<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Spondylolisthesis and can you explain it in depth? [/INST] Spondylolisthesis is the displacement of one spinal vertebra compared to another. While some medical dictionaries define spondylolisthesis specifically as the forward or anterior displacement of a vertebra over the vertebra inferior to it (or the sacrum), it is often defined in medical textbooks as displacement in any direction. Spondylolisthesis is graded based upon the degree of slippage of one vertebral body relative to the subsequent adjacent vertebral body. Spondylolisthesis is classified as one of the six major etiologies: degenerative, traumatic, dysplastic, isthmic, pathologic, or post-surgical. Spondylolisthesis most commonly occurs in the lumbar spine, primarily at the L5-S1 level with the L5 vertebral body anteriorly translating over the S1 vertebral body.

Types
Olisthesis (synonym olisthy) is a term that more explicitly denotes displacement in any direction. Forward or anterior displacement can specifically be called anterolisthesis. Anterolisthesis commonly involves the fifth lumbar vertebra. Backward displacement is called retrolisthesis. Lateral displacement is called lateral listhesis or laterolisthesis.A hangmans fracture is a specific type of spondylolisthesis where the second cervical vertebra (C2) is displaced anteriorly relative to the C3 vertebra due to fractures of the C2 vertebras pedicles.

Anterolisthesis
Classification
Anterolisthesis can be categorized by cause, location and severity.

By causes
Degenerative anterolisthesis (a.k.a. type 3) is a disease of the older adult that develops as a result of facet arthritis and joint remodeling. Joint arthritis, and ligamentum flavum weakness, may result in slippage of a vertebra. Degenerative forms are more likely to occur in women, persons older than fifty, and African Americans.
Traumatic anterolisthesis is rare and results from acute fractures in the neural arch, other than the pars.
Dysplastic anterolisthesis (a.k.a. type 1) results from congenital abnormalities of the upper sacral facets or inferior facets of the fifth lumbar vertebra, and accounts for 14% to 21% of all anterolisthesis.
Isthmic anterolisthesis (a.k.a. type 2) is caused by a defect in the pars interarticularis but it can also be seen with an elongated pars.
Pathologic anterolisthesis (a.k.a. type 5) is caused by either infection or a malignancy.
Post-surgical/iatrogenic anterolisthesis (a.k.a. type 6) is caused by complications after surgery.

By location
Anterolisthesis location includes which vertebrae are involved, and may also specify which parts of the vertebrae are affected.
Isthmic anterolisthesis is where there is a defect in the pars interarticularis. It is the most common form of spondylolisthesis; also called spondylolytic spondylolisthesis, it occurs with a reported prevalence of 5–7 percent in the US population. A slip or fracture of the intravertebral joint is usually acquired between the ages of 6 and 16 years, but remains unnoticed until adulthood. Roughly 90 percent of these isthmic slips are low-grade (less than 50 percent slip) and 10 percent are high-grade (greater than 50 percent slip). It is divided into three subtypes:
A: pars fatigue fracture
B: pars elongation due to multiple healed stress effects
C: pars acute fracture

Severity
Classification by degree of the slippage, as measured as percentage of the width of the vertebral body: Grade I spondylolisthesis accounts for approximately 75% of all cases.
Grade I: 0–25%
Grade II: 25- 50%
Grade III: 50–75%
Grade IV: 75–100%
Grade V: greater than 100%

Signs and symptoms
Symptoms of lumbar anterolisthesis include:

A general stiffening of the back and a tightening of the hamstrings, with a resulting change in both posture and gait.
A leaning-forward or semi-kyphotic posture may be seen, due to compensatory changes.
A "waddle" may be seen in more advanced causes, due to compensatory pelvic rotation due to decreased lumbar spine rotation.
A result of the change in gait is often a noticeable atrophy in the gluteal muscles due to lack of use.
Generalized lower-back pain may also be seen, with intermittent shooting pain from the buttocks to the posterior thigh, and/or lower leg via the sciatic nerve.Other symptoms may include tingling and numbness. Coughing and sneezing can intensify the pain. An individual may also note a "slipping sensation" when moving into an upright position. Sitting and trying to stand up may be painful and difficult.

Physical Exam
The major components of the physical exam for spondylolisthesis consists of observation, palpation, and maneuvers. The most common finding is pain with lumbar extension. The following physical involves specific assessment for spondylolisthesis. However, a general examination, most importantly neurological examination, must be done to rule out alternative causes for signs and symptoms. Neurological examination is often normal in patients with spondylolisthesis, but lumbosacral radiculopathy is commonly seen in patients with degenerate spondylolisthesis.

Observation
The patient should be observed walking and standing. Most patients present with a normal gait. An abnormal gait is often the sign of a high grade case. A patient with high grade spondylolisthesis may present with a posterior pelvic tilt causing a loss in the normal contour of the buttocks. An antalgic gait, rounded back and decreased hip extension, can result from severe pain. While standing, the patient should be observed from the front, back, and sides. Increased and decreased lumbar lordosis, inward curvature of the lower spine, has been seen.

Palpation
Detection of spondylolisthesis by palpation is most often done by palpating for the spinous process. Each level of the lumbar spine should be palpated. Spinous process palpation by itself is not a definitive method for the detection of spondylolisthesis.

Maneuvers
Spinal range of motion testing – Range of motion limitations may be seen.
Lumbar hyperextension – Extension often elicits pain. This can be assessed by having the patient hyperextend the lumbar spine, provide resistance against back extensions, or undergo repeated lumbar extensions.
Sport-specific motion – Patient can be asked to repeat aggravating movements that they experience during their activity. During the movement, ask patient to point to any places with focal pain.
Straight leg raise – Maneuver used to assess for hamstring tightness. The straight leg raise has been found to be positive in only 10% of patients with spondylolisthesis.
Muscle strength exercises – Lower abdominal, gluteal, and lumbar extensors should be assessed for weakness. Weakness in these muscles can increase lordosis and contribute to sacroiliac instability. Abdominal flexor strength can be assessed with the abdominal flexor endurance test. The test involves the patient lying supine while holding a 45 degree flexed trunk and 90 degree flexed knees for 30 seconds. Gluteal strength can be assessed with a single-leg squat. Lastly, lumbar extension can be assessed with a single-leg bridge.

Diagnostic Imaging
In adults with non-specific low back pain, strong evidence suggests medical imaging should not be done within the first six weeks. It is also suggested to avoid advanced imaging, such as CT or MRI, for adults without neurological symptoms or "red flags" in the patients history. General recommendations for initial low back pain treatment is remaining active, avoiding twisting and bending, avoiding activities that worsen pain, avoiding bed rest, and possibly initiating a trial of non-steroidal anti-inflammatory drugs after consulting a physician. Children and adolescents with persistent low back pain may require earlier imaging and should be seen by physician. Once imaging is deemed necessary, a combination of plain radiography, computed tomography, and magnetic resonance imaging may be used. Images are most often taken of the lumbar spine due to spondylolisthesis most commonly involving the lumbar region. Images of the thoracic spine can be taken if a patients history and physical suggest thoracic involvement.

Plain Radiography (X-Ray)
Plain radiography is often the first step in medical imaging. Anteroposterior (front-back) and lateral (side) images are used to allow the physician to view the spine at multiple angles. Oblique view are no longer recommended. In evaluating for spondylolithesis, plain radiographs provide information on the positioning and structural integrity of the spine. Therefore, if further detail is needed a physician may request advanced imaging.

Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging is the preferred advanced imaging technique for evaluation of spondylolisthesis. Preference is due to effectiveness, lack of radiation exposure, and ability to evaluate for soft tissue abnormalities and spinal canal involvement. MRI is limited in its ability to evaluate fractures in great detail, compared to other advanced imaging modalities.

Computed Tomography (CT)
Computed tomography can be helpful in evaluating bony vertebral abnormalities, such as fractures. This can be helpful in determining if the fracture is a new, old, and/or progressing fracture. CT use in spondylolisthesis evaluation is controversial due to high radiation exposure.

Treatment
Spondylolisthesis patients without symptoms do not need to be treated.

Conservative
Non-operative management, also referred to as conservative treatment, is the recommended treatment for spondylolisthesis in most cases with or without neurological symptoms. Most patients with spondylolisthesis respond to conservative treatment. Conservative treatment consists primarily of physical therapy, intermittent bracing, aerobic exercise, pharmacological intervention, and epidural steroid injections. The majority of patients with degenerative spondylolisthesis do not require surgical intervention.
Physical therapy can evaluate and address postural and compensatory movement abnormalities. Physical therapy primarily includes spinal flexion and extension exercises with a focus on core stabilization and muscle strengthening. In particular, lumbar spondylolisthesis may benefit from core stabilization exercises focusing on lower abdominal, lumbar muscles, hamstrings, and hip flexors, which may temporarily or permanently improve symptoms and improve general function.
Some patients may benefit from bracing in combination with physical therapy. Additionally, bracing was found to be beneficial when performed immediately following the onset of symptoms, in particular patients with lumbar pars interarticular defects.
Exercises such as cycling, elliptical training, swimming, and walking are considered low-impact aerobic exercises and are recommended for pain relief.
Anti-inflammatory medications (NSAIDS) in combination with paracetamol can be tried initially. If a severe radicular component is present, a short course of oral steroids such as prednisone or methylprednisolone can be considered </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Prurigo nodularis and can you explain it in depth? [/INST] Prurigo nodularis (PN), also known as nodular prurigo, is a skin disease characterised by pruritic (itchy) nodules which usually appear on the arms or legs. Patients often present with multiple excoriated lesions caused by scratching. PN is also known as Hyde prurigo nodularis, Pickers nodules, atypical nodular form of neurodermatitis circumscripta, lichen corneus obtusus.
Lichen simplex chronicus is a distinct clinical entity.

Signs and symptoms
Nodules are discrete, generally symmetric, hyperpigmented or purpuric, and firm. They are greater than 0.5 cm in both width and depth (as opposed to papules which are less than 0.5 cm). They can appear on any part of the body, but generally begin on the arms and legs.
Excoriated lesions are often flat, umbilicated, or have a crusted top.
Nodules may appear to begin in the hair follicles.
Nodule pattern may be follicular.
In true prurigo nodularis, a nodule forms before itching begins. Typically, these nodules are extremely pruritic and are alleviated only by steroids.

Causes
The cause of prurigo nodularis is unknown, although other conditions may induce PN. PN has been linked to Beckers nevus, linear IgA disease, an autoimmune condition, liver disease and T cells. Systemic pruritus has been linked to cholestasis, thyroid disease, polycythaemia rubra vera, uraemia, Hodgkins disease, HIV and other immunodeficiency diseases. Internal malignancies, liver failure, kidney failure, and psychiatric illnesses have been considered to induce PN, although more recent research has refuted a psychiatric cause for PN. Patients report an ongoing battle to distinguish themselves from those with psychiatric disorders, such as delusions of parasitosis and other psychiatric conditions.

Pathophysiology
Chronic and repetitive scratching, picking, or rubbing of the nodules may result in permanent changes to the skin, including nodular lichenification, hyperkeratosis, hyperpigmentation, and skin thickening </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Erythema multiforme minor and can you explain it in depth? [/INST] Erythema multiforme  is usually a reaction of the skin and mucous membranes that occurs suddenly. It appears as a symmetrical rash and may include the mucous membrane lesions. This means that the body is sensitive to something that causes the skin and mucous membranes to react </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Localized lipodystrophy and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Glutaric acidemia type 2 and can you explain it in depth? [/INST] Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy.  Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called acidosis.

Genetics
Mutations in the ETFA, ETFB, and ETFDH genes cause glutaric acidemia type II. Mutations in these genes result in a deficiency in one of two enzymes that normally work together in the mitochondria, which are the energy-producing centers of cells. The ETFA and ETFB genes encode two subunits of the enzyme electron transfer flavoprotein, while the ETFDH gene encodes the enzyme electron-transferring-flavoprotein dehydrogenase. When one of these enzymes is defective or missing, the mitochondria cannot function normally, partially broken-down proteins and fats accumulate in the cells and damage them; this damage leads to the signs and symptoms of glutaric acidemia type II.This condition is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the gene – one from each parent – are needed to inherit the disorder. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the defective gene, but do not show signs and symptoms of the disorder themselves.

Diagnosis
Glutaric acidemia type 2 often appears in infancy as a sudden metabolic crisis, in which acidosis and low blood sugar (hypoglycemia) cause weakness, behavior changes, and vomiting </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Noma neonatorum and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Carnivore protoparvovirus 1 and can you explain it in depth? [/INST] Carnivore protoparvovirus 1 (CPPV 1) is a species of parvovirus that infects carnivorans. It causes a highly contagious disease in both dogs and cats. The disease is generally divided into two major genogroups: CPV-1 containing the classical feline panleukopenia virus (FPLV), and CPV-2 containing the canine parvovirus (CPV) which appeared in the 1970s.FPLV is known to infect all wild and domestic members of the felid (cat) family worldwide.  It is a highly contagious, severe infection that causes gastrointestinal, immune system, and nervous system disease. Its primary effect is to decrease the number of white blood cells, causing the disease known as feline panleukopenia.
It was once thought that only CPV-1 or FPLV infects cats. However, it has been confirmed that a feline panleukopenia illness can be caused by CPV 2a, 2b, and 2c.FPLV is commonly referred to as:

feline infectious enteritis virus (FIE)
feline parvovirus (FPV or FP or "feline parvo")
feline parvoviral enteritisIt is sometimes confusingly referred to as "cat plague" and "feline distemper".In addition to members of the felid family, it can also affect other carnivorans (e.g. raccoon, mink).

Etymology
Formed within English using elements derived from Greek: pan- a combining form meaning "universal" or "worldwide", -leuco- a combining form meaning (in biologic sciences) "white blood cell", and -penia a combining form meaning "loss of" or "decrease of". Thus the word means universal loss of white blood cells. The universal part refers to both its worldwide distribution and to the fact that all species of cats are infected.

Transmission
The feline panleukopenia virus is considered ubiquitous, meaning it is in virtually every place that is not regularly disinfected. The infection is highly contagious among unvaccinated cats.Antibodies against FPLV, produced by the adaptive immune system, play an important role in the feline response to the virus. Maternally-derived antibodies (MDA) efficiently protect kittens from fatal infection. This passively acquired immunity is later replaced by an active immune response obtained by vaccination or as a consequence of a natural infection. In kittens, the period of greatest susceptibility to infection is when maternal antibodies are absent, or waning, and vaccine-induced immunity has not yet fully developed.Free-roaming cats are thought to be exposed to the virus during their first year of life. Those that develop a subclinical infection or survive acute illness mount a robust, long-lasting, protective immune response.An infected cat sheds large amounts of virus in all body secretions including feces, vomit, urine, saliva, and mucus during the acute phase of illness. It can continue to shed the virus for as long as 6 weeks after recovery.  Subclinically ill cats can also shed the virus in body secretions. The virus can be carried or transferred on an infected object (such as bedding, food dishes, fur) or by other animals, fleas, and humans  (see: fomites). It persists long after evidence of the original body secretion has faded away, and can be transported long distances. Like all parvoviruses, FPLV is extremely resistant to inactivation and can survive for longer than one year in a suitable environment. Kitten deaths have been reported in households of fully vaccinated cats, possibly because of exposure to large amounts of virus in the environment.Infection occurs when the virus enters the body through the mouth or nose. Whether illness results or not depends on the immunity in the victim vs. the number of individual virus particles (i.e. the amount of virus) entering the body.

