === The causality theory suggests that certain types of substance use may causally lead to mental illness. There is strong evidence that using cannabis can produce psychotic and affective experiences. When it comes to persisting effects, there is a clear increase in the incidence of psychotic outcomes in people who had used cannabis, even when they had used it only once. More frequent use of cannabis strongly augmented the risk for psychosis. The evidence for affective outcomes is less strong. However, this connection between cannabis and psychosis does not prove that cannabis causes psychotic disorders. The causality theory for cannabis has been challenged as despite explosive increases in cannabis consumption over the past 40 years in western society, the rate of schizophrenia (and psychosis in general) has remained relatively stable. === Attention-deficit hyperactivity disorder === One in four people who have a substance use disorder also have attention-deficit hyperactivity disorder, which makes the treatment of both conditions more difficult. ADHD is associated with an increased craving for drugs. Having ADHD makes it more likely that an individual will initiate substance misuse at a younger age than their peers. They are also more likely to experience poorer outcomes, such as longer time to remission, and to have increased psychiatric complications from substance misuse. While generally stimulant medications do not seem to worsen substance use, they are known to be non-medically used in some cases. Psychosocial therapy and/or nonstimulant medications and extended release stimulants are ADHD treatment options that reduce these risks. === Autism spectrum disorder === Unlike ADHD, which significantly increases the risk of substance use disorder, autism spectrum disorder has the opposite effect of significantly reducing the risk of substance use. This is because introversion, inhibition and lack of sensation seeking personality traits, which are typical of autism spectrum disorder, protect against substance use and thus substance use levels are low in individuals who are on the autism spectrum. However, certain forms of substance use disorders, especially alcohol use disorder, can cause or worsen certain neuropsychological symptoms which are common to autism spectrum disorder. This includes impaired social skills due to the neurotoxic effects of alcohol on the brain, especially in the prefrontal cortex area of the brain. The social skills that are impaired by alcohol use disorder include impairments in perceiving facial emotions, prosody perception problems and theory of mind deficits; the ability to understand humour is also impaired in people who consume excessive amounts of alcohol === Gambling === The inclusion of behavioral addictions like pathological gambling must change our way of understanding and dealing with addictions. Pathological (disordered) gambling has commonalities in clinical expression, etiology, comorbidity, physiology and treatment with substance use disorders (DSM-5). A challenge is to understand the development of compulsivity at a neurochemical level not only for drugs. === Past exposure to psychiatric medications theory === The past exposure theory suggests that exposure to psychiatric medication alters neural synapses, introducing an imbalance that was not previously present. Discontinuation of the drug is expected to result in symptoms of psychiatric illness which resolve once the drug is restarted. This theory suggests that while it may appear that the medication is working, it is only treating a disorder caused by the medication itself. New exposure to psychiatric medication may lead to heightened sensitivity to the effects of drugs such as alcohol, which has a deteriorating effect on the patient. === Self-medication theory === The self-medication theory suggests that people with severe mental illnesses misuse substances in order to relieve a specific set of symptoms and counter the negative side-effects of antipsychotic medication. Khantizan proposes that substances are not randomly chosen, but are specifically selected for their effects. For example, using stimulants such as nicotine or amphetamines can be used to combat the sedation that can be caused by higher doses of certain types of antipsychotic medication. Conversely, some people taking medications with a stimulant effect such as the SNRI antidepressants Effexor (venlafaxine) or Wellbutrin (bupropion) may seek out benzodiazepines or opioid narcotics to counter the anxiety and insomnia that such medications sometimes evoke. Some studies show that nicotine administration can be effective for reducing motor side-effects of antipsychotics, with both bradykinesia (stiff muscles) and dyskinesia (involuntary movement) being prevented. === Alleviation of dysphoria theory === The alleviation of dysphoria theory suggests that people with severe mental illness commonly have a negative self-image, which makes them vulnerable to using psychoactive substances to alleviate these feelings. Despite the