<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Gestational diabetes and explain in detail? [/INST] Gestational diabetes is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms; however, it does increase the risk of pre-eclampsia, depression, and requiring a Caesarean section. Babies born to mothers with poorly treated gestational diabetes are at increased risk of being too large, having low blood sugar after birth, and jaundice. If untreated, it can also result in a stillbirth. Long term, children are at higher risk of being overweight and developing type 2 diabetes.Gestational diabetes can occur during pregnancy because of insulin resistance or reduced production of insulin. Risk factors include being overweight, previously having gestational diabetes, a family history of type 2 diabetes, and having polycystic ovarian syndrome. Diagnosis is by blood tests. For those at normal risk, screening is recommended between 24 and 28 weeks gestation. For those at high risk, testing may occur at the first prenatal visit.Prevention is by maintaining a healthy weight and exercising before pregnancy. Gestational diabetes is treated with a diabetic diet, exercise, medication (such as metformin), and possibly insulin injections. Most women are able to manage their blood sugar with diet and exercise. Blood sugar testing among those who are affected is often recommended four times a day. Breastfeeding is recommended as soon as possible after birth.Gestational diabetes affects 3–9% of pregnancies, depending on the population studied. It is especially common during the last three months of pregnancy. It affects 1% of those under the age of 20 and 13% of those over the age of 44. A number of ethnic groups including Asians, American Indians, Indigenous Australians, and Pacific Islanders are at higher risk. In 90% of cases, gestational diabetes will resolve after the baby is born. Women, however, are at an increased risk of developing type 2 diabetes.

Classification
Gestational diabetes is formally defined as "any degree of glucose intolerance with onset or first recognition during pregnancy". This definition acknowledges the possibility that a woman may have previously undiagnosed diabetes mellitus, or may have developed diabetes coincidentally with pregnancy. Whether symptoms subside after pregnancy is also irrelevant to the diagnosis.
A woman is diagnosed with gestational diabetes when glucose intolerance continues beyond 24 to 28 weeks of gestation.
The White classification, named after Priscilla White, who pioneered research on the effect of diabetes types on perinatal outcome, is widely used to assess maternal and fetal risk. It distinguishes between gestational diabetes (type A) and pregestational diabetes (diabetes that existed prior to pregnancy). These two groups are further subdivided according to their associated risks and management.The two subtypes of gestational diabetes under this classification system are:

Type A1: abnormal oral glucose tolerance test (OGTT), but normal blood glucose levels during fasting and two hours after meals; diet modification is sufficient to control glucose levels
Type A2: abnormal OGTT compounded by abnormal glucose levels during fasting and/or after meals; additional therapy with insulin or other medications is requiredDiabetes which existed prior to pregnancy is also split up into several subtypes under this system:
Type B: onset at age 20 or older and duration of less than 10 years.
Type C: onset at age 10–19 or duration of 10–19 years.
Type D: onset before age 10 or duration greater than 20 years.
Type E: overt diabetes mellitus with calcified pelvic vessels.
Type F: diabetic nephropathy.
Type R: proliferative retinopathy.
Type RF: retinopathy and nephropathy.
Type H: ischemic heart disease.
Type T: prior kidney transplant.An early age of onset or long-standing disease comes with greater risks, hence the first three subtypes.Two other sets of criteria are available for diagnosis of gestational diabetes, both based on blood-sugar levels.Criteria for diagnosis of gestational diabetes, using the 100 gram Glucose Tolerance Test, according to Carpenter and Coustan:
Fasting 95 mg/dl
1 hour 180 mg/dl
2 hours 155 mg/dl
3 hours 140 mg/dlCriteria for diagnosis of gestational diabetes according to National Diabetes Data Group:
Fasting 105 mg/dl
1 hour 190 mg/dl
2 hours 165 mg/dl
3 hours 145 mg/dl

Risk factors
Classical risk factors for developing gestational diabetes are:
Polycystic ovary syndrome
A previous diagnosis of gestational diabetes or prediabetes, impaired glucose tolerance, or impaired fasting glycaemia
A family history revealing a first-degree relative with type 2 diabetes
Maternal age – a womans risk factor increases as she gets older (especially for women over 35 years of age).
Paternal age – one study found that a fathers age over 55 years was associated with GD
Ethnicity (those with higher risk factors include African-Americans, Afro-Caribbeans, Native Americans, Hispanics, Pacific Islanders, and people originating from South Asia)
Being overweight, obese or severely obese increases the risk by a factor 2.1, 3.6 and 8.6, respectively.
A previous pregnancy which resulted in a child with a macrosomia (high birth weight: >90th centile or >4000 g (8 lbs 12.8 oz))
Previous poor obstetric history
Other genetic risk factors: There are at least 10 genes where certain polymorphism are associated with an increased risk of gestational diabetes, most notably TCF7L2.In addition to this, statistics show a double risk of GDM in smokers.  Some studies have looked at more controversial potential risk factors, such as short stature.About 40–60% of women with GDM have no demonstrable risk factor; for this reason many advocate to screen all women. Typically, women with GDM exhibit no symptoms (another reason for universal screening), but some women may demonstrate increased thirst, increased urination, fatigue, nausea and vomiting, bladder infection, yeast infections and blurred vision.

Pathophysiology
The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. The interference probably occurs at the level of the cell signaling pathway beyond the insulin receptor. Since insulin promotes the entry of glucose into most cells, insulin resistance prevents glucose from entering the cells properly. As a result, glucose remains in the bloodstream, where glucose levels rise. More insulin is needed to overcome this resistance; about 1.5–2.5 times more insulin is produced than in a normal pregnancy.Insulin resistance is a normal phenomenon emerging in the second trimester of pregnancy, which in cases of GDM progresses thereafter to levels seen in a non-pregnant woman with type 2 diabetes. It is thought to secure glucose supply to the growing fetus. Women with GDM have an insulin resistance that they cannot compensate for with increased production in the β-cells of the pancreas. Placental hormones, and, to a lesser extent, increased fat deposits during pregnancy, seem to mediate insulin resistance during pregnancy. Cortisol and progesterone are the main culprits, but human placental lactogen, prolactin and estradiol contribute, too. Multivariate stepwise regression analysis reveals that, in combination with other placental hormones, leptin, tumor necrosis factor alpha, and resistin are involved in the decrease in insulin sensitivity occurring during pregnancy, with tumor necrosis factor alpha named as the strongest independent predictor of insulin sensitivity in pregnancy. An inverse correlation with the changes in insulin sensitivity from the time before conception through late gestation accounts for about half of the variance in the decrease in insulin sensitivity during gestation: in other words, low levels or alteration of TNF alpha factors corresponds with a greater chance of, or predisposition to, insulin resistance or sensitivity.It is unclear why some women are unable to balance insulin needs and develop GDM; however, a number of explanations have been given, similar to those in type 2 diabetes: autoimmunity, single gene mutations, obesity, along with other mechanisms.Though the clinical presentation of gestational diabetes is well characterized, the biochemical mechanism behind the disease is not well known. One proposed biochemical mechanism involves insulin-producing β-cell adaptation controlled by the HGF/c-MET signaling pathway. β-cell adaption refers to the change that pancreatic islet cells undergo during pregnancy in response to maternal hormones in order to compensate for the increased physiological needs of mother and baby. These changes in the β-cells cause increased insulin secretion as a result of increased β-cell proliferation.
HGF/c-MET has also been implicated in β-cell regeneration, which suggests that HGF/c-MET may help increase β-cell mass in order to compensate for insulin needs during pregnancy.  Recent studies support that loss of HGF/c-MET signaling results in aberrant β-cell adaptation.c-MET is a receptor tyrosine kinase (RTK) that is activated by its ligand, hepatocyte growth factor (HGF), and is involved in the activation of several cellular processes. When HGF binds c-MET, the receptor homodimerizes and self-phosphorylates to form an SH2 recognition domain. The downstream pathways activated include common signaling molecules such as RAS and MAPK, which affect cell motility, and cell cycle progression.Studies have shown that HGF is an important signaling molecule in stress related situations where more insulin is needed. Pregnancy causes increased insulin resistance and so a higher insulin demand. The β-cells must compensate for this by either increasing insulin production or proliferating. If neither of the processes occur, then markers for gestational diabetes are observed. It has been observed that pregnancy increases HGF levels, showing a correlation that suggests a connection between the signaling pathway and increased insulin needs. In fact, when no signaling is present, gestational diabetes is more likely to occur.The exact mechanism of HGF/c-MET regulated β-cell adaptation is not yet known but there are several hypotheses about how the signaling molecules contribute to insulin levels during pregnancy. c-MET may interact with FoxM1, a molecule important in the cell cycle, as FOXM1 levels decrease when c-MET is not present. Additionally, c-MET may interact with p27 as the protein levels increase with c-MET is not present. Another hypothesis says that c-MET may control β-cell apoptosis because a lack of c-MET causes increases cell death but the signaling mechanisms have not been elucidated.Although the mechanism of HGF/c-MET control of gestational diabetes is not yet well understood, there is a strong correlation between the signaling pathway and the inability to produce an adequate amount of insulin during pregnancy and thus it may be the target for future diabetic therapies.Because glucose travels across the placenta (through diffusion facilitated by GLUT1 carrier), which is located in the syncytiotrophoblast on both the microvillus and basal membranes, these membranes may be the rate-limiting step in placental glucose transport. There is a two- to three-fold increase in the expression of syncytiotrophoblast glucose transporters with advancing gestation. Finally, the role of GLUT3/GLUT4 transport remains speculative. If the untreated gestational diabetes fetus is exposed to consistently higher glucose levels, this leads to increased fetal levels of insulin (insulin itself cannot cross the placenta). The growth-stimulating effects of insulin can lead to excessive growth and a large body (macrosomia). After birth, the high glucose environment disappears, leaving these newborns with ongoing high insulin production and susceptibility to low blood glucose levels (hypoglycemia).