Clinical signs
The clinical manifestations of FPLV are variable based on the dose of the virus, the age of the cat, potential breed predispositions, and prior immunity from maternal antibodies, previous exposure, or vaccination. Most infections are subclinical, as evidenced by the high seroprevalence of anti-FPV antibodies among some populations of unvaccinated, healthy cats. The cats that become clinically ill are usually less than one year old, but older cats are also at risk. There is high mortality in clinically affected kittens and sudden death can occur.Clinical signs usually develop in 4–6 days after exposure, but can show in 2–14 days. The virus infects and destroys actively dividing cells in bone marrow, lymphoid tissues, intestinal epithelium, and—in very young animals—in the cerebellum and retina. The virus primarily attacks the lining of the gastrointestinal tract, causing internal ulceration and, ultimately, total sloughing of the intestinal epithelium.
Primary signs include:

anorexia
lethargy
profuse watery to bloody diarrhea (bloody diarrhea is more common in dogs with parvovirus than cats)
vomiting (most common in cats)Clinical laboratory findings include (but are not limited to):
electrolyte and total protein concentrations that reflect dehydration, vomiting, and diarrhea.
leukopenia
lymphopenia
neutropenia
thrombocytopeniaOther signs include: fever, loss of skin elasticity due to dehydration, abdominal pain, sternal recumbency with splayed legs and head droop, nasal discharge and conjunctivitis. Cats may sit at a water bowl, but not drink. Terminal cases are hypothermic and may develop septic shock and disseminated intravascular coagulation.Infection in pregnant cats can result in fetal resorption, mummification, abortion, or stillbirth of neonates. Fetuses infected in utero that survive and kittens less than a few weeks of age that become infected can have cerebellar hypoplasia, retinal dysplasia, and optic neuropathy.

Diagnosis
A presumptive clinical diagnosis of FPLV can be made for kittens with appropriate signalment, history, clinical findings and the history of no prior vaccination.The clinical diagnosis is usually supported by documenting parvovirus antigen in feces by ELISA (enzyme-linked immunosorbent assay) and PCR (polymerase chain reaction) assays. The availability of validated assays varies by country but is becoming more common.  PCR assays are so sensitive that FPV DNA can be amplified from feces of cats vaccinated with modified live strains of the virus. At least one of the ELISA antigen tests for dogs (SNAP®Parvo; IDEXX Laboratories) detects FPV in feline feces and has a cut point for a positive test result that excludes most vaccinated cats. Thus, this ELISA is superior to PCR for screening cats for FPV infection and can also be performed in the veterinary clinic. (These are only approved and licensed for detecting canine parvovirus, but it is generally known that they also detect FPL viral antigen in feline feces. These tests are used extra-label because they allow rapid, inexpensive, in-house detection of the virus.)  Some cats will have completed the shedding period by the time the test is run, leading to false-negative results.  Electron microscopy, virus isolation and seroconversion can also be used to document active or recent infection.
Leukopenia on a complete blood count (nadir 50–3,000 WBC/μL) supports a diagnosis of FPLV. In an unvaccinated cat, the presence of antibodies against FPV indicates that the cat either has the disease or has had the disease in the past. Elevated IgM titers (1:10 or greater) indicate active infection and if clinical signs are obvious (diarrhea, panleukopenia) the prognosis is poor. Elevated IgG titers (1:100 or greater) in a cat with clinical signs indicates a better prognosis.Differential diagnoses include salmonellosis, enteric toxins, feline immunodeficiency virus (FIV), feline leukemia virus (FeLV), cryptosporidiosis, pancreatitis, septicaemia with acute endotoxemia, toxoplasmosis, peritonitis, and lymphoma.

Treatment
To contain the virus, cats with suspected or diagnosed FPLV should be kept in isolation.It requires immediate, aggressive treatment if the cat is to survive, as it can be fatal in less than 24 hours. Several articles and publications provide guidance for rescuers and veterinarians for optimizing outcomes.Treatment involves:
anti-emetics
IV antibiotics
intravenous fluids with electrolytes
injections of vitamin B
plasma or whole blood transfusionFeeding should be continued as long as possible. A highly digestible diet is preferred, but the individual animals preferences may dictate giving whatever it will eat. In anorexic, hypoproteinemic, vomiting and diarrheic cats parenteral nutrition is required.In a disease outbreak, unvaccinated kittens or adults can be given anti-FPV serum containing FPV antibodies injected subcutaneously or intraperitoneal. This may provide protection for 2–4 weeks. Therapeutic efficacy of anti-FPV serum has been demonstrated in dogs, and similar beneficial effects may be expected in cats.Several studies have shown recombinant feline interferon omega  is effective in the treatment of parvoviral enteritis in dogs and also inhibits replication of FPV in cell culture. So far no data are available on its efficacy in FPV-infected cats.

Complications
Cats typically die due to complications associated with sepsis, dehydration, and disseminated intravascular coagulopathy (DIC). Leukocytopenia predisposes patients to secondary infections, especially bacterial and fungal, though secondary viral infections also occur.
It has been stated that cats with FPLV may be at risk for endocarditis or cardiomyopathy (since CPV-2 is a well-known cause of viral myocarditis in young puppies), but a 2017 retrospective study concluded that "Feline Panleukopenia Virus Is Not Associated With Myocarditis or Endomyocardial Restrictive Cardiomyopathy in Cats".

Prognosis
Mortality in affected felid litters varies between 20 and 100%.  Mortality of FPLV is 25–90% in domestic cats with the acute form of the disease and up to 100% in cats with peracute disease.In 2010, a retrospective study of 244 infected cats showed that "leukocyte and thrombocyte counts as well as serum albumin and potassium concentrations at presentation are prognostic indicators in cats with panleukopenia, whereas vaccination status, age, clinical signs, and housing conditions are not."A survival rate of about 50% has been reported with supportive therapies. Cats with FPLV that survive the first 5 days of treatment usually recover, however the decrease in the cats white blood cells compromises its immune system, leaving it vulnerable to secondary infection.Lifelong immunity is thought to follow recovery from disease, and a carrier state of the disease has never been identified.

Preventing transmission from infected cats
Quarantine/isolation
Cats with suspected or diagnosed FPLV should be kept in isolation. This non-enveloped virus is very resistant to environmental conditions and many disinfectants, is highly contagious, and rapidly accumulates in the environment due to high shedding of virus from affected animals. Strict protocols for containment – with isolation, minimal handling, and disinfection of all potential sources of fomites – is warranted </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Polysubstance dependence and can you explain it in depth? [/INST] Polysubstance dependence refers to a type of substance use disorder in which an individual uses at least three different classes of substances indiscriminately and does not have a favorite substance that qualifies for dependence on its own. Although any combination of three substances can be used, studies have shown that alcohol is commonly used with another substance. This is supported by one study on polysubstance use that separated participants who used multiple substances into groups based on their preferred substance. The results of a longitudinal study on substance use led the researchers to observe that excessively using or relying on one substance increased the probability of excessively using or relying on another substance.