existence of a wide range of dysphoric feelings (anxiety, depression, boredom, and loneliness), the literature on self-reported reasons for use seems to lend support for the experience of these feelings being the primary motivator for alcohol use disorder and other drug misuse. === Multiple risk factor theory === Another theory is that there may be shared risk factors that can lead to both substance use and mental illness. Mueser hypothesizes that these may include factors such as social isolation, poverty, lack of structured daily activity, lack of adult role responsibility, living in areas with high drug availability, and association with people who already misuse drugs. Other evidence suggests that traumatic life events, such as sexual abuse, are associated with the development of psychiatric problems and substance use. === The supersensitivity theory === The supersensitivity theory proposes that certain individuals who have severe mental illness also have biological and psychological vulnerabilities, caused by genetic and early environmental life events. These interact with stressful life events and can result in either a psychiatric disorder or trigger a relapse into an existing illness. The theory states that although anti-psychotic medication can reduce the vulnerability, substance use may increase it, causing the individual to be more likely to experience negative consequences from using relatively small amounts of substances. These individuals, therefore, are "supersensitive" to the effects of certain substances, and individuals with psychotic illness such as schizophrenia may be less capable of sustaining moderate substance use over time without experiencing negative symptoms. Although there are limitations in the research studies conducted in this area, namely that most have focused primarily on schizophrenia, this theory provides an explanation of why relatively low levels of substance misuse often result in negative consequences for individuals with severe mental illness. == Avoiding categorical diagnosis == Current nosological approach does not provide a framework for internal (sub-threshold symptoms) or external (comorbidity) heterogeneity of the different diagnostic categories. The prevailing "Neo-Kraepelinian" diagnostic system solely accounts for a categorical diagnosis, therefore not allowing for the possibility of dual diagnosis. There has been substantial criticism to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), due to problems of diagnostic overlap, lack of clear boundaries between normality and disease, a failure to take into account findings from novel research and the lack of diagnostic stability over time. == History == The traditional method for treating patients with dual diagnosis was a parallel treatment program. In this format, patients received mental health services from one clinician while addressing their substance use with a separate clinician. However, researchers found that parallel treatments were ineffective, suggesting a need to integrate the services addressing mental health with those addressing substance use. During the mid-1980s, a number of initiatives began to combine mental health and substance use disorder services in an attempt to meet this need. These programs worked to shift the method of treatment for substance use from a confrontational approach to a supportive one. They also introduced new methods to motivate clients and worked with them to develop long-term goals for their care. Although the studies conducted by these initiatives did not have control groups, their results were promising and became the basis for more rigorous efforts to study and develop models of integrated treatment. The COVID-19 pandemic has been associated with increased rates of substance use and psychological distress, potentially increasing co-occurring disorders in vulnerable populations. == References == == Further reading == Blanco, Carlos; Alegría, Analucía A.; Liu, Shang-Min; Secades-Villa, Roberto; Sugaya, Luisa; Davies, Carrie; Nunes, Edward V. (2012). "Differences Among Major Depressive Disorder with and Without Co-occurring Substance Use Disorders and Substance-Induced Depressive Disorder". The Journal of Clinical Psychiatry. 73 (6): 865–873. doi:10.4088/JCP.10m06673. PMID 22480900. Sciacca, Kathleen_2009. "Best Practices for Dual Diagnosis Treatment and Program Development: Co-occurring Mental Illness and Substance Disorders in Various Combinations". In Angela Brown-Miller (ed.). The Praeger International Collection on Addictions. Vol. 3. Praeger. pp. 161–188.{{cite book}}: CS1 maint: numeric names: authors list (link) Sciacca, K. (2011). "Integrated Group Treatment for People Experiencing Mental Health - Substance Use Problems". In David B. Cooper (ed.). Intervention in Mental Health - Substance Use. Radcliffe Pub. pp. 114–127. Sciacca, K.; Hatfield, A. B. (1995). "The Family and the Dually Diagnosed Patient". In Lehman, A. F.; Dixon, L. B. (eds.). Double Jeopardy. Harwood Academic Publishers. pp. 193–209. Giglioti, M. A. (October 1986). "Program Initiatives for Dually-Diagnosed at Harlem Valley Psychiatric Center. Dual Diagnosis -Co-occurring Disorders". New York State Commission on Quality of Care Publication (28). Samet S, Nunes E, Hassin D, et al. (2006). "Diagnosis of comorbid psychiatric disorders in substance users assesses with the Psychiatric Research Interview for Substance and Mental Disorders for DSM-IV". American Journal of Psychiatry. 163 (4): 689–696. doi:10.1176/appi.ajp.163.4.689. PMID 16585445. Sciacca, K. (1997). "Peer Support for People Challenged by Dual Diagnosis: 'Helpful People in Touch' (Consumer Led Self-Help)" (PDF). In Mowbray, C.T.; Moxley, D.P.; Jasper, C.A.; Howell, L.L. (eds.). Consumers as Providers in Psychosocial Rehabilitation. IAPSRS Publisher. p. 82. Archived from the original (PDF) on 1 February 2012. Retrieved 2 September 2011. Adamson, Simon J.; Todd, Fraser C.; Douglas Sellman, J.; Huriwai, Terry; Porter, Joel (2006). "Coexisting Psychiatric Disorders in a New Zealand Outpatient Alcohol and other Drug Clinical Population". Australian & New Zealand Journal of Psychiatry. 40 (2): 164–170. doi:10.1080/j.1440-1614.2006.01764.x. PMID 16476135. S2CID 208628311.	Wikipedia/Dual_diagnosis
The respiratory rate is the rate at which breathing occurs; it is set and controlled by the respiratory center of the brain. A person's respiratory rate is usually measured in breaths per minute. == Measurement == The respiratory rate in humans is measured by counting the number of breaths for one minute through counting how many times the chest rises. A fibre-optic breath rate sensor can be used for monitoring patients during a magnetic resonance imaging scan. Respiration rates may increase with fever, illness, or other medical conditions. Inaccuracies in respiratory measurement have been reported in the literature. One study compared respiratory rate counted using a 90-second count period, to a full minute, and found significant differences in the rates.. Another study found that rapid respiratory rates in babies, counted using a stethoscope, were 60–80% higher than those counted from beside the cot without the aid of the stethoscope. Similar results are seen with animals when they are being handled and not being handled—the invasiveness of touch apparently is enough to make significant changes in breathing. Various other methods to measure respiratory rate are commonly used, including impedance pneumography, and capnography which are commonly implemented in patient monitoring. In addition, novel techniques for automatically monitoring respiratory rate using wearable sensors are in development, such as estimation of respiratory rate from the electrocardiogram, photoplethysmogram, or accelerometry signals. Breathing rate is often interchanged with the term breathing frequency. However, this should not be considered the frequency of breathing because realistic breathing signal is composed of many frequencies. == Normal range == For humans, the typical respiratory rate for a healthy adult at rest is 12–15 breaths per minute. The respiratory center sets the quiet respiratory rhythm at around two seconds for an inhalation and three seconds exhalation. This gives the lower of the average rate at 12 breaths per minute. Average resting respiratory rates by age are: birth to 6 weeks: 30–40 breaths per minute 6 months: 25–40 breaths per minute 3 years: 20–30 breaths per minute 6 years: 18–25 breaths per minute 10 years: 17–23 breaths per minute Adults: 15–18 breaths per minute 50 years: 18-25 breaths per minute Elderly ≥ 65 years old: 12–28 breaths per minute. Elderly ≥ 80 years old: 10-30 breaths per minute. == Minute volume == Respiratory minute volume is the volume of air which is inhaled (inhaled minute volume) or exhaled (exhaled minute volume) from the lungs in one minute. == Diagnostic value == The value of respiratory rate as an indicator of potential respiratory dysfunction has been investigated but findings suggest it is of limited value. One study found that only 33% of people presenting to an emergency department with an oxygen saturation below 90% had an increased respiratory rate. An evaluation of respiratory rate for the differentiation of the severity of illness in babies under 6 months found it not to be very useful. Approximately half of the babies had a respiratory rate above 50 breaths per minute, thereby questioning the value of having a "cut-off" at 50 breaths per minute as the indicator of serious respiratory illness. It has also been reported that factors such as crying, sleeping, agitation and age have a significant influence on the respiratory rate. As a result of these and similar studies the value of respiratory rate as an indicator of serious illness is limited. Nonetheless, respiratory rate is widely used to monitor the physiology of acutely-ill hospital patients. It is measured regularly to facilitate identification of changes in physiology along with other vital signs. This practice has been widely adopted as part of early warning systems. == Abnormal respiratory rates == == See also == Subparabrachial nucleus - nucleus in the brain stem that regulates breathing rate Respiratory system Heart rate and pulse and systolic and diastolic blood pressure measurements and the level of oxygen saturation- some other vital signs- can provide related information about the heart and lungs and the great vessels, since these systems work with one another, are relatively close together in gross (macroscopic) anatomy, and are physiologically very related. == References ==	Wikipedia/Respiratory_rate
Diagnosis-related group (DRG) is a system to classify hospital cases into one of originally 467 groups, with the last group (coded as 470 through v24, 999 thereafter) being "Ungroupable". This system of classification was developed as a collaborative project by Robert B Fetter, PhD, of the Yale School of Management, and John D. Thompson, MPH, of the Yale School of Public Health. The system is also referred to as "the DRGs", and its intent was to identify the "products" that a hospital provides. One example of a "product" is an appendectomy. The system was developed in anticipation of convincing Congress to use it for reimbursement, to replace "cost based" reimbursement that had been used up to that point. DRGs are assigned by a "grouper" program based on ICD (International Classification of Diseases) diagnoses, procedures, age, sex, discharge status, and the presence of complications or comorbidities. DRGs have been used in the US since 1982 to determine how much Medicare pays the hospital for each "product", since patients within each category are clinically similar and are expected to use the same level of hospital resources. DRGs may be further grouped into Major Diagnostic Categories (MDCs). DRGs are also standard practice for establishing reimbursements for other Medicare related reimbursements such as to home healthcare providers. == Purpose == The original objective of diagnosis-related groups (DRG) was to develop a classification system that identified the "products" that the patient received. Since the introduction of DRGs in the early 1980s, the healthcare industry has evolved and developed an increased demand for a patient classification system that can serve its original objective at a higher level of sophistication and precision. To meet those evolving needs, the objective of the DRG system had to expand in scope. Several different DRG systems have been developed in the United States. They include: Medicare DRG (CMS-DRG & MS-DRG) Refined DRGs (R-DRG) All Patient DRGs (AP-DRG) Severity DRGs (S-DRG) All Patient, Severity-Adjusted DRGs (APS-DRG) All Patient Refined DRGs (APR-DRG) International-Refined DRGs (IR-DRG) Other DRG systems have been developed for markets such as Latin America and ASIA, for example: AVEDIAN DRG Grouper (LAT-GRC) == Statistics == As of 2003, the top 10 DRGs accounted for almost 30% of acute hospital admissions.: 6 In 1991, the top 10 DRGs overall were: normal newborn (vaginal delivery), heart failure, psychoses, Caesarean section, neonate with significant problems, angina pectoris, specific cerebrovascular disorders, pneumonia, and hip/knee replacement. These DRGs comprised nearly 30 percent of all hospital discharges. In terms of geographic variation, as of 2011 hospital payments varied across 441 labor markets. == History == The system was created in the early 1970s by Robert Barclay Fetter and John D. Thompson at Yale University with the material support of the former Health Care Financing Administration (HCFA), now called the Centers for Medicare & Medicaid Services (CMS). DRGs were first implemented in New Jersey, beginning in 1980 at the initiative of NJ Health Commissioner Joanne Finley: 13 with a small number of hospitals partitioned into three groups according to their budget positions — surplus, breakeven, and deficit — prior to the imposition of DRG payment. The New Jersey experiment continued for three years, with additional cadres of hospitals being added to the number of institutions each year until all hospitals in New Jersey were dealing with this prospective payment system. DRGs were designed to be homogeneous units of hospital activity to which binding prices could be attached. A central theme in the advocacy of DRGs was that this reimbursement system would, by constraining the hospitals, oblige their administrators to alter the behaviour of the physicians and surgeons comprising their medical staffs. Hospitals were forced to leave the "nearly risk-free world of cost reimbursement" and face the uncertain financial consequences associated with the provision of health care. DRGs were designed to provide practice pattern information that administrators could use to influence individual physician behaviour. DRGs were intended to describe all types of patients in an acute hospital setting. DRGs encompassed elderly patients as well as new born, pediatric and adult populations. The prospective payment system implemented as DRGs had been designed to limit the share of hospital revenues derived from the Medicare program budget. In 1982 the US Congress passed Tax Equity and Fiscal Responsibility Act with provisions to reform Medicare payment, and in 1983, an amendment was passed to use DRGs for Medicare,: 16 with HCFA (now CMS) maintaining the definitions. In 1988, New York state passed legislation instituting DRG-based payments for all non-Medicare patients. This legislation required that the New York State Department of Health (NYS DOH) evaluate the applicability of Medicare DRGs to a non-Medicare population. This evaluation concluded that the Medicare DRGs were not adequate for a non-Medicare population. Based on this evaluation, the NYS DOH entered into an agreement with 3M to research and develop all necessary DRG modifications. The modifications resulted in the initial APDRG, which differed from the Medicare DRG in that it provided support for transplants, high-risk obstetric care, nutritional disorders, and pediatrics along with support for other populations. One challenge in working with the APDRG groupers is that there is no set of common data/formulas that is shared across all states as there is with CMS. Each state maintains its own information. The history, design, and classification rules of the DRG system, as well as its application to patient discharge data and updating procedures, are presented in the CMS DRG Definitions Manual (Also known as the Medicare DRG Definitions Manual and the Grouper Manual). A new version generally appears every October. The 20.0 version appeared in 2002. In 2007, author Rick Mayes described DRGs as: ...the single most influential postwar innovation in medical financing: Medicare's prospective payment system (PPS). Inexorably rising medical inflation and deep economic deterioration forced policymakers in the late 1970s to pursue radical reform of Medicare to keep the program from insolvency. Congress and the Reagan administration eventually turned to the one alternative reimbursement system that analysts and academics had studied more than any other and had even tested with apparent success in New Jersey: prospective payment with diagnosis-related groups (DRGs). Rather than simply reimbursing hospitals whatever costs they charged to treat Medicare patients, the new model paid hospitals a predetermined, set rate based on the patient's diagnosis. The most significant change in health policy since Medicare and Medicaid's passage in 1965 went virtually unnoticed by the general public. Nevertheless, the change was nothing short of revolutionary. For the first time, the federal government gained the upper hand in its financial relationship with the hospital industry. Medicare's new prospective payment system with DRGs triggered a shift in the balance of political and economic power between the providers of medical care (hospitals and physicians) and those who paid for it - power that providers had successfully accumulated for more than half a century. == United States state-based usage == DRGs were originally developed in New Jersey before the federal adoption for Medicare in 1983.: 16 After the federal adoption, the system was adopted by states, including in Medicaid payment systems, with twenty states using some DRG-based system in 1991; however, these systems may have their own unique adjustments.: 17 In 1992, New Jersey repealed the DRG payment system after political controversy.: 21 == Example calculation == == DRG changes == == International == DRGs and similar systems have expanded internationally; for example, in Europe some countries imported the scheme from US or Australia, and in other cases they were developed independently. In England, a similar set of codes exist called Health Resource Groups.: 199 As of 2018, Asian countries such as South Korea, Japan, and Thailand have limited adoption of DRGs. Latin American countries use a DRG system adapted to regionally extended medical classifications and nomenclatures. This DRG system is called AVEDIAN DRG GROUPER (LAT-GRC). == See also == Case mix index Diagnosis code Healthcare Resource Group, UK's implementation International Classification of Diseases (ICD) Medical classification Ambulatory Patient Group, similar to DRG but for outpatient care Risk of mortality (ROM) Severity of illness (SOI) Pay for Performance == References == == External links == Official CMS website CMS Acute Inpatient Prospective Payment System DRG codes for FY2005, also referred to as version 23 DRG codes for FY2010, also referred to as version 27 MS-DRG Grouper version 35 (FY2018) Software, PC and Mainframe, supports versions 16-35 Healthcare Cost and Utilization Project (Search engine can be used to find Definitions Manual) Agency for Healthcare Research and Quality (AHRQ). DRG definition. Most Frequent Diagnoses and Procedures for DRGs Archived 2012-06-19 at the Wayback Machine. Medical Billing and Coding Information Guide Diagnosis Related Groups (DRGs) and the Medicare Program - Implications for Medical Technology (PDF format). A 1983 document found in the "CyberCemetery: OTA Legacy" section of University of North Texas Libraries Government Documents department. Mayes, Rick, "The Origins, Development, and Passage of Medicare's Revolutionary Prospective Payment System" Journal of the History of Medicine and Allied Sciences Volume 62, Number 1, January 2007, pp. 21–55	Wikipedia/Diagnosis-related_group
A retrospective diagnosis (also retrodiagnosis or posthumous diagnosis) is the practice of identifying an illness after the death of the patient (sometimes a historical figure) using modern knowledge, methods and disease classifications. Alternatively, it can be the more general attempt to give a modern name to an ancient and ill-defined scourge or plague. == Historical research == Retrospective diagnosis is practised by medical historians, general historians and the media with varying degrees of scholarship. At its worst it may become "little more than a game, with ill-defined rules and little academic credibility". The process often requires "translating between linguistic and conceptual worlds separated by several centuries", and assumes our modern disease concepts and categories are privileged. Crude attempts at retrospective diagnosis fail to be sensitive to historical context, may treat historical and religious records as scientific evidence, or ascribe pathology to behaviours that require none. Darin Hayton, a historian of science at Haverford College, claims that retrodiagnosing famous individuals with autism in the media is pointless, as historical accounts often contain incomplete information. The understanding of the history of illness can benefit from modern science. For example, knowledge of the insect vectors of malaria and yellow fever can be used to explain the changes in extent of those diseases caused by drainage or urbanisation in historical times. The practice of retrospective diagnosis has been applied in parody, where characters from fiction are "diagnosed"; e.g., authors have speculated that Squirrel Nutkin may have had Tourette syndrome and that Tiny Tim could have had distal renal tubular acidosis (type I). == Postmortem diagnosis == Post-mortem diagnosis is considered a research tool, and also a quality control practice and it allows to evaluate the performance of the clinical case definitions. The term retrospective diagnosis is also sometimes used by a clinical pathologist to describe a medical diagnosis in a person made some time after the original illness has resolved or after death. In such cases, analysis of a physical specimen may yield a confident medical diagnosis. The search for the origin of AIDS has involved posthumous diagnosis of AIDS in people who died decades before the disease was first identified. Another example is where analysis of preserved umbilical cord tissue enables the diagnosis of congenital cytomegalovirus infection in a patient who had later developed a central nervous system disorder. == Examples == Did Abraham, Moses, Jesus, Saint Paul or Muhammad have psychotic spectrum psychological symptoms? Did Tutankhamun have Klippel–Feil syndrome? Did Alfred the Great have Crohn's disease? Did botulism cause the religious visions experienced by Julian of Norwich? Was the English sweat caused by hantavirus? Was the Black Death due to bubonic plague? Was "the great pox" syphilis or several venereal diseases? Did King George III of the United Kingdom exhibit the classic symptoms of porphyria? Were the conditions blamed on witches at the Salem witch trials caused by ergotism? Did Napoleon die from stomach cancer, or was he poisoned with arsenic? Could Franklin D. Roosevelt's paralytic illness have been Guillain–Barré syndrome rather than poliomyelitis? Did Abraham Lincoln have Marfan syndrome? Did Karl Marx have hidradenitis suppurativa? Could Burke and Wills have died of thiaminase poisoning? Did René Descartes have Exploding head syndrome? == Retrospective diagnoses of autism == There have been many published speculative retrospective diagnoses of autism of historical figures. English scientist Henry Cavendish is believed by some to have been autistic. George Wilson, a notable chemist and physician, wrote a book about Cavendish entitled The Life of the Honourable Henry Cavendish (1851), which provides a detailed description that indicates Cavendish may have exhibited many classic signs of autism. The practice of retrospectively diagnosing autism is controversial. Professor Fred Volkmar of Yale University is not convinced; he claims that "There is unfortunately a sort of cottage industry of finding that everyone has Asperger's." == See also == Charles Darwin's illness List of people with epilepsy (includes notes on retrospective diagnosis and misdiagnosis of historical figures) Mental health of Jesus Paleopathology Samuel Johnson's health == References == == Further reading == Mackowiak, Philip A. (2007). Post-Mortem: Solving History's Great Medical Mysteries. The American College of Physicians. ISBN 978-1-930513-89-1. Historical Clinicopathological Conference	Wikipedia/Posthumous_diagnosis

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