Screening
A number of screening and diagnostic tests have been used to look for high levels of glucose in plasma or serum in defined circumstances. One method is a stepwise approach where a suspicious result on a screening test is followed by diagnostic test. Alternatively, a more involved diagnostic test can be used directly at the first prenatal visit for a woman with a high-risk pregnancy. (for example in those with polycystic ovarian syndrome or acanthosis nigricans).Non-challenge blood glucose tests involve measuring glucose levels in blood samples without challenging the subject with glucose solutions. A blood glucose level is determined when fasting, two hours after a meal, or simply at any random time. In contrast, challenge tests involve drinking a glucose solution and measuring glucose concentration thereafter in the blood; in diabetes, they tend to remain high. The glucose solution has a very sweet taste which some women find unpleasant; sometimes, therefore, artificial flavours are added. Some women may experience nausea during the test, and more so with higher glucose levels.There is currently not enough research to show which way is best at diagnosing gestational diabetes. Routine screening of women with a glucose challenge test may find more women with gestational diabetes than only screening women with risk factors. It is not clear how these screening tests affect the rest of the pregnancy. Future research should include how the method of screening impacts the mother and baby.

Pathways
Opinions differ about optimal screening and diagnostic measures, in part due to differences in population risks, cost-effectiveness considerations, and lack of an evidence base to support large national screening programs. The most elaborate regimen entails a random blood glucose test during a booking visit, a screening glucose challenge test around 24–28 weeks gestation, followed by an OGTT if the tests are outside normal limits. If there is a high suspicion, a woman may be tested earlier.In the United States, most obstetricians prefer universal screening with a screening glucose challenge test. In the United Kingdom, obstetric units often rely on risk factors and a random blood glucose test. The American Diabetes Association and the Society of Obstetricians and Gynaecologists of Canada recommend routine screening unless the woman is low risk (this means the woman must be younger than 25 years and have a body mass index less than 27, with no personal, ethnic or family risk factors) The Canadian Diabetes Association and the American College of Obstetricians and Gynecologists recommend universal screening. The U.S. Preventive Services Task Force found there is insufficient evidence to recommend for or against routine screening, and a 2017 a Cochrane review found that there is not evidence to determine which screening method is best for women and their babies.Some pregnant women and careproviders choose to forgo routine screening due to the absence of risk factors, however this is not advised due to the large proportion of women who develop gestational diabetes despite having no risk factors present and the dangers to the mother and baby if gestational diabetes remains untreated.

Non-challenge blood glucose tests
When a plasma glucose level is found to be higher than 126 mg/dL (7.0 mmol/L) after fasting, or over 200 mg/dL (11.1 mmol/L) on any occasion, and if this is confirmed on a subsequent day, the diagnosis of GDM is made, and no further testing is required. These tests are typically performed at the first antenatal visit. They are simple to administer and inexpensive, but have a lower test performance compared to the other tests, with moderate sensitivity, low specificity and high false positive rates.

Screening glucose challenge test
The screening glucose challenge test (sometimes called the OSullivan test) is performed between 24 and 28 weeks, and can be seen as a simplified version of the oral glucose tolerance test (OGTT). No previous fasting is required for this screening test, in contrast to the OGTT. The OSullivan test involves drinking a solution containing 50 grams of glucose, and measuring blood levels one hour later.If the cut-off point is set at 140 mg/dL (7.8 mmol/L), 80% of women with GDM will be detected. If this threshold for further testing is lowered to 130 mg/dL, 90% of GDM cases will be detected, but there will also be more women who will be subjected to a consequent OGTT unnecessarily.

Oral glucose tolerance test
A standardized oral glucose tolerance test (OGTT) should be done in the morning after an overnight fast of between 8 and 14 hours. During the three previous days the subject must have an unrestricted diet (containing at least 150 g carbohydrate per day) and unlimited physical activity. The subject should remain seated during the test and should not smoke throughout the test.
The test involves drinking a solution containing a certain amount of glucose, usually 75 g or 100 g, and drawing blood to measure glucose levels at the start and on set time intervals thereafter.
The diagnostic criteria from the National Diabetes Data Group (NDDG) have been used most often, but some centers rely on the Carpenter and Coustan criteria, which set the cutoff for normal at lower values. Compared with the NDDG criteria, the Carpenter and Coustan criteria lead to a diagnosis of gestational diabetes in 54 percent more pregnant women, with an increased cost and no compelling evidence of improved perinatal outcomes.The following are the values which the American Diabetes Association considers to be abnormal during the 100 g of glucose OGTT:

Fasting blood glucose level ≥95 mg/dL (5.33 mmol/L)
1 hour blood glucose level ≥180 mg/dL (10 mmol/L)
2 hour blood glucose level ≥155 mg/dL (8.6 mmol/L)
3 hour blood glucose level ≥140 mg/dL (7.8 mmol/L)An alternative test uses a 75 g glucose load and measures the blood glucose levels before and after one and two hours, using the same reference values. This test will identify fewer women who are at risk, and there is only a weak concordance (agreement rate) between this test and a three-hour 100 g test.The glucose values used to detect gestational diabetes were first determined by OSullivan and Mahan (1964) in a retrospective cohort study (using a 100 grams of glucose OGTT) designed to detect risk of developing type 2 diabetes in the future. The values were set using whole blood and required two values reaching or exceeding the value to be positive. Subsequent information led to alterations in OSullivans criteria. When methods for blood glucose determination changed from the use of whole blood to venous plasma samples, the criteria for GDM were also changed.

Urinary glucose testing
Women with GDM may have high glucose levels in their urine (glucosuria). Although dipstick testing is widely practiced, it performs poorly, and discontinuing routine dipstick testing has not been shown to cause underdiagnosis where universal screening is performed. Increased glomerular filtration rates during pregnancy contribute to some 50% of women having glucose in their urine on dipstick tests at some point during their pregnancy. The sensitivity of glucosuria for GDM in the first two trimesters is only around 10% and the positive predictive value is around 20%.

Prevention
Vitamin D supplementation during pregnancy may help to prevent gestational diabetes. A 2015 review found that when done during pregnancy moderate physical exercise is effective for the prevention of gestational diabetes. A 2014 review however did not find a significant effect. It is uncertain if additional dietary advice interventions help to reduce the risk of gestational diabetes. However, data from the Nurses Health Study shows that adherence to a healthy plant-based diet is associated with lower risk for GDM.Diet and physical activity interventions designed to prevent excessive gestational weight gain reduce the rates of gestational diabetes. However, the impact of these interventions varies with the body-mass index of the person as well as with the region in which the studies were performed.Moderate-quality evidence suggest that there is a reduced risk of gestational diabetes mellitus and caesarean section with combined diet and exercise interventions during pregnancy as well as reductions in gestational weight gain, compared with standard care.It has been suggested that for women who have had gestational diabetes, support between pregnancies may lower their chances of having gestational diabetes again in future pregnancies. This support might include diet and exercise, education, and lifestyle advice. However, there is no research to show whether interventions between pregnancies lower the number of women who develop gestational diabetes again.Theoretically, smoking cessation may decrease the risk of gestational diabetes among smokers.

Management
Treatment of GDM with diet and insulin reduces health problems mother and child. Treatment of GDM is also accompanied by more inductions of labour.A repeat OGTT should be carried out 6 weeks after delivery, to confirm the diabetes has disappeared. Afterwards, regular screening for type 2 diabetes is advised.Lifestyle interventions include exercise, diet advice, behavioural interventions, relaxation, self-monitoring glucose, and combined interventions. Women with gestational diabetes who receive lifestyle interventions seem to have less postpartum depression, and were more likely to reach their weight loss targets after giving birth, than women who had no intervention. Their babies are also less likely to be large for their gestational age, and have less percentage of fat when they are born. More research is needed to find out which lifestyle interventions are best. Some women with GDM use probiotics but it is very uncertain if there are any benefits in terms of blood glucose levels, high blood pressure disorders or induction of labour.If a diabetic diet or G.I. Diet, exercise, and oral medication are inadequate to control glucose levels, insulin therapy may become necessary.
The development of macrosomia can be evaluated during pregnancy by using sonography.  Women who use insulin, with a history of stillbirth, or with hypertension are managed like women with overt diabetes.

Lifestyle
Counselling before pregnancy (for example, about preventive folic acid supplements) and multidisciplinary management are important for good pregnancy outcomes. Most women can manage their GDM with dietary changes and exercise. Self monitoring of blood glucose levels can guide therapy. Some women will need antidiabetic drugs, most commonly insulin therapy.
Any diet needs to provide sufficient calories for pregnancy, typically 2,000–2,500 kcal with the exclusion of simple carbohydrates. The main goal of dietary modifications is to avoid peaks in blood sugar levels. This can be done by spreading carbohydrate intake over meals and snacks throughout the day, and using slow-release carbohydrate sources—known as the G.I. Diet. Since insulin resistance is highest in mornings, breakfast carbohydrates need to be restricted more. Ingesting more fiber in foods with whole grains, or fruit and vegetables can also reduce the risk of gestational diabetes. There is not enough evidence to indicate if one type of dietary advice is better than another.Regular moderately intense physical exercise is advised, although there is no consensus on the specific structure of exercise programs for GDM. Pregnant women who exercise have lower blood sugar levels when fasting and after meals compared to those who do not exercise. It is not clear which form of exercise is best when pregnant.Self monitoring can be accomplished using a handheld capillary glucose dosage system. Compliance with these glucometer systems can be low. There is not a lot of research into what target blood sugar levels should be for women with gestational diabetes and targets recommended to women vary around the world. Target ranges advised by the Australasian Diabetes in Pregnancy Society are as follows:
fasting capillary blood glucose levels <5.5 mmol/L
1 hour postprandial capillary blood glucose levels <8.0 mmol/L
2 hour postprandial blood glucose levels <6.7 mmol/LRegular blood samples can be used to determine HbA1c levels, which give an idea of glucose control over a longer time period.Research suggests a possible benefit of breastfeeding to reduce the risk of diabetes and related risks for both mother and child.