Common combinations
The three substances were cocaine, alcohol, and heroin, which implies that those three are very popular. Other studies have found that opiates, cannabis, amphetamines, hallucinogens, inhalants and benzodiazepines are often used in combination as well.

Presentation
Associated cognitive impairments
Cognition refers to what happens in the mind, such as mental functions like "perception, attention, memory, language, problem solving, reasoning, and decision making." Although many studies have looked at cognitive impairments of individuals who are dependent on one substance, there are few researchers who have tried to determine the problems with cognitive functioning that are caused by dependence on multiple substances. Therefore, what is known about the effects of polysubstance dependence on mental abilities is based on the results of a few studies.

Learning ability
The effect of polysubstance dependence on learning ability is one area of interest to researchers. A study involving 63 polysubstance dependent women and 46 controls (participants who were not using substances) used the Benton Visual Retention Test (BVRT) and the California Verbal Learning Test (CVLT) to look at visual memory and verbal ability. This study showed that in polysubstance dependent women, verbal learning ability was significantly decreased, though visual memory was not affected. In addition, alcohol and cocaine use led to more severe issues with verbal learning, recall, and recognition.

Memory, reasoning and decision making
Sometimes studies about specific groups in the general population can be informative. One study decided to test the cognitive abilities of participants in rave parties who used multiple substances. To do this, they compared 25 rave party attenders with 27 control participants who were not using substances. The results of this study indicated that in general, the rave attender group did not perform as well on tasks that tested speed of information processing, working memory, knowledge of similarities between words, ability to attend to a task with interference in the background, and decision making. Certain substances were associated with particular mental functions, but the researchers suggested that the impairments for working memory and reasoning were caused by the misuse of multiple substances.Another study that tried to find differences between the effects of particular substances focused on people with polysubstance use who were seeking treatment for addictions to cannabis, cocaine, and heroin. They studied a group of people with polysubstance use and a group that was not dependent on any substances. Because alcohol was a common co-substance for nearly all of the people in the polysubstance use group, it was difficult to tell exactly which substances were affecting certain cognitive functions. The researchers found that the difference in the two groups performance levels on executive function, or higher-level cognitive processing tasks were consistently showing that the polysubstance group scored lower than the control group. In general, this meant that multiple substances negatively affected the polysubstance groups cognitive functioning. More specifically, the researchers found that the amount of cannabis and cocaine affected the verbal part of working memory, the reasoning task, and decision making, while cocaine and heroin had a similar negative effect on visual and spatial tasks, but cannabis particularly affected visual and spatial working memory. These results suggest that the combined use of cannabis, cocaine, and heroin impair more cognitive functions more severely than if used separately.Alcohols negative effects on learning, spatial abilities and memory has been shown in many studies. This raises a question: does using alcohol in combination with other substances impair cognitive functioning even more? One study decided to try to determine if people with polysubstance use who also recreationally use alcohol would display poorer performance on a verbal learning and memory test in comparison to those who consumed excessive amounts of alcohol specifically. The California Verbal Learning Test (CVLT) was used due to its ability to "quantify small changes in verbal learning and memory" by evaluating errors made during the test and the strategies used to make those errors. The results of this study showed that the group of people with polysubstance and alcohol use performed poorly on the CVLT recall and recognition tests compared to the group of people who exclusively consumed excessive alcohol only, which implies that polysubstance use impaired the memory and learning in a different way than the effects of alcohol alone can explain.

Length of abstinence matter
To examine whether abstinence for long periods of time helps people with polysubstance use recover their cognitive function, a group of researchers tested 207 polysubstance dependent men, of whom 73.4% were dependent on three or more substances. The researchers were interested in six areas of cognitive functioning, which included visual memory, verbal memory, knowledge of words, abstract reasoning, inhibition (interference), and attention. The study used the Benton Visual Retention Test (BVRT) for testing visual memory, the California Verbal Learning Test (CVLT) for verbal memory, the Wechsler Adult Intelligence Scale vocabulary portion for knowledge of words, the Booklet Category Test for abstract reasoning, the Stroop Neuropsychological Screening task for inhibition, and the Trail Making Test for attention. The results showed that neuropsychological ability did not improve with increases in the length of time abstinent. This suggests that polysubstance dependence leads to serious impairment which cannot be recovered much over the span of a year.

Causes
Biological
There is data to support that some genes contribute to substance dependence. Some studies have focused on finding genes that predispose the person to be dependent on marijuana, cocaine, or heroin by studying genes that control a persons dopamine and opioid receptors, but no conclusive findings were reported. Other researchers found a connection between dopamine receptor genes and dependency on a substance. A potential problem with this study was that alcohol is commonly used with another substance, so the results of the study may not have been caused by dependency on a single substance. This means that multiple substances may have been contributing to the results, but the researchers suggested that further research should be done.However, there are studies that have found evidence of the influence of genes on vulnerability to substance dependence. These studies often use genotype, or the genetic information found on a persons chromosomes, and phenotype, which consists of the visible features of a person, to look at genetic patterns. One study examined the phenotype and genotype of 1,858 participants from 893 families to look at differences in three nicotinic acetylcholine receptor genes found within these individuals. The experimenters found significant connections between receptor genes for nicotine and polysubstance dependence, which indicated that differences in these genes can create the risk of being dependent on multiple substances.

Psychological
A 1989 study conducted by Khantzian and Treece found that nearly 60% of their opioid-dependent sample met criteria for an Axis II diagnosis. In the same study, 93% of the sample had a comorbid disorder, implying that the comorbid disorder plays some role in the addiction. It has also been shown that depression and polysubstance dependence are often both present at the same time. If a person is genetically predisposed to be depressed then they are at a higher risk of having polysubstance dependence.Possibly the most widely accepted cause of addictions is the self-medication hypothesis, that views substance addiction as a form of coping with stress through negative reinforcement, by temporarily alleviating awareness of or concerns over the stressor. People who use substances learn that the effects of each type of substance works to relieve or better painful states. They use substances as a form of self-medication to deal with difficulties of self-esteem, relationships, and self-care. Individuals with substance use disorders often are overwhelmed with emotions and painful situations and turn to substances as a coping method.

Sociocultural
The sociocultural causes are areas in a persons life that might have influenced their decision to start and continue using multiple substances. Sociocultural causes can be divided into social causes and cultural causes.

Social Causes: Some studies have shown that adolescents have one of the highest rates of polysubstance dependence. According to one study this population, ages 12–25, represents about half of the nations population that uses illicit substances. Of these individuals, half of them have started using substances by the end of 12th grade. This could be attributed to social expectations of peers, peer pressure to fit it, or a way of numbing their emotions. Some of these young kids start trying different substances initially to fit in, but then after a while they start to develop a tolerance for these substances and experience withdrawal if they dont have enough substances in their system and eventually become dependent on having the effects of substance dependence. With tolerance comes the craving for additional substances to get high, this constant need for that feeling is polysubstance dependence.In the older generations, polysubstance dependence had been linked to additional considerations such as personality disorder, homelessness, bipolar disorder, major depressive disorder and so on. Medical care being so expensive and difficult to get long term has been linked to polysubstance dependence. Those who need psychological help sometimes use multiple substances as a type of self medication to help manage their mental illnesses.

Comorbidity of mental disorders
For most of these disorders, in relation to polysubstance dependence, there is a vicious cycle that those with a dependence go through. First, Ingesting the substance creates a need for more, which creates a dopamine surge, which then creates pleasure. As the dopamine subsides, the pleasure adds to the emotional and physical pain and triggers stress transmitters, which in turn creates a craving, which must then be medicated, and thus the cycle begins again. However, the next time they use, more of the substance will need to be used to get to the same degree of intoxication .

Depression
Scientists have hypothesized that the use of a substance either causes a mood disorder such as depression or at least attributes to a pre-existing one. Additionally, the substances that people with depression use can be a misguided method of self-medication in order to manage their depression. This is the classic chicken or egg hypothesis, does the pre-existing condition cause dependence or does dependence cause the condition? The underlying mental illness needs to be identified and treated in conjunction with treating the polysubstance dependence in order to increase the success rate of treatment and decrease the probability of relapse. One specific study focused on alcohol and depression, because they are so commonly inter-related. Researchers have discovered that depression continues for several weeks after a patient had been rehabilitated and those who relapsed developed depression again. This means that the onset of depression happens after alcohol dependence occurs, which means that alcohol is a major contributor to depression.

Eating disorders
One study showed that patients who are recovering from an addiction, who have had an eating disorder in the past, often use food to try to replace the substance that they are no longer getting. Or they obsess over controlling their weight and appearance. Some rehabilitation centers have licensed nutritionists to help patients develop healthy eating habits to help them cope while recovering from their addictions. It is important that those who have a former eating disorder be taught how to eat healthfully, so they dont continuously switch from one addiction back to another.

Diagnosis
According to the DSM-IV, a diagnosis of polysubstance dependence must include a person who has used at least three different substances (not including caffeine or nicotine) indiscriminately, but does not have a preference to any specific one. In addition they must show a minimum of three of the following symptoms listed below, all within the past twelve months. There is a distinct difference between a person having three separate dependence issues and having Polysubstance dependence the main difference is polysubstance dependence means that they are not specifically addicted to one particular substance. This is often confused with multiple specific dependences present at the same time. To elaborate, if a person is addicted to three separate substance such as cocaine, methamphetamines and alcohol and is dependent on all three then they would be diagnosed with three separate dependence disorders existing together (cocaine dependence, methamphetamine dependence and alcohol dependence,) not polysubstance dependence. In addition to using three different substances without a preference to one, there has to be a certain level of dysfunction in a persons life to qualify for a diagnosis of polysubstance dependence. One of the bigger challenges that often occurs when trying to diagnose is the fact that people dont always report what they are taking because they are afraid of getting into legal trouble. When coding polysubstance Dependence in a DSM-IV it would be a multiaxial diagnosis 304.80- Polysubstance Dependence", next to the classification, it is accompanied by a list of other types of Substance dependence (e.g. "305.00 Alcohol Abuse" or "305.60 Cocaine Abuse").The DSM-IV requires at least three of the following symptoms present during a 12-month period for a diagnoses of polysubstance dependence.
Tolerance: Use of increasingly high amounts of a substance or they find the same amount less and less effective ( the amount has to be at least 50% more of the original amount needed.)
Withdrawal: Either withdrawal symptoms when the substance stops being used or the substance is used to prevent withdrawal symptoms.
Loss of control: Repeated use of more substance than was initially planned or use of the substances over longer periods of time than was planned.
Inability to stop using: Either unsuccessfully attempted to cut down or stop using the substances or a persistent desire to stop using.
Time: Spending a lot of time studying substances, obtaining substances, using substances, being under the influence of substances, and recovering from the effects of substances.
Interference with activities: Give up or reduce the amount of time involved in recreational activities, social activities, and/or occupational activities because of the use of substances.
Harm to self: Continuous use of substances despite having a physical or psychological problem caused by or made worse by the use of substances.DSM-5 eliminated polysubstance disorder; there the substances must be specified, among other related changes.

Treatment
Treatment for polysubstance dependence has many critical aspects. Substance rehabilitation is a lengthy and difficult process. Treatment must be individualized and last a sufficient amount of time to ensure the patient has kicked the addictions and to ensure the prevention of relapse. The most common forms of treatment for polysubstance dependence include: inpatient and outpatient treatment centers, counseling and behavioral treatments, and medications. It is important that treatments be carried on throughout the patients life in order to prevent relapse. It is a good idea that recovering addicts continue to attend social support groups or meet with counselors to ensure they do not relapse.

Inpatient treatment center
Inpatient treatment centers are treatment centers where addicts move to the facility while they are undergoing treatment. Inpatient treatment centers offer a safe environment where patients will not be exposed to potentially harmful situations during their treatments as they would on the outside. Inpatients usually undergo the process of detoxification. Detox involves withdrawing the user (usually medically) from all substances of concern. During their stay in the treatment facility, patients often are learning to manage and identify their substance addictions and to find alternate ways to cope with whatever is the cause of their addiction.

Outpatient treatments
Outpatient treatments include many of the same activities offered in an inpatient treatment facility, but the patient is not protected by the secure and safe environment of an inpatient treatment center. For this reason, they are significantly less effective. The patient usually continues to hold a job and goes to treatment nightly.

Twelve-step programs
Both in-patient and out-patient treatments can offer introductions to 12-step programs. Suggested 12-step programs are Alcoholics Anonymous (AA) and Narcotics Anonymous (NA). They offer regular meetings where members can discuss their experiences in a non-judgmental and supportive place.

Cognitive behavioral therapy
Also offered to patients are one-on-one counseling sessions and cognitive behavioral therapy(CBT). When looked at through a cognitive-behavioral perspective, addictions are the result of learned behaviors developed through positive experiences. In other words, when an individual uses a substance and receives desired results (happiness, reduced stress, etc.) it may become the preferred way of attaining those results, leading to addictions. The goal of CBT is to identify the needs that the addictions are being used to meet and to develop skills and alternative ways of meeting those needs. The therapist will work with the patient to educate them on their addictions and give them the skills they need to change their cognitions and behaviors.Addicts will learn to identify and correct problematic behavior. They will be taught how to identify harmful thoughts and substance cravings. CBT is an effective treatment for addictions.

Medications
Medications can be very helpful in the long-term treatment of polysubstance dependence. Medications are a useful aid in helping to prevent or reducing substance cravings. Another benefit of medications is helping to preventing relapse. Since substance use disorders affect brain functioning, medications assist in returning to normal brain functioning. People who use multiple substances require medications for each substance they use, as the current medications do not treat all substance use disorders simultaneously. Medications are a useful aid in treatments, but are not effective when they are the sole treatment method.

Substance use Disorder Medications
Methadone treatment for heroin addiction.
Naltrexone: Reduces opiates and alcohol cravings.
Disulfiram: induces intense nausea after drinking alcohol.
Acamprosate: normalizes brain chemistry disrupted by alcohol withdrawal and aids alcohol abstinence.
Buprenorphine/naloxone: The two medications together reduce cravings and block the pleasure from opiates.

Epidemiology
There are not very many studies that have examined how often polysubstance dependence occurs or how many people are dependent on multiple substances. However, according to a study that analyzed the results from the National Epidemiological Survey on Alcohol and Related Conditions, approximately 215.5 out of a total of 43,093 individuals in the United States (0.5%) met the requirements for polysubstance use disorder. Another study suggested that the number of new cases of polysubstance dependence has been going up. This idea was supported by a study that took place in Munich, Germany. A group of researchers chose to look at responses to a survey using the M-Composite International Diagnostic Interview (M-CIDI). The M-CIDI is a version of the Composite International Diagnostic Interview (CIDI). The researchers collected data from 3,021 participants, all between the ages of 14 and 24, to estimate the prevalence, or total number of cases, of substance use and of polysubstance use/dependence. The results of this study indicated that of the 17.3% who said that they regularly used substances, 40% said that they used more than one substance, but 3.9% specifically reported using three or more substances, indicating that there is a lot of overlap in the use of different substances </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Vascular malformation and can you explain it in depth? [/INST] A vascular malformation is a blood vessel or lymph vessel abnormality. Vascular malformations are one of the classifications of vascular anomalies, the other grouping is vascular tumors. They may cause aesthetic problems as they have a growth cycle, and can continue to grow throughout life.
Vascular malformations of the brain (VMBs) include those involving capillaries, and those involving the veins and arteries. Capillary malformations in the brain are known as cerebral cavernous malformations or capillary cavernous malformations (CCMs). Those involving the mix of vessels are known as cerebral arteriovenous malformations (AVMs or cAVMs). The arteriovenous type is the most common in the brain.

Types
A simple division of the vascular malformations is made into low-flow and high-flow types. Low-flow malformations involve a single type of blood or lymph vessel, and are known as simple vascular malformations; high-flow malformations involve an artery. There are also malformations that are of mixed-flow involving more than one type of vessel, such as an arteriovenous malformation.Low-flow vascular malformations include capillary malformations, venous malformations, and lymphatic malformations.

Capillary malformation
Capillary malformations involve the capillaries, and are the most common type. They used to refer only to port-wine stains but now include others. Capillary malformations are limited to the superficial layers of the skin but they can thicken, become nodular, and sometimes become disfiguring.
It has been proposed that the category of capillary malformations, also called vascular stains, be classified into seven major clinical types including nevus flammeus nuchae also known as nevus simplex, commonly known as stork bite or salmon patch.A capillary malformation is also a feature of the disorder macrocephaly-capillary malformation.

Venous malformation
Venous malformations are typically ill-defined masses, coloured from pale to dark blue. They can affect any tissue in the body </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Perichondritis and can you explain it in depth? [/INST] Perichondritis  is inflammation of the perichondrium, a layer of connective tissue which surrounds cartilage </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Neuronal ceroid lipofuscinosis and can you explain it in depth? [/INST] Neuronal ceroid lipofuscinosis  is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the bodys tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.

Signs and symptoms
The classic characterization of the group of neurodegenerative, lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs) is through the progressive, permanent loss of motor and psychological ability with a severe intracellular accumulation of lipofuscins, with the United States and Northern European populations having slightly higher frequency with an occurrence of one in 10,000. Four classic diagnoses have received the most attention from researchers and the medical field, differentiated from one another by age of symptomatic onset, duration, early-onset manifestations such as blindness or seizures, and the forms which lipofuscin accumulation takes.In the early infantile variant of NCL (also called INCL or Santavuori-Haltia), probands appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age, a vegetative state is reached, and by 4 years, isoelectric encephalograms confirm brain death. Late infantile variant usually manifests between 2 and 4 years of age with seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years. Juvenile NCL (JNCL, Batten disease, or Spielmeyer-Vogt), with a prevalence of one in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinal dystrophy, with seizures, psychological degeneration, and eventual death in the mid- to late 20s or 30s ensuing. Adult variant NCL (ANCL or Kufs disease) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs 10 years later.All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism – most commonly with the reuse of vesicle proteins.

Genetics
Childhood NCLs are generally autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective gene, each of their children faces a one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children. The most commonly identified mutations are in the CLN3 gene, which is located on the short arm of chromosome 16 (16p12.1). The normal function of the gene is not presently known, but results in a transmembrane protein.Adult NCL may be inherited as an autosomal recessive (Kufs), or less often, as an autosomal dominant (Parrys) disorder. In autosomal dominant inheritance, all people who inherit a single copy of the disease gene develop the disease. As a result, no carriers of the gene are unaffected.Many authorities refer to the NCLs collectively as Batten disease.

Diagnosis
Because vision loss is often an early sign, NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often, an eye specialist or other physician who suspects NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose NCL, the neurologist needs the patients medical history and information from various laboratory tests.Diagnostic tests used for NCLs include:

Skin or tissue sampling: The doctor can examine a small piece of tissue under a  microscope to spot typical NCL deposits. These deposits are found in many different tissues, including skin, muscle, conjunctiva, rectal and others. Blood can also be used. These deposits take on characteristic shapes, depending on the variant under which they are said to occur: granular osmophilic deposits (GRODs) are generally characteristic of INCL, while curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively.
Electroencephalogram or EEG: An EEG uses special patches placed on the scalp to record electrical currents inside the brain. This helps doctors see telltale patterns in the brains electrical activity that suggest a patient has seizures.
Electrical studies of the eyes: These tests, which include visual-evoked responses and electroretinograms, can detect various eye problems common in childhood NCLs.
Brain scans: Imaging can help doctors look for changes in the brains appearance. The most commonly used imaging technique is computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brains tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. An increasingly common tool is magnetic resonance imaging, which uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.
Enzyme assay: A recent development in diagnosis of NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile versions only. This is a quick and easy diagnostic test.

Types
The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene.CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.

Mutations
Infantile form
Nonsense and frameshift mutations in the CLN1 gene (located at
1p32) always induce classical INCL, while some missense mutations have been associated with ANCL in addition to the infantile and juvenile forms. The mutation typically results in a deficient form of a lysosomal enzyme called palmitoyl protein thioesterase 1 (PPT1).The wild-type PPT1 is a 306-amino acid polypeptide that is typically targeted for transport into lysosomes by the mannose 6-phosphate (M6P) receptor-mediated pathway. Here, the protein appears to function in removing palmitate residues by cleaving thioester linkages in s-acylated (or palmitoylated) proteins, encouraging their breakdown. Defective polypeptides, however, are unable to exit the endoplasmic reticulum (ER), most likely due to misfolding; further analyses of this pathway could serve to categorize INCL among lysosomal enzyme deficiencies. The human PPT gene shows 91% similarity to bovine PPT and 85% similarity to rat PPT; these data indicate that the PPT gene is highly conserved and likely plays a vital role in cell metabolism. In addition, buildup of defective PPT1 in the ER has been shown to cause the increased release of Ca2+. This homeostasis-altering event leads to increased mitochondrial membrane permeability and subsequent activation of caspase-9, eventually leading to an accumulation of cleft and uncleft poly(ADP-ribose) polymerase  and eventual apoptosis.

Late infantile form
The CLN2 gene encodes a 46kDa protein called lysosomal tripeptidyl peptidase I (TPP1), which cleaves tripeptides from terminal amine groups of partially unfolded proteins. Mutations of this gene typically result in a LINCL phenotype.On April 27, 2017, the U.S. Food and Drug Administration approved cerliponase alfa (Brineura) as the first specific treatment for NCL. It is enzyme replacement therapy manufactured through recombinant DNA technology. The active ingredient in Brineura, cerliponase alfa, is intended to slow loss of walking ability in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as TPP1 deficiency. Brineura is administered into the cerebrospinal fluid by infusion via a surgically implanted reservoir and catheter in the head (intraventricular access device).

Juvenile form
All mutations resulting in the juvenile variant of NCL have been shown to occur at the CLN3 gene on 16p12; of the mutations known to cause JNCL, 85% result from a 1.02-kb deletion, with a loss of amino acids 154–438, while the remaining 15% appear to result from either point or frameshift mutations. The wild-type CLN3 gene codes for a protein with no known function, but studies of the yeast CLN3 ortholog, the product of which is called battenin (after its apparent connections to Battens disease, or JNCL), have suggested that the protein may play a role in lysosomal pH homeostasis. Furthermore, recent studies have also implied the proteins role in cathepsin D deficiency; the overexpression of the defective protein appears to have significant effects on cathepsin D processing, with implications suggesting that accumulation of ATP synthase subunit C would result. Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D.

Adult dominant form
Between 1.3 and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other NCLs, retinal degeneration is absent. Pathologically, the ceroid-lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial ATP synthase.Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation. The mutations occur in a cysteine-string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of the encoded protein cysteine-string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene.

Treatment
Currently, no widely accepted treatment can cure, slow down, or halt the symptoms in the great majority of patients with NCL, but seizures may be controlled or reduced with use of antiepileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible. Several experimental treatments are under investigation.

Cystagon
In 2001, a drug used to treat cystinosis, a rare genetic disease that can cause kidney failure if not treated, was reported to be  useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL.Currently, two drug trials are underway for infantile NCL, both using Cystagon.

Gene therapy
A gene therapy trial using an adenoassociated virus vector called AAV2CUhCLN2 began in June 2004 in an attempt to treat the manifestations of late infantile NCL. The trial was conducted by Weill Medical College of Cornell University and sponsored by the Nathans Battle Foundation. In May 2008,  the gene therapy given to the recipients reportedly was "safe, and that, on average, it significantly slowed the diseases progression during the 18-month follow-up period" and "suggested that higher doses and a better delivery system may provide greater benefit".A second gene therapy trial for late infantile NCL using an adenoassociated virus derived from the rhesus macaque (a species of Old World monkey) called AAVrh.10 began in August 2010, and is once again being conducted by Weill Medical College of Cornell University. Animal models of late infantile NCL showed that the AAVrh.10 delivery system "was much more effective, giving better spread of the gene product and improving survival greatly".A third gene therapy trial, using the same AAVrh.10 delivery system, began in 2011 and has been expanded to include late infantile NCL patients with moderate tosevere impairment or uncommon genotypes, and uses a novel administration method that reduces general anesthesia time by 50% to minimize potential adverse side effects.

Flupirtine
A painkiller available in several European countries, flupirtine, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently, the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina, or the Hospital for Sick Children in Toronto.

Stem cells
On October 20, 2005, the Food and Drug Administration approved a phase-I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment was to be carried out in Oregon.Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone-marrow or stem-cell transplants for this condition. A bone-marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998.Trials testing the effectiveness of bone-marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported.

Immunosuppressants
In late 2007,  Dr. David Pearce et al. reported that Cellcept, an immunosuppressant medication commonly used in bone-marrow transplants, may be useful in slowing down the progress of juvenile NCL.

Enzyme replacement therapy
On April 27, 2017, the U.S. FDA approved cerliponase alfa as the first specific treatment for NCL.

Epidemiology
Incidence can vary greatly from type-to-type, and from country-to-country.In Germany, one study reported an incidence of 1.28 per 100,000.A study in Italy reported an incidence of 0.56 per 100,000.A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades.

History
19th century
The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, who described 4 affected siblings in a small mining community in Norway </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Gender dysphoria and can you explain it in depth? [/INST] Gender dysphoria (GD) is the distress a person experiences due to a mismatch between their gender identity—their personal sense of their own gender—and their sex assigned at birth. The diagnostic label gender identity disorder (GID) was used until 2013 with the release of the diagnostic manual DSM-5. The condition was renamed to remove the stigma associated with the term disorder.People with gender dysphoria commonly identify as transgender. Gender nonconformity is not the same thing as gender dysphoria and does not always lead to dysphoria or distress. According to the American Psychiatric Association, not all transgender people experience dysphoria; the critical element of gender dysphoria is "clinically significant distress".The causes of gender dysphoria are unknown but a gender identity likely reflects genetic, biological, environmental, and cultural factors. Treatment for gender dysphoria may include supporting the individuals gender expression or their desire for hormone therapy or surgery. Treatment may also include counseling or psychotherapy.Some researchers and transgender people support declassification of the condition because they say the diagnosis pathologizes gender variance and reinforces the binary model of gender. Without the classification of gender dysphoria as a medical disorder, HRT and gender affirming surgery may be viewed as cosmetic treatments by health insurance, as opposed to medically necessary treatment, and may not be covered.

Signs and symptoms
Distress arising from an incongruence between a persons felt gender and assigned sex/gender (usually at birth) is the cardinal symptom of gender dysphoria.Gender dysphoria in those assigned male at birth (AMAB) tends to follow one of two broad trajectories: early-onset or late-onset. Early-onset gender dysphoria is behaviorally visible in childhood. Sometimes gender dysphoria will stop for a while in this group and they will identify as gay or homosexual for a period of time, followed by recurrence of gender dysphoria. This group is usually sexually attracted to members of their natal sex in adulthood, commonly identifying as heterosexual. Late-onset gender dysphoria does not include visible signs in early childhood, but some report having had wishes to be the opposite sex in childhood that they did not report to others. Transgender people assigned male at birth who experience late-onset gender dysphoria will usually be attracted to women and may identify as lesbians or bisexual, while those with early-onset will usually be attracted to men. A similar pattern occurs in those assigned female at birth (AFAB), with those experiencing early-onset GD being most likely to be attracted to women and those with late-onset being most likely to be attracted to men and identify as gay.Symptoms of GD in children include preferences for opposite sex-typical toys, games, or activities; great dislike of their own genitalia; and a strong preference for playmates of the opposite sex.  Some children may also experience social isolation from their peers, anxiety, loneliness, and depression.  In adolescents and adults, symptoms include the desire to be and to be treated as a different gender. Adults with GD are at increased risk for stress, isolation, anxiety, depression, poor self-esteem, and suicide.  Transgender people are also at heightened risk for eating disorders and substance abuse.

Causes
The specific causes of gender dysphoria remain unknown, and treatments targeting the etiology or pathogenesis of gender dysphoria do not exist. Evidence from studies of twins suggests that genetic factors play a role in the development of gender dysphoria. Gender identity is thought to likely reflect a complex interplay of biological, environmental, and cultural factors.

Diagnosis
The American Psychiatric Association permits a diagnosis of gender dysphoria in adolescents or adults if two or more of the following criteria are experienced for at least six months duration:
A strong desire to be of a gender other than ones assigned gender
A strong desire to be treated as a gender other than ones assigned gender
A significant incongruence between ones experienced or expressed gender and ones sexual characteristics
A strong desire for the sexual characteristics of a gender other than ones assigned gender
A strong desire to be rid of ones sexual characteristics due to incongruence with ones experienced or expressed gender
A strong conviction that one has the typical reactions and feelings of a gender other than ones assigned genderIn addition, the condition must be associated with clinically significant distress or impairment.The DSM-5 moved this diagnosis out of the sexual disorders category and into a category of its own. The diagnosis was renamed from gender identity disorder to gender dysphoria, after criticisms that the former term was stigmatizing. Subtyping by sexual orientation was deleted. The diagnosis for children was separated from that for adults, as "gender dysphoria in children". The creation of a specific diagnosis for children reflects the lesser ability of children to have insight into what they are experiencing, or ability to express it if they have insight. Other specified gender dysphoria or unspecified gender dysphoria can be diagnosed if a person does not meet the criteria for gender dysphoria but still has clinically significant distress or impairment. Intersex people are now included in the diagnosis of GD.The International Classification of Diseases (ICD-10) lists several disorders related to gender identity:
Transsexualism (F64.0): Desire to live and be accepted as a member of the opposite sex, usually accompanied by a desire for surgery and hormonal treatment
Gender identity disorder of childhood (F64.2): Persistent and intense distress about ones assigned gender, manifested prior to puberty
Other gender identity disorders (F64.8)
Gender identity disorder, unspecified (F64.9)
Sexual maturation disorder (F66.0): Uncertainty about ones gender identity or sexual orientation, causing anxiety or distressThe ICD-11, which came into effect on 1 January 2022, significantly revised classification of gender identity-related conditions. Under "conditions related to sexual health", the ICD-11 lists "gender incongruence", which is coded into three conditions:
Gender incongruence of adolescence or adulthood (HA60): replaces F64.0
Gender incongruence of childhood (HA61): replaces F64.2
Gender incongruence, unspecified (HA6Z): replaces F64.9In addition, sexual maturation disorder has been removed, along with dual-role transvestism. ICD-11 defines gender incongruence as "a marked and persistent incongruence between an individuals experienced gender and the assigned sex", with no requirement for significant distress or impairment.

Treatment
Treatment for a person diagnosed with GD may include psychological counseling, supporting the individuals gender expression, or hormone therapy or surgery. This may involve physical transition resulting from medical interventions such as hormonal treatment, genital surgery, electrolysis or laser hair removal, chest/breast surgery, or other reconstructive surgeries.  The goal of treatment may simply be to reduce problems resulting from the persons transgender status, for example, counseling the patient in order to reduce guilt associated with cross-dressing.Guidelines have been established to aid clinicians. The World Professional Association for Transgender Health (WPATH) Standards of Care are used by some clinicians as treatment guidelines. Others use guidelines outlined in Gianna Israel and Donald Tarvers Transgender Care. Guidelines for treatment generally follow a "harm reduction" model.

Children
Medical, scientific, and governmental organizations have opposed conversion therapy, defined as treatment viewing gender nonconformity as pathological and something to be changed, instead supporting approaches that affirm childrens diverse gender identities. People are more likely to keep having gender dysphoria the more intense their gender dysphoria, cross-gendered behavior, and verbal identification with the desired/experienced gender are (i.e. stating that they are a different gender rather than wish to be a different gender).Professionals who treat gender dysphoria in children sometimes prescribe puberty blockers to delay the onset of puberty until a child is believed to be old enough to make an informed decision on whether hormonal or surgical gender reassignment is in their best interest.A review published in Child and Adolescent Mental Health found that puberty blockers are fully reversible, and that they are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.A review commissioned by the UK Department of Health found that there was very low certainty of quality of evidence about puberty blocker outcomes in terms of mental health, quality of life and impact on gender dysphoria. The Finnish government commissioned a review of the research evidence for treatment of minors and the Finnish Ministry of Health concluded that there are no research-based health care methods for minors with gender dysphoria. Nevertheless, they recommend the use of puberty blockers for minors on a case-by-case basis, and the American Academy of Pediatrics state that "pubertal suppression in children who identify as TGD [transgender and gender diverse] generally leads to improved psychological functioning in adolescence and young adulthood.".In the United States, several states have introduced or are considering legislation that would prohibit the use of puberty blockers in the treatment of transgender children. The American Medical Association, the Endocrine Society, the American Psychological Association, the American Academy of Child and Adolescent Psychiatry and the American Academy of Pediatrics oppose bans on puberty blockers for transgender children. In the UK, in the case of Bell v Tavistock, an appeal court, overturning the original decision, ruled that children under 16 could give consent to receiving puberty blockers.

Psychological treatments
Until the 1970s, psychotherapy was the primary treatment for gender dysphoria and generally was directed to helping the person adjust to their assigned sex. Psychotherapy is any therapeutic interaction that aims to treat a psychological problem. Psychotherapy may be used in addition to biological interventions, although some clinicians use only psychotherapy to treat gender dysphoria. Psychotherapeutic treatment of GD involves helping the patient to adapt to their gender incongruence or to explorative investigation of confounding co-occurring mental health issues. Attempts to alleviate GD by changing the patients gender identity to reflect assigned sex have been ineffective and are regarded as conversion therapy by most health organizations.: 1741

Biological treatments
Biological treatments physically alter primary and secondary sex characteristics to reduce the discrepancy between an individuals physical body and gender identity. Biological treatments for GD are typically undertaken in conjunction with psychotherapy; however, the WPATH Standards of Care state that psychotherapy should not be an absolute requirement for biological treatments.Hormonal treatments have been shown to reduce a number of symptoms of psychiatric distress associated with gender dysphoria. A WPATH commissioned systematic review of the outcomes of hormone therapy "found evidence that gender-affirming hormone therapy may be associated with improvements in [quality of life] scores and decreases in depression and anxiety symptoms among transgender people." The strength of the evidence was low due to methodological limitations of the studies undertaken. Some literature suggests that gender-affirming surgery is associated with improvements in quality of life and decreased incidence of depression. Those who choose to undergo sex reassignment surgery report high satisfaction rates with the outcome, though these studies have limitations including risk of bias (lack of randomization, lack of controlled studies, self-reported outcomes) and high loss to follow up.For adolescents, much is unknown, including persistence. Disagreement among practitioners regarding treatment of adolescents is in part due to the lack of long-term data. Young people qualifying for biomedical treatment according to the Dutch model (including having GD from early childhood on which intensifies at puberty and absence of psychiatric comorbidities that could challenge diagnosis or treatment) found reduction in gender dysphoria, although limitations to these outcome studies have been noted, such as lack of controls or considering alternatives like psychotherapy.In its position statement published December 2020, the Endocrine Society stated that there is durable evidence for a biological underpinning to gender identity and that pubertal suppression, hormone therapy, and medically indicated surgery are effective and relatively safe when monitored appropriately and have been established as the standard of care. They noted a decrease in suicidal ideation among youth who have access to gender-affirming care and comparable levels of depression to cisgender peers among socially transitioned pre-pubertal youth. In its 2017 guideline on treating those with gender dysphoria, it recommends puberty blockers be started when the child has started puberty (Tanner Stage 2 for breast or genital development) and cross-sex hormones be started at 16, though they note "there may be compelling reasons to initiate sex hormone treatment prior to the age of 16 years in some adolescents with GD/gender incongruence". They recommend a multidisciplinary team of medical and mental health professionals manage the treatment for those under 18. They also recommend "monitoring clinical pubertal development every 3 to 6 months and laboratory parameters every 6 to 12 months during sex hormone treatment".A review published in Child and Adolescent Mental Health found that puberty blockers are fully reversible, and that they are associated with such positive outcomes as decreased suicidality in adulthood, improved affect and psychological functioning, and improved social life.More rigorous studies are needed to assess the effectiveness, safety, and long-term benefits and risks of hormonal and surgical treatments. For instance, a 2020 Cochrane review found insufficient evidence to determine whether feminizing hormones were safe or effective. Several studies have found significant long-term psychological and psychiatric pathology after surgical treatments.In 