Medication
If monitoring reveals failing control of glucose levels with these measures, or if there is evidence of complications like excessive fetal growth, treatment with insulin might be necessary. This is most commonly fast-acting insulin given just before eating to blunt glucose rises after meals. Care needs to be taken to avoid low blood sugar levels due to excessive insulin. Insulin therapy can be normal or very tight; more injections can result in better control but requires more effort, and there is no consensus that it has large benefits. A 2016 Cochrane review concluded that quality evidence is not yet available to determine the best blood sugar range for improving health for pregnant women with GDM and their babies.There is some evidence that certain medications by mouth might be safe in pregnancy, or at least, are less dangerous to the developing fetus than poorly controlled diabetes. When comparing which diabetes tablets (medication by mouth) work best and are safest, there is not enough quality research to support one medication over another. The medication metformin is better than glyburide. If blood glucose cannot be adequately controlled with a single agent, the combination of metformin and insulin may be better than insulin alone. Another review found good short term safety for both the mother and baby with metformin but unclear long term safety.People may prefer metformin by mouth to insulin injections. Treatment of polycystic ovarian syndrome with metformin during pregnancy has been noted to decrease GDM levels.Almost half of the women did not reach sufficient control with metformin alone and needed supplemental therapy with insulin; compared to those treated with insulin alone, they required less insulin, and they gained less weight. With no long-term studies into children of women treated with the drug, there remains a possibility of long-term complications from metformin therapy. Babies born to women treated with metformin have been found to develop less visceral fat, making them less prone to insulin resistance in later life.

Prognosis
Gestational diabetes generally resolves once the baby is born. Based on different studies, the chances of developing GDM in a second pregnancy, if a woman had GDM in her first pregnancy, are between 30 and 84%, depending on ethnic background. A second pregnancy within one year of the previous pregnancy has a large likelihood of GDM recurrence.Women diagnosed with gestational diabetes have an increased risk of developing diabetes mellitus in the future. The risk is highest in women who needed insulin treatment, had antibodies associated with diabetes (such as antibodies against glutamate decarboxylase, islet cell antibodies and/or insulinoma antigen-2), women with more than two previous pregnancies, and women who were obese (in order of importance). Women requiring insulin to manage gestational diabetes have a 50% risk of developing diabetes within the next five years. Depending on the population studied, the diagnostic criteria and the length of follow-up, the risk can vary enormously. The risk appears to be highest in the first 5 years, reaching a plateau thereafter. One of the longest studies followed a group of women from Boston, Massachusetts; half of them developed diabetes after 6 years, and more than 70% had diabetes after 28 years. In a retrospective study in Navajo women, the risk of diabetes after GDM was estimated to be 50 to 70% after 11 years. Another study found a risk of diabetes after GDM of more than 25% after 15 years. In populations with a low risk for type 2 diabetes, in lean subjects and in women with auto-antibodies, there is a higher rate of women developing type 1 diabetes (LADA).Children of women with GDM have an increased risk for childhood and adult obesity and an increased risk of glucose intolerance and type 2 diabetes later in life. This risk relates to increased maternal glucose values. It is currently unclear how much genetic susceptibility and environmental factors contribute to this risk, and whether treatment of GDM can influence this outcome.Relative benefits and harms of different oral anti-diabetic medications are not yet well understood as of 2017.There are scarce statistical data on the risk of other conditions in women with GDM; in the Jerusalem Perinatal study, 410 out of 37,962 women were reported to have GDM, and there was a tendency towards more breast and pancreatic cancer, but more research is needed to confirm this finding.Research is being conducted to develop a web-based clinical decision support system for GDM prediction using machine learning techniques. Results so far demonstrated great potential in clinical practicality for automatic GDM prognosis.

Complications
GDM poses a risk to mother and child. This risk is largely related to uncontrolled blood glucose levels and its consequences. The risk increases with higher blood glucose levels. Treatment resulting in better control of these levels can reduce some of the risks of GDM considerably.The two main risks GDM imposes on the baby are growth abnormalities and chemical imbalances after birth, which may require admission to a neonatal intensive care unit. Infants born to mothers with GDM are at risk of being both large for gestational age (macrosomic) in unmanaged GDM, and small for gestational age and Intrauterine growth retardation in managed GDM. Macrosomia in turn increases the risk of instrumental deliveries (e.g. forceps, ventouse and caesarean section) or problems during vaginal delivery (such as shoulder dystocia). Macrosomia may affect 12% of normal women compared to 20% of women with GDM. However, the evidence for each of these complications is not equally strong; in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study for example, there was an increased risk for babies to be large but not small for gestational age in women with uncontrolled GDM. In a recent birth cohot study of 5150 deliveries, a research group active at the University of Helsinki and Helsinki University Hospital, Finland demonstrated that the mothers GDM is an independent factor that increases the risk of fetal hypoxia, during labour. The study was published in the Acta Diabetologica in June 2021. Another finding was that GDM increased the susceptibility of the fetus to intrapartum hypoxia, regardless of the size of the fetus </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Beta thalassemia and explain in detail? [/INST] Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.HBB blockage over time leads to decreased beta-chain synthesis. The bodys inability to construct new beta-chains leads to the underproduction of HbA (adult hemoglobin). Reductions in HbA available overall to fill the red blood cells in turn leads to microcytic anemia. Microcytic anemia ultimately develops in respect to inadequate HBB protein for sufficient red blood cell functioning. Due to this factor, the patient may require blood transfusions to make up for the blockage in the beta-chains.
Repeated blood transfusions cause severe problems associated with iron overload.

Signs and symptoms
Three main forms have been described: thalassemia minor, thalassemia intermedia, and thalassemia major which vary from asymptomatic or mild symptoms to severe anemia requiring lifelong transfusions. Individuals with beta thalassemia major (those who are homozygous for thalassemia mutations, or inheriting 2 mutations) usually present within the first two years of life with symptomatic severe anemia, poor growth, and skeletal abnormalities. Untreated thalassemia major eventually leads to death, usually by heart failure; therefore, prenatal screening is very important. Those with beta thalassemia intermedia (those who are compound heterozygoutes for the beta thalassemia mutation) usually present later in life with mild to moderate symptoms of anemia. Beta thalassemia trait (also known as beta thalassemia minor) involves heterozygous inheritance of a beta-thalassemia mutation and patients usually have borderline microcytic, hypochromic anemia and they are usually asymptomatic or have mild symptoms. Beta thalassemia minor can also present as beta thalassemia silent carriers; those who inherit a beta thalassemic mutation but have no hematologic abnormalities nor symptoms. Some people with thalassemia are susceptible to health complications that involve the spleen (hypersplenism) and gallstones (due to hyperbilirubinemia from peripheral hemolysis). These complications are mostly found in thalassemia major and intermedia patients.Excess iron (from hemolysis or transfusions) causes serious complications within the liver, heart, and endocrine glands. Severe symptoms include liver cirrhosis, liver fibrosis, and in extreme cases, liver cancer. Heart failure, growth impairment, diabetes and osteoporosis are life-threatening conditions which can be caused by beta thalassemia major. The main cardiac abnormalities seen as a result of beta thalassemia and iron overload include left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valvulopathy, arrhythmias, and pericarditis. Increased gastrointestinal iron absorption is seen in all grades of beta thalassemia, and increased red blood cell destruction by the spleen due to ineffective erythropoiesis further releases additional iron into the bloodstream.Additional symptoms of beta thalassemia major or intermedia include the classic symptoms of moderate to severe anemia including fatigue, growth and developmental delay in childhood, leg ulcers and organ failure. Ineffective erythropoiesis (red blood cell production) can also lead to compensatory bone marrow expansion which can then lead to bony changes/deformities, bone pain and craniofacial abnormalities. Extramedullary organs such as the liver and spleen that can also undergo erythropoiesis become activated leading to hepatosplenomegaly (enlargement of the liver and spleen). Other tissues in the body can also become sites of erythropoiesis, leading to extramedullary hematopoietic pseudotumors which may cause compressive symptoms if they occur in the thoracic cavity or spinal canal.

Cause
Mutations
Two major groups of mutations can be distinguished:

Nondeletion forms: These defects, in general, involve a single base substitution or small insertions near or upstream of the β globin gene. Most often, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.
Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary persistence of fetal hemoglobin syndromes.Mutations are characterized as (βo) if they prevent any formation of β globin chains, mutations are characterized as (β+) if they allow some β globin chain formation to occur.

mRNA assembly
Beta thalassemia is a hereditary disease affecting hemoglobin. As with about half of all hereditary diseases, an inherited mutation damages the assembly of the messenger-type RNA (mRNA) that is transcribed from a chromosome. DNA contains both the instructions (genes) for stringing amino acids together into proteins, as well as stretches of DNA that play important roles in regulating produced protein levels.In thalassemia, an additional, contiguous length or a discontinuous fragment of non-coding instructions is included in the mRNA. This happens because the mutation obliterates the boundary between the intronic and exonic portions of the DNA template. Because all the coding sections may still be present, normal hemoglobin may be produced and the added genetic material, if it produces pathology, instead disrupts regulatory functions enough to produce anemia. Hemoblogins normal alpha and beta subunits each have an iron-containing central portion (heme) that allows the protein chain of a subunit to fold around it. Normal adult hemoglobin contains 2 alpha and 2 beta subunits. Thalassemias typically affect only the mRNAs for production of the beta chains (hence the name). Since the mutation may be a change in only a single base (single-nucleotide polymorphism), on-going efforts seek gene therapies to make that single correction.

Risk factors
Family history and ancestry are factors that increase the risk of beta thalassemia. Depending on family history, if a persons parents or grandparents had beta thalassemia major or intermedia, there is a 75% (3 out of 4) probability (see inheritance chart at top of page) of the mutated gene being inherited by an offspring. Even if a child does not have beta thalassemia major or intermedia, they can still be a carrier, possibly resulting in future generations of their offspring having beta thalassemia.Another risk factor is ancestry. Beta thalassemia occurs most often in people of Italian, Greek, Middle Eastern, Southern Asian, and African ancestry.

Diagnosis
Abdominal pain due to hypersplenism, splenic infarction and right-upper quadrant pain caused by gallstones are major clinical manifestations. However, diagnosing thalassemia from symptoms alone is inadequate. Physicians note these signs as associative due to this diseases complexity. The following associative signs can attest to the severity of the phenotype: pallor, poor growth, inadequate food intake, splenomegaly, jaundice, maxillary hyperplasia, dental malocclusion, cholelithiasis, systolic ejection murmur in the presence of severe anemia and pathologic fractures. Based on symptoms, tests are ordered for a differential diagnosis. These tests include complete blood count; hemoglobin electrophoresis; serum transferrin, ferritin, total iron-binding capacity; urine urobilin and urobilogen; peripheral blood smear, which may show codocytes, or target cells; hematocrit; and serum bilirubin. The expected pattern on hemoglobin electrophoresis in people with beta-thalassemia is an increased level of hemoglobin A2 and slightly increased hemoglobin F. The diagnosis is confirmed with hemoglobin electrophoresis or high performance liquid chromatography.Skeletal changes associated with expansion of the bone marrow:

Chipmunk facies: bossing of the skull, prominent malar eminence, depression of the bridge of the nose, tendency to a mongoloid slant of the eye, and exposure of the upper teeth due to hypertrophy of the maxillae.
Hair-on-end (or "crew cut") on skull X-ray: new bone formation due to the inner table.

DNA analysis
All beta thalassemias may exhibit abnormal red blood cells; a family history is followed by DNA analysis. This test is used to investigate deletions and mutations in the alpha- and beta-globin-producing genes. Family studies can be done to evaluate carrier status and the types of mutations present in other family members. DNA testing is not routine, but can help diagnose thalassemia and determine carrier status. In most cases the treating physician uses a clinical prediagnosis assessing anemia symptoms: fatigue, breathlessness and poor exercise tolerance. Further genetic analysis may include HPLC should routine electrophoresis prove difficult.

Prevention
Beta thalassemia is a hereditary disease allowing for a preventative treatment by carrier screening and prenatal diagnosis. It can be prevented if one parent has normal genes, giving rise to screenings that empower carriers to select partners with normal hemoglobin. A study aimed at detecting the genes that could give rise to offspring with sickle cell disease. Patients diagnosed with beta thalassemia have MCH ≤ 26 pg and an RDW < 19. Of 10,148 patients, 1,739 patients had a hemoglobin phenotype and RDW consistent with beta thalassemia. After the narrowing of patients, the HbA2 levels were tested presenting 77 patients with beta thalassemia. This screening procedure proved insensitive in populations of West African ancestry because of the indicators has high prevalence of alpha thalassemia. Countries have programs distributing information about the reproductive risks associated with carriers of haemoglobinopathies. Thalassemia carrier screening programs have educational programs in schools, armed forces, and through mass media as well as providing counseling to carriers and carrier couples. Screening has shown reduced incidence; by 1995 the prevalence in Italy reduced from 1:250 to 1:4000, and a 95% decrease in that region. The decrease in incidence has benefitted those affected with thalassemia, as the demand for blood has decreased, therefore improving the supply of treatment.

Treatment
Beta thalassemia major
Affected children require regular lifelong blood transfusions. Bone marrow transplants can be curative for some children. Patients receive frequent blood transfusions that lead to or potentiate iron overload. Iron chelation treatment is necessary to prevent damage to internal organs in cases of iron overload. Advances in iron chelation treatments allow patients with thalassemia major to live long lives with access to proper treatment. Popular chelators include deferoxamine and deferiprone.The oral chelator deferasirox was approved for use in 2005 in some countries. Bone marrow transplantation is the only cure and is indicated for patients with severe thalassemia major. Transplantation can eliminate a patients dependence on transfusions. Absent a matching donor, a savior sibling can be conceived by preimplantation genetic diagnosis (PGD) to be free of the disease as well as to match the recipients human leukocyte antigen (HLA) type.Serum ferritin (the storage form of iron) is routinely measured in those with beta thalassemia to determine the degree of iron overload; with increased ferritin levels directing the use of iron chelation therapy. The three iron chelators; subcutaneous deferoxamine, oral deferiprone and oral deferasirox can be used as monotherapy or in combination, they have all been shown to decrease serum/systemic iron levels, hepatic and cardiac iron levels as well as decreasing the risk of cardiac arrhythmia, heart failure and death. Hepatic and myocardial MRI is also used to quantify the iron deposition in target organs, especially the heart and liver, to guide therapy.Scientists at Weill Cornell Medical College have developed a gene therapy strategy that could feasibly treat both beta-thalassemia and sickle cell disease. The technology is based on delivery of a lentiviral vector carrying both the human β-globin gene and an ankyrin insulator to improve gene transcription and translation, and boost levels of β-globin production.On June 10, 2022, a U.S. federal advisory panel recommended that the FDA approve a gene therapy treatment for use with beta thalassemia.

Surgical
Patients with thalassemia major are more inclined to have a splenectomy. The use of splenectomies have been declining in recent years due to decreased prevalence of hypersplenism in adequately transfused patients. Splenectomy is also associated with increased risk of infections and increased morbidity due to vascular disease, as the spleen is involved in scavenging to rid the body of pathologic or abnormal red blood cells. Patients with hypersplenism are more likely to have a lower amount of healthy blood cells in their body than normal and reveal symptoms of anemia. The different surgical techniques are the open and laparoscopic method. The laparoscopic method requires longer operating time but a shorter recovery period with a smaller and less prominent surgical scar. If it is unnecessary to remove the entire spleen a partial splenectomy may occur; this method preserves some of the immune function while reducing the probability of hypersplenism. Those undergoing splenectomy should receive an appropriate pneumococcal vaccine at least one week (preferably three weeks) before the surgery.

Therapeutic
Long-term transfusion therapy (in those with transfusion dependent beta thalassemia) is a treatment used to maintain hemoglobin levels at a target pre-transfusion hemoglobin level of 9–10.5 g/dL (11-12 g/dL in those with concomitant heart disease). To ensure quality blood transfusions, the packed red blood cells should be leucoreduced. By having leucoreduced blood packets, the patient is at a lower risk to develop adverse reactions by contaminated white cells and preventing platelet alloimmunisation. Patients with allergic transfusion reactions or unusual red cell antibodies must receive washed red cells or cryopreserved red cells. Washed red cells have been removed of plasma proteins that would have become a target of the patients antibodies allowing the transfusion to be carried out safely. Cryopreserved red cells are used to maintain a supply of rare donor units for patients with unusual red cell antibodies or missing common red cell antigens. These regular transfusions promote normal growth, physical activities and suppress bone marrow hyperactivity.

Pharmaceutical
During normal iron homeostasis the circulating iron is bound to transferrin. But with iron overload (such as with frequent blood transfusions), the ability for transferrin to bind iron is exceeded and non-transferrin bound iron accumulated. This unbound iron is toxic due to its high propensity to induce oxygen species and is responsible for cellular damage. The prevention of iron overload protects patients from morbidity and mortality. The primary aim is to bind to and remove iron from the body and a rate equal to the rate of transfusional iron input or greater than iron input. Iron chelation is a medical therapy that may prevent the complications of iron overload. Every unit of transfused blood contains 200–250 mg of iron and the body has no natural mechanism to remove excess iron. The excess iron can be removed by iron chelators (deferoxamine, deferiprone and deferasirox).Luspatercept (ACE-536) is a recombinant fusion protein that is used as a treatment in adults with transfusion dependent beta thalassemia. It consists of a modified extra-cellular domain of  human activin receptor type IIB bound to the Fc portion of the human IgG1 antibody. The molecule binds to select transforming growth factor beta superfamily ligands to block SMAD2 and 3 signaling, thus enhancing erythroid maturation. The medication has been shown to reduce the transfusion burden by 33% in adults with transfusion dependent beta thalassemia as compared to placebo and was also associated with decreased ferritin levels (with no significant decreases in liver or cardiac iron levels).

Beta thalassemia intermedia
Patients with beta thalassemia intermedia require no transfusions or may require episodic blood transfusions during certain circumstances (infection, pregnancy, surgery). Patients with frequent transfusions may develop iron overload and require chelation therapy. Transmission is autosomal recessive; however, dominant mutations and compound heterozygotes have been reported. Genetic counseling is recommended and prenatal diagnosis may be offered.

Beta thalassemia minor
Patients with beta thalassemia minor are usually asymptomatic and are often monitored without treatment. Beta thalassemia minor may coexist with other conditions such as chronic hepatitis B, chronic hepatitis C, non-alcoholic fatty liver disease and alcoholic liver disease that, when combined or co-existing, may cause a person to have iron overload of the liver and more severe liver disease.

Epidemiology
The beta form of thalassemia is particularly prevalent among the Mediterranean peoples and this geographical association is responsible for its naming: thalassa (θάλασσα) is the Greek word for sea and haima (αἷμα) is the Greek word for blood. In Europe, the highest concentrations of the disease are found in Greece and the Turkish coastal regions. The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Corsica, Cyprus, Malta and Crete are heavily affected in particular. Other Mediterranean peoples, as well as those in the vicinity of the Mediterranean, also have high incidence rates, including people from West Asia and North Africa. The data indicate that 15% of the Greek and Turkish Cypriots are carriers of beta-thalassaemia genes, while 10% of the population carry alpha-thalassaemia genes.

Evolutionary adaptation
The thalassemia trait may confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common, thus conferring a selective survival advantage on carriers (known as heterozygous advantage), thus perpetuating the mutation. In that respect, the various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease.

Incidence
The disorder is more prevalent in certain ethnicities and age groups. Beta thalassemia is most prevalent in the "thalassemia belt" which includes areas in Sub-Saharan Africa, the Mediterranean extending into the Middle East and Southeast Asia. This geographical distribution is thought to be due to beta-thalassemia carrier state (beta thalassemia minor) conferring a resistance to malaria. In the United States, thalassemias prevalence is approximately 1 in 272,000 or 1,000 people. There have been 4,000 hospitalized cases in England in 2002 and 9,233 consultant episodes for thalassemia. Men accounted for 53% of hospital consultant episodes and women accounted for 47%. The mean patient age is 23, with only 1% of consultants being older than 75, and 69% being 15–59. It is estimated that 1.5% of the worlds population are carriers and 40,000 affected infants are born with the disease annually. Beta thalassemia major is usually fatal in infancy if blood transfusions are not initiated immediately.

See also
Alpha-thalassemia
Anisopoikilocytosis (variance in red blood cell size, usually as a result of beta thalassemia)
Delta-thalassemia
Hemoglobinopathy

References
Further reading
Cao, Antonio; Galanello, Renzo (2010). "Beta-Thalassemia".  In Pagon, Roberta A; Bird, Thomas D; Dolan, Cynthia R; Stephens, Karen; Adam, Margaret P (eds.). GeneReviews. University of Washington, Seattle. PMID 20301599.
Bahal, Raman; McNeer, Nicole Ali; Quijano, Elias; Liu, Yanfeng; Sulkowski, Parker; Turchick, Audrey; Lu, Yi-Chien; Bhunia, Dinesh C.; Manna, Arunava; Greiner, Dale L.; Brehm, Michael A.; Cheng, Christopher J.; López-Giráldez, Francesc; Ricciardi, Adele; Beloor, Jagadish; Krause, Diane S.; Kumar, Priti; Gallagher, Patrick G.; Braddock, Demetrios T.; Saltzman, W </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pyloric stenosis and explain in detail? [/INST] Pyloric stenosis is a narrowing of the opening from the stomach to the first part of the small intestine (the pylorus). Symptoms include projectile vomiting without the presence of bile. This most often occurs after the baby is fed. The typical age that symptoms become obvious is two to twelve weeks old.The cause of pyloric stenosis is unclear. Risk factors in babies include birth by cesarean section, preterm birth, bottle feeding, and being first born. The diagnosis may be made by feeling an olive-shaped mass in the babys abdomen. This is often confirmed with ultrasound.Treatment initially begins by correcting dehydration and electrolyte problems.  This is then typically followed by surgery, although some treat the condition without surgery by using atropine. Results are generally good both in the short term and in the long term.About one to two per 1,000 babies are affected, and males are affected about four times more often than females. The condition is very rare in adults. The first description of pyloric stenosis was in 1888 with surgery management first carried out in 1912 by Conrad Ramstedt. Before surgical treatment most babies died.

Signs and symptoms
Babies with this condition usually present any time in the first weeks to 6 months of life with progressively worsening vomiting. It is more likely to affect the first-born with males more commonly than females at a ratio of 4 to 1. The vomiting is often described as non-bile stained ("non bilious") and "projectile vomiting", because it is more forceful than the usual spitting up (gastroesophageal reflux) seen at this age.  Some infants present with poor feeding and weight loss but others demonstrate normal weight gain. Dehydration may occur which causes a baby to cry without having tears and to produce less wet or dirty diapers due to not urinating for hours or for a few days. Symptoms usually begin between 3 and 12 weeks of age. Findings include epigastric fullness with visible peristalsis in the upper abdomen from the infants left to right. Constant hunger, belching, and colic are other possible signs that the baby is unable to eat properly.

Cause
Rarely, infantile pyloric stenosis can occur as an autosomal dominant condition. It is uncertain whether it is a congenital anatomic narrowing or a functional hypertrophy of the pyloric sphincter muscle.

Pathophysiology
The gastric outlet obstruction due to the hypertrophic pylorus impairs emptying of gastric contents into the duodenum. As a consequence, all ingested food and gastric secretions can only exit via vomiting, which can be of a projectile nature. While the exact cause of the hypertrophy remains unknown, one study suggested that neonatal hyperacidity may be involved in the pathogenesis. This physiological explanation for the development of clinical pyloric stenosis at around 4 weeks and its spontaneous long term cure without surgery if treated conservatively, has recently been further reviewed.Persistent vomiting results in loss of stomach acid (hydrochloric acid). The vomited material does not contain bile because the pyloric obstruction prevents entry of duodenal contents (containing bile) into the stomach. The chloride loss results in a low blood chloride level which impairs the kidneys ability to excrete bicarbonate. This is the factor that prevents correction of the alkalosis leading to metabolic alkalosis.A secondary hyperaldosteronism develops due to the decreased blood volume. The high aldosterone levels causes the kidneys to avidly retain Na+ (to correct the intravascular volume depletion), and excrete increased amounts of K+ into the urine (resulting in a low blood level of potassium).The bodys compensatory response to the metabolic alkalosis is hypoventilation resulting in an elevated arterial pCO2.

Diagnosis
Diagnosis is via a careful history and physical examination, often supplemented by radiographic imaging studies. Pyloric stenosis should be suspected in any young infant with severe vomiting. On physical exam, palpation of the abdomen may reveal a mass in the epigastrium. This mass, which consists of the enlarged pylorus, is referred to as the olive, and is sometimes evident after the infant is given formula to drink. Rarely, there are peristaltic waves that may be felt or seen (video on NEJM) due to the stomach trying to force its contents past the narrowed pyloric outlet.Most cases of pyloric stenosis are diagnosed/confirmed with ultrasound, if available, showing the thickened pylorus and non-passage of gastric contents into the proximal duodenum. Muscle wall thickness 3 millimeters (mm) or greater and pyloric channel length of 15 mm or greater are considered abnormal in infants younger than 30 days. Gastric contents should not be seen passing through the pylorus because if it does, pyloric stenosis should be excluded and other differential diagnoses such as pylorospasm should be considered. The positions of superior mesenteric artery and superior mesenteric vein should be noted because altered positions of these two vessels would be suggestive of intestinal malrotation instead of pyloric stenosis.Although the baby is exposed to radiation, an upper GI series (X-rays taken after the baby drinks a special contrast agent) can be diagnostic by showing the pylorus with elongated, narrow lumen and a dent in the duodenal bulb. This phenomenon caused "string sign" or the "railroad track/double track sign" on X-rays after contrast is given. Plain x-rays of the abdomen sometimes shows a dilated stomach.Although upper gastrointestinal endoscopy would demonstrate pyloric obstruction, physicians would find it difficult to differentiate accurately between hypertrophic pyloric stenosis and pylorospasm.Blood tests will reveal low blood levels of potassium and chloride in association with an increased blood pH and high blood bicarbonate level due to loss of stomach acid (which contains hydrochloric acid) from persistent vomiting. There will be exchange of extracellular potassium with intracellular hydrogen ions in an attempt to correct the pH imbalance. These findings can be seen with severe vomiting from any cause.

Treatment
Infantile pyloric stenosis is typically managed with surgery; very few cases are mild enough to be treated medically.
The danger of pyloric stenosis comes from the dehydration and electrolyte disturbance rather than the underlying problem itself. Therefore, the baby must be initially stabilized by correcting the dehydration and the abnormally high blood pH seen in combination with low chloride levels with IV fluids. This can usually be accomplished in about 24–48 hours.Intravenous and oral atropine may be used to treat pyloric stenosis. It has a success rate of 85-89% compared to nearly 100% for pyloromyotomy, however it requires prolonged hospitalization, skilled nursing and careful follow up during treatment. It might be an alternative to surgery in children who have contraindications for anesthesia or surgery, or in children whose parents do not want surgery.

Surgery
The definitive treatment of pyloric stenosis is with surgical pyloromyotomy known as Ramstedts procedure (dividing the muscle of the pylorus to open up the gastric outlet).  This surgery can be done through a single incision (usually 3–4 cm long) or laparoscopically (through several tiny incisions), depending on the surgeons experience and preference.Today, the laparoscopic technique has largely supplanted the traditional open repairs which involved either a tiny circular incision around the navel or the Ramstedt procedure.  Compared to the older open techniques, the complication rate is equivalent, except for a markedly lower risk of wound infection.  This is now considered the standard of care at the majority of childrens hospitals across the US, although some surgeons still perform the open technique </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Essential tremor and explain in detail? [/INST] Essential tremor (ET), also called benign tremor, familial tremor, and idiopathic tremor, is a medical condition characterized by involuntary rhythmic contractions and relaxations (oscillations or twitching movements) of certain muscle groups in one or more body parts of unknown cause. It is typically symmetrical, and affects the arms, hands, or fingers; but sometimes involves the head, vocal cords, or other body parts.  Essential tremor is either an action (intention) tremor—it intensifies when one tries to use the affected muscles during voluntary movements such as eating and writing—or it is a postural tremor, present with sustained muscle tone. This means that it is distinct from a resting tremor, such as that caused by Parkinsons disease, which is not correlated with movement.Essential tremor is a progressive neurological disorder, and the most common movement disorder. Its onset is usually after age 40, but it can occur at any age. The cause is unknown. Diagnosis is by observing the typical pattern of the tremor coupled with the exclusion of known causes of such a tremor.
While essential tremor is distinct from Parkinsons disease, which causes a resting tremor, essential tremor is nevertheless sometimes misdiagnosed as Parkinsons disease. Some patients have been found to have both essential tremors and resting tremors.Treatments for essential tremor include medications, typically given sequentially to determine which provides the best compromise between effectiveness and troublesome side effects. Clostridium botulinum toxin (Botox) injections and ultrasound are also sometimes used for cases refractory to medications.

Signs and symptoms
In mild cases, ET can manifest as the inability to stop the tongue or hands from shaking, the ability to sing only in vibrato, and difficulty doing small, precise tasks such as threading a needle. Even simple tasks such as cutting in a straight line or using a ruler can range from difficult to impossible, depending on the severity of the condition. In disabling cases, ET can interfere with a persons activities of daily living, including feeding, dressing, and taking care of personal hygiene. Essential tremor generally presents as a rhythmic tremor (4–12 Hz) that occurs only when the affected muscle is exerting effort. Any sort of physical or mental stress tends to make the tremor worse.The tremor may also occur in the head (neck), jaw, and voice, as well as other body regions, with the general pattern being that the tremor begins in the arms and then spreads to these other regions in some people. Women are more likely to develop the head tremor than are men. Other types of tremor may also occur, including postural tremor of the outstretched arms, intention tremor of the arms, and rest tremor in the arms. Some people may have unsteadiness and problems with gait and balance.ET-related tremors do not occur during sleep, but people with ET sometimes complain of an especially coarse tremor upon awakening that becomes noticeably less coarse within the first few minutes of wakefulness. Tremor and disease activity/intensity can worsen in response to fatigue, strong emotions, low blood sugar, cold and heat, caffeine, lithium salts, some antidepressants, and other factors. Typically, the tremor worsens in "performance" situations, such as when writing a cheque for payment at a store or giving a presentation.Parkinsons disease and parkinsonism can also occur simultaneously with ET. The degree of tremor, rigidity, and functional disability did not differ from patients with idiopathic Parkinsons disease. Hand tremor predominated (as it did in Parkinsons disease), and occurred in nearly all cases, followed by head tremor, voice tremor, neck, face, leg, tongue, and trunk tremor. Most other tremors occurred in association with hand tremor. More severe tremors, a lower sleep disorder frequency, and a similar prevalence of other non-motor symptoms also can occur.Walking difficulties in essential tremor are common. About half of patients have associated dystonia, including cervical dystonia, writers cramp, spasmodic dysphonia, and cranial dystonia, and 20% of the patients had associated parkinsonism. Olfactory dysfunction (loss of sense of smell) is common in Parkinsons disease, and has also been reported to occur in patients with essential tremor. A number of patients with essential tremor also exhibit many of the same neuropsychiatric disturbances seen in idiopathic Parkinsons disease.Essential tremor with tremor onset after the age of 65 has been associated with mild cognitive impairment, as well as dementia; although the link between these conditions, if any, is still not understood.Essential tremor has two tremor components,  central and peripheral. These two tremor components were identified by measuring the tremor of ET patients once with no weights on their hands and then with 1-lb weights on their hands. The addition of the weights resulted in a tremor spectrum with two peaks, one that maintained the same frequency (the central tremor) and one that decreased in frequency (the peripheral tremor). Only with the addition of the weights was the peripheral tremor distinguishable from the central tremor.The frequency of essential tremor is 4 to 11 Hz, depending on which body segment is affected. Proximal segments are affected at lower frequencies, and distal segments are affected at higher frequencies

Cause
Genetic
The underlying cause of essential tremor is not clear, but many cases seem to be familial. About half of the cases are due to a genetic mutation and the pattern of inheritance is most consistent with autosomal dominant transmission. No genes have been identified yet, but genetic linkage has been established with several chromosomal regions.

Toxins
Some environmental factors, including toxins, are also under active investigation, as they may play a role in the diseases cause.

Pathophysiology
In terms of pathophysiology, clinical, physiological and imaging studies point to an involvement of the cerebellum and/or cerebellothalamocortical circuits. Changes in the cerebellum could also be mediated by alcoholic beverage consumption. Purkinje cells are especially susceptible to ethanol excitotoxicity. Impairment of Purkinje synapses is a component of cerebellar degradation that could underlie essential tremor. Some cases have Lewy bodies in the locus ceruleus. ET cases that progress to Parkinsons disease are less likely to have had cerebellar problems. Recent neuroimaging studies have suggested that the efficiency of the overall brain functional network in ET is disrupted.
Recent post mortem studies have evidenced alterations in (leucine-rich repeat and Ig domain containing 1 (LINGO1) gene and GABA receptors in the cerebellum of people with essential tremor.  HAPT1 mutations have also been linked to ET, as well as to Parkinsons disease, multiple system atrophy, and progressive supranuclear palsy.In 2012, the National Toxicology Program concluded that sufficient evidence exists of an association between blood lead exposure at levels >10 μg/dl and essential tremor in adults, and limited evidence at blood lead levels >5 μg/dl.

Diagnosis
Usually, the diagnosis is established on clinical grounds. Tremors can start at any age, from birth through advanced ages (senile tremor). Any voluntary muscle in the body may be affected, although the tremor is most commonly seen in the hands and arms and slightly less commonly in the neck (causing the persons head to shake), tongue, and legs. A resting tremor of the hands is sometimes present. Tremor occurring in the legs might be diagnosable as orthostatic tremor.
ET occurs within multiple neurological disorders besides Parkinsons disease. This includes migraine disorders, where co-occurrences between ET and migraines have been examined.

Treatment
General measures
Not all individuals with ET require treatment, but  many treatment options are available depending on symptom severity.  Caffeine and stress should be avoided, and adequate good-quality sleep is recommended.

Oral medications
First-line
When symptoms are sufficiently troublesome to warrant treatment, the first medication choices are beta blockers such as propranolol or alternately, nadolol and timolol. Atenolol and pindolol are not effective for tremor.  The anticonvulsant primidone may also be effective.  ET is generally responsive to alcohol, but the risks of regular drinking are greater than the potential benefit. Nonetheless, ET patients sometimes self-medicate with alcohol.Propranolol and primidone only have tremor-reducing effects on about half of ET patients, and the effects are moderate.

Second-line
Second-line medications are the anticonvulsants topiramate, gabapentin (as monotherapy) or levetiracetam, or  benzodiazepines such as alprazolam.

Third-line
Third-line medications are clonazepam and mirtazapine.

Fourth-line
Theophylline has been used by some practitioners to treat ET, though it may also induce tremor.  However, its use is debated due to conflicting data on its efficacy.  Some evidence shows that low doses may lead to improvement.Ethanol has shown superior efficacy to those of benzodiazepines in small trials. It improves tremor in small doses and its effects are usually noticeable within 20 minutes for 3–5 hours, but occasionally appears in a rebound tremor augmentation later.Some systematic reviews of medications for the treatment of ET have been conducted.  A 2017 review of topiramate found limited data and low quality evidence to support its efficacy and the occurrence of treatment-limiting adverse effects, a 2017 review of zonisamide found insufficient information to assess efficacy and safety, and a 2016 review of pregabalin determined the effects to be uncertain due to the low quality of evidence.

Botulinum injection
When medications do not control the tremor or the person does not tolerate medication, C. botulinum toxin, deep brain stimulation, or occupational therapy can be helpful. The electrodes for deep brain stimulation are usually placed in the  "tremor center" of the brain, the ventral intermediate nucleus of the thalamus.

Ultrasound
Additionally, MRI-guided high-intensity focused ultrasound is a nonsurgical treatment option for people with essential tremor who are medication refractory. MRI-guided high-intensity focused ultrasound does not achieve healing, but can improve the quality of life. While its long-term effects are not yet established, the improvement in tremor score from baseline was durable at 1 year and 2 years following the treatment. To date, reported adverse events and side effects have been mild to moderate. Possible adverse events include gait difficulties, balance disturbances, paresthesias, headache, skin burns with ulcerations, skin retraction, scars, and blood clots. This procedure is contraindicated in pregnant women, persons who have non-MRI compatible implanted metallic devices, allergy to MR contrast agents, cerebrovascular disease, abnormal bleeding, hemorrhage and/or blood clotting disorders, advanced kidney disease or on dialysis, heart conditions, severe hypertension, and ethanol or substance abuse, among others. The US Food and Drug Administration (FDA) approved Insightecs Exablate Neuro system to treat essential tremor in 2016.Another treatment for essential tremor is a surgical option; deep brain stimulation is used.

Prognosis
Although essential tremor is often mild, people with severe tremor have difficulty performing many of their routine activities of daily living.  ET is generally progressive in most cases (sometimes rapidly, sometimes very slowly), and can be disabling in severe cases.

Epidemiology
ET is one of the most common neurological diseases, with a prevalence around 4% in persons age 40 and older and considerably higher among persons in their 60s, 70s, and 80s, with an estimated 20% of individuals in their 90s and over. Aside from enhanced physiological tremor, it is the most common type of tremor and one of the most commonly observed movement disorders.

Society and culture
Actress Katharine Hepburn (1907–2003) had an essential tremor, possibly inherited from her grandfather, that caused her head—and sometimes her hands—to shake. The tremor was noticeable by the time of her performance in the 1979 film The Corn Is Green, when critics mentioned the "palsy that kept her head trembling". Hepburns tremor worsened in her later life.Charles M. Schulz, American cartoonist and creator of the Peanuts comic strip, was affected during the last two decades of his life.
West Virginia Senator Robert Byrd also had essential tremor.
In 2010, musician Daryl Dragon of The Captain and Tennille was diagnosed with essential tremor, with the condition becoming so severe that Dragon was no longer able to play the keyboards.Director-writer-producer-comedian Adam McKay was diagnosed with essential tremor.Downton Abbey creator Julian Fellowes has the condition, as does the shows character Charlie Carson.In 2022, Matthew Caws of Nada Surf and his son made a PSA called "Living with a Mild Essential Tremor".

Research
Harmaline is a widely used model of essential tremor (ET) in rodents. Harmaline is thought to act primarily on neurons in the inferior olive. Olivocerebellar neurons exhibit rhythmic excitatory action when harmaline is applied locally.Harmane or harmaline has been implicated not only in essential tremors, but is also found in greater quantities in the brain fluid of people with Parkinsons disease as well as cancer. Higher levels of the neurotoxin are associated with greater severity of the tremors. Harmane is particularly abundant in meats, and certain cooking practices (e.g., long cooking times) increase its concentration, however, at least one study has shown that harmane blood concentrations do not go up after meat consumption in ET patients with already elevated harmane levels, where as the control groups harmane levels increase accordingly, suggesting that another factor, like a metabolic defect, may be responsible for the higher harmane levels in E.T </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pressure ulcer and explain in detail? [/INST] Pressure ulcers, also known as pressure sores, bed sores or pressure injuries, are localised damage to the skin and/or underlying tissue that usually occur over a bony prominence as a result of usually long-term pressure, or pressure in combination with shear or friction. The most common sites are the skin overlying the sacrum, coccyx, heels, and hips, though other sites can be affected, such as the elbows, knees, ankles, back of shoulders, or the back of the cranium.
Pressure ulcers occur due to pressure applied to soft tissue resulting in completely or partially obstructed blood flow to the soft tissue. Shear is also a cause, as it can pull on blood vessels that feed the skin. Pressure ulcers most commonly develop in individuals who are not moving about, such as those who are on chronic bedrest or consistently use a wheelchair. It is widely believed that other factors can influence the tolerance of skin for pressure and shear, thereby increasing the risk of pressure ulcer development. These factors are protein-calorie malnutrition, microclimate (skin wetness caused by sweating or incontinence), diseases that reduce blood flow to the skin, such as arteriosclerosis, or diseases that reduce the sensation in the skin, such as paralysis or neuropathy. The healing of pressure ulcers may be slowed by the age of the person, medical conditions (such as arteriosclerosis, diabetes or infection), smoking or medications such as anti-inflammatory drugs.
Although often prevented and treatable if detected early, pressure ulcers can be very difficult to prevent in critically ill people, frail elders and individuals with impaired mobility such as wheelchair users (especially where spinal injury is involved). Primary prevention is to redistribute pressure by regularly turning the person. The benefit of turning to avoid further sores is well documented since at least the 19th century. In addition to turning and re-positioning the person in the bed or wheelchair, eating a balanced diet with adequate protein and keeping the skin free from exposure to urine and stool is important.The rate of pressure ulcers in hospital settings is high; the prevalence in European hospitals ranges from 8.3% to 23%, and the prevalence was 26% in Canadian healthcare settings from 1990 to 2003. In 2013, there were 29,000 documented deaths from pressure ulcers globally, up from 14,000 deaths in 1990.

Presentation
Complications
Pressure ulcers can trigger other ailments, cause considerable suffering, and can be expensive to treat. Some complications include autonomic dysreflexia, bladder distension, bone infection, pyarthrosis, sepsis, amyloidosis, anemia, urethral fistula, gangrene and very rarely malignant transformation (Marjolins ulcer - secondary carcinomas in chronic wounds). Sores may recur if those with pressure ulcers do not follow recommended treatment or may instead develop seromas, hematomas, infections, or wound dehiscence. Paralyzed individuals are the most likely to have pressure sores recur. In some cases, complications from pressure sores can be life-threatening. The most common causes of fatality stem from kidney failure and amyloidosis.
Pressure ulcers are also painful, with individuals of all ages and all stages of pressure ulcers reporting pain.

Cause
There are four mechanisms that contribute to pressure ulcer development:
External (interface) pressure applied over an area of the body, especially over the bony prominences can result in obstruction of the blood capillaries, which deprives tissues of oxygen and nutrients, causing ischemia (deficiency of blood in a particular area), hypoxia (inadequate amount of oxygen available to the cells), edema, inflammation, and, finally, necrosis and ulcer formation. Ulcers due to external pressure occur over the sacrum and coccyx, followed by the trochanter and the calcaneus (heel).
Friction is damaging to the superficial blood vessels directly under the skin. It occurs when two surfaces rub against each other. The skin over the elbows can be injured due to friction. The back can also be injured when patients are pulled or slid over bed sheets while being moved up in bed or transferred onto a stretcher.
Shearing is a separation of the skin from underlying tissues. When a patient is partially sitting up in bed, their skin may stick to the sheet, making them susceptible to shearing in case underlying tissues move downward with the body toward the foot of the bed. This may also be possible on a patient who slides down while sitting in a chair.
Moisture is also a common pressure ulcer culprit. Sweat, urine, feces, or excessive wound drainage can further exacerbate the damage done by pressure, friction, and shear. It can contribute to maceration of surrounding skin thus potentially expanding the deleterious effects of pressure ulcers.

Risk factors
There are over 100 risk factors for pressure ulcers. Factors that may place a patient at risk include immobility, diabetes mellitus, peripheral vascular disease, malnutrition, cerebral vascular accident and hypotension. Other factors are age of 70 years and older, current smoking history, dry skin, low body mass index, urinary and fecal incontinence,  physical restraints, malignancy, and history of pressure ulcers.

Pathophysiology
Pressure ulcers may be caused by inadequate blood supply and resulting reperfusion injury when blood re-enters tissue. A simple example of a mild pressure sore may be experienced by healthy individuals while sitting in the same position for extended periods of time: the dull ache experienced is indicative of impeded blood flow to affected areas. Within 2 hours, this shortage of blood supply, called ischemia, may lead to tissue damage and cell death. The sore will initially start as a red, painful area. The other process of pressure ulcer development is seen when pressure is high enough to damage the cell membrane of muscle cells. The muscle cells die as a result and skin fed through blood vessels coming through the muscle die. This is the deep tissue injury form of pressure ulcers and begins as purple intact skin.According to Centers for Medicare and Medicaid Services, pressure ulcers are one of the eight preventable iatrogenic illnesses. If a pressure ulcer is acquired in the hospital, the hospital will no longer receive reimbursement for the persons care. Hospitals spend about $5 billion annually for treatment of pressure ulcers.

Sites
Common pressure sore sites include the skin over the ischial tuberosity, the sacrum, the heels of the feet, over the heads of the long bones of the foot, buttocks, over the shoulder, and over the back of the head.

Biofilm
Biofilm is one of the most common reasons for delayed healing in pressure ulcers. Biofilm occurs rapidly in wounds and stalls healing by keeping the wound inflamed. Frequent debridement and antimicrobial dressings are needed to control the biofilm. Infection prevents healing of pressure ulcers. Signs of pressure ulcer infection include slow or delayed healing and pale granulation tissue. Signs and symptoms of systemic infection include fever, pain, redness, swelling, warmth of the area, and purulent discharge. Additionally, infected wounds may have a gangrenous smell, be discolored, and may eventually produce more pus.In order to eliminate this problem, it is imperative to apply antiseptics at once. Hydrogen peroxide (a near-universal toxin) is not recommended for this task as it increases inflammation and impedes healing.  Dressings with cadexomer iodine, silver, or honey have been shown to penetrate bacterial biofilms. Systemic antibiotics are not recommended in treating local infection in a pressure ulcer, as it can lead to bacterial resistance. They are only recommended if there is evidence of advancing cellulitis, bony infection, or bacteria in the blood.

Diagnosis
Classification
The definitions of the pressure ulcer stages are revised periodically by the National Pressure Injury Advisory Panel (NPUAP) in the United States and the European Pressure Ulcer Advisory Panel (EPUAP) in Europe. Different classification systems are used around the world, depending upon the health system, the health discipline and the purpose for the classifying (e.g. health care versus, prevalence studies versus funding.  Briefly, they are as follows:
Stage I: Intact skin with non-blanchable redness of a localized area usually over a bony prominence. Darkly pigmented skin may not have visible blanching; its color may differ from the surrounding area. The area differs in characteristics such as thickness and temperature as compared to adjacent tissue. Stage 1 may be difficult to detect in individuals with dark skin tones. May indicate "at risk" persons (a heralding sign of risk).
Stage II: Partial thickness loss of dermis presenting as a shallow open ulcer with a red pink wound bed, without slough. May also present as an intact or open/ruptured serum-filled blister. Presents as a shiny or dry shallow ulcer without slough or bruising. This stage should not be used to describe skin tears, tape burns, perineal dermatitis, maceration or excoriation.
Stage III: Full thickness tissue loss. Subcutaneous fat may be visible but bone, tendon or muscle are not exposed. Slough may be present but does not obscure the depth of tissue loss. May include undermining and tunneling. The depth of a stage 3 pressure ulcer varies by anatomical location. The bridge of the nose, ear, occiput and malleolus do not have (adipose) subcutaneous tissue and stage 3 ulcers can be shallow. In contrast, areas of significant adiposity can develop extremely deep stage 3 pressure ulcers. Bone/tendon is not visible or directly palpable.
Stage IV: Full thickness tissue loss with exposed bone, tendon or muscle. Slough or eschar may be present on some parts of the wound bed. Often include undermining and tunneling. The depth of a stage 4 pressure ulcer varies by anatomical location. The bridge of the nose, ear, occiput and malleolus do not have (adipose) subcutaneous tissue and these ulcers can be shallow. Stage 4 ulcers can extend into muscle and/or supporting structures (e.g., fascia, tendon or joint capsule) making osteomyelitis likely to occur. Exposed bone/tendon is visible or directly palpable. In 2012, the National Pressure Injury Advisory Panel stated that pressure ulcers with exposed cartilage are also classified as a stage 4.
Unstageable: Full thickness tissue loss in which actual depth of the ulcer is completely obscured by slough (yellow, tan, gray, green or brown) and/or eschar (tan, brown or black) in the wound bed. Until enough slough and/or eschar is removed to expose the base of the wound, the true depth, and therefore stage, cannot be determined. Stable (dry, adherent, intact without erythema or fluctuance) eschar on the heels is normally protective and should not be removed.
Suspected deep tissue injury: A purple or maroon localized area of discolored intact skin or blood-filled blister due to damage of underlying soft tissue from pressure and/or shear. The area may be preceded by tissue that is painful, firm, mushy, boggy, warmer or cooler as compared to adjacent tissue. A deep tissue injury may be difficult to detect in individuals with dark skin tones. Evolution may include a thin blister over a dark wound bed. The wound may further evolve and become covered by thin eschar. Evolution may be rapid exposing additional layers of tissue even with optimal treatment.The term medical device related pressure ulcer refers to a cause rather than a classification. Pressure ulcers from a medical device are classified according to the same classification system being used for pressure ulcers arising from other causes, but the cause is usually noted.

Ischemic fasciitis
Ischemic fasciitis (IF) is a benign tumor in the class of fibroblastic and myofibroblastic tumors that, like pressure ulcers, may develop in elderly, bed-ridden individuals. These tumors commonly form in the subcutaneous tissues (i.e. lower most tissue layer of the skin) that overlie bony protuberances such as those in or around the hip, shoulder, greater trochanter of the femur, iliac crest, lumbar region, or scapular region. IF tumors differ from pressure ulcers in that they typically do not have extensive ulcerations of the skin and on histopathological microscopic analysis lack evidence of acute inflammation as determined by the presence of various types of white blood cells. These tumors are commonly treated by surgical removal.

Prevention
In the United Kingdom, the Royal College of Nursing has published guidelines in Pressure Ulcer Risk Assessment and Prevention that call for identifying people at risk and taking preventive action; the UK National Standards for Care Homes to do so as well. Recent efforts in the United States and South Korea have sought to automate risk assessment and classification by training machine learning models on electronic health records.Internationally, the NPIAP, EPUAP and Pan Pacific Pressure Injury Alliance, together with wound organizations from 15 countries around the world, published updated the international evidence-based clinical practice guideline in 2019. The 2019 guideline was developed by an international team of over 180 clinical specialists and updates the 2009 EPUAP/NPUAP clinical guideline and the 2014 NPUAP/EPUAP/PPPIA clinical guideline. The guideline includes recommendations on strategies to treat pressure ulcers, including the use of bed rest, pressure redistributing support surfaces, nutritional support, repositioning, wound care (e.g. debridement, wound dressings) and biophysical agents (e.g. electrical stimulation). Reliable scientific evidence to support the use of many of these interventions, though, is lacking. More research is needed to assess how to best support the treatment of pressure ulcers, for example by repositioning. Also, the benefit of using systemic or topical antibiotics in the management of pressure ulcer is still unclear.

Redistributing pressure
The most important care for a person at risk for pressure ulcers and those with bedsores is the redistribution of pressure so that no pressure is applied to the pressure ulcer. In the 1940s Ludwig Guttmann introduced a program of turning paraplegics every two hours thus allowing bedsores to heal. Previously such individuals had a two-year life-expectancy, normally succumbing to blood and skin infections. Guttmann had learned the technique from the work of Boston physician Donald Munro.There is lack of evidence on prevention of pressure ulcer whether the patient is put in 30 degrees position or at the standard 90 degrees position.Nursing homes and hospitals usually set programs in place to avoid the development of pressure ulcers in those who are bedridden, such as using a routine time frame for turning and repositioning to reduce pressure. The frequency of turning and repositioning depends on the persons level of risk.

Support surfaces
A 2015 Cochrane systematic review found that people who lay on high specification or high density foam mattresses were 60% less likely to develop new pressure ulcers compared to regular foam mattresses. Sheepskin overlays on top of mattresses were also found to prevent new pressure ulcer formation. There is unclear research on the effectiveness of alternating pressure mattresses. Pressure-redistributive mattresses are used to reduce high values of pressure on prominent or bony areas of the body. There are several important terms used to describe how these support surfaces work. These terms were standardized through the Support Surface Standards Initiative of the NPUAP. Many support surfaces redistribute pressure by immersing and/or enveloping the body into the surface. Some support surfaces, including antidecubitus mattresses and cushions, contain multiple air chambers that are alternately pumped. Methods to standardize the products and evaluate the efficacy of these products have only been developed in recent years through the work of the S3I within NPUAP. For individuals with paralysis, pressure shifting on a regular basis and using a wheelchair cushion featuring pressure relief components can help prevent pressure wounds.
A 2022 Cochrane systematic review aimed to find out how effective pressure redistributing static chairs (as opposed to wheelchairs) are for preventing pressure ulcers. Static chairs can include: standard hospital chairs; chairs with no cushions or manual/dynamic function; and chairs with integrated pressure redistributing surfaces and recline, rise or tilt functions. The authors did not find any randomised controlled trials that were eligible for inclusion. More research is needed to establish how effective pressure redistributing static chairs are for preventing pressure ulcers.
Controlling the heat and moisture levels of the skin surface, known as skin microclimate management, also plays a significant role in the prevention and control of pressure ulcers.

Nutrition
In addition, adequate intake of protein and calories is important. Vitamin C has been shown to reduce the risk of pressure ulcers. People with higher intakes of vitamin C have a lower frequency of bed sores in those who are bedridden than those with lower intakes. Maintaining proper nutrition in newborns is also important in preventing pressure ulcers. If unable to maintain proper nutrition through protein and calorie intake, it is advised to use supplements to support the proper nutrition levels. Skin care is also important because damaged skin does not tolerate pressure. However, skin that is damaged by exposure to urine or stool is not considered a pressure ulcer. These skin wounds should be classified as Incontinence Associated Dermatitis.

Organisational changes
There is some suggestion that organisational changes may reduce incidence of pressure ulcers. Cochrane systematic reviews on organisation of health services, risk assessment tools, wound care teams, and education have concluded that evidence is uncertain as to the benefit of these organisational changes. This is largely due to the lack of high-quality research in these areas.

Other prevention therapies
A Cochrane systematic review found use of creams containing fatty acids may be more effective in reducing incidence of pressure ulcers compared to creams without fatty acids. Silicone dressings may also reduce pressure ulcer incidence. There is no evidence that massage reduces pressure ulcer incidence.

Treatment
Internationally, the NPIAP, EPUAP and Pan Pacific Pressure Injury Alliance, together with wound organizations from 15 countries around the world published updated their international evidence-based clinical practice guideline in 2019.  The 2019 guideline was developed by an international team of over 180 clinical specialists and updates the 2009 EPUAP/NPUAP clinical guideline and the 2014 NPUAP/EPUAP/PPPIA clinical guideline. The guideline includes recommendations on strategies to treat pressure ulcers, including the use of bed rest, pressure redistributing support surfaces, nutritional support, repositioning, wound care (e.g. debridement, wound dressings) and biophysical agents (e.g. electrical stimulation). Reliable scientific evidence to support the use of many of these interventions, though, is lacking. More research is needed to assess how to best support the treatment of pressure ulcers, for example by repositioning. A 2020 Cochrane systematic review of randomized controlled trials concluded that more research is needed to determine whether or not electrical stimulation is an effective treatment for pressure ulcers. In addition, the benefit of using systemic or topical antibiotics in the management of pressure ulcer is still unclear.

Debridement
Necrotic tissue should be removed in most pressure ulcers. The heel is an exception in many cases when the limb has an inadequate blood supply. Necrotic tissue is an ideal area for bacterial growth, which has the ability to greatly compromise wound healing. There are five ways to remove necrotic tissue.

Autolytic debridement is the use of moist dressings to promote autolysis with the bodys own enzymes and white blood cells. It is a slow process, but mostly painless, and is most effective in individuals with a properly functioning immune system.
Biological debridement, or maggot debridement therapy, is the use of medical maggots to feed on necrotic tissue and therefore clean the wound of excess bacteria. Although this fell out of favor for many years, in January 2004, the FDA approved maggots as a live medical device.
Chemical debridement, or enzymatic debridement, is the use of prescribed enzymes that promote the removal of necrotic tissue.
Mechanical debridement, is the use of debriding dressings, whirlpool or ultrasound for slough in a stable wound.
Surgical debridement, or sharp debridement, is the fastest method, as it allows a surgeon to quickly remove dead tissue.

Dressings
A 2017 Cochrane review found that it was unclear whether one topical agent or dressing was better than another for treating pressure ulcers. Protease-modulating dressings, foam dressings or collagenase ointment may be better at healing than gauze. The wound dressing should be selected based on the wound and condition of the surrounding skin. There are some studies that indicate that antimicrobial products that stimulate the epithelization may improve the wound healing. However, there is no international consensus on the selection of the dressings for pressure ulcers. Cochrane reviews summarise evidence on alginate dressings, foam dressings, and hydrogel dressings. Due to a lack of robust evidence, the benefits of these dressings over other treatments is unclear.
Some guidelines for dressing are:

Other treatments
Other treatments include anabolic steroids, negative pressure wound therapy, phototherapy, support surfaces, reconstructive surgery, ultrasound, topical phenytoin and pressure relieving devices </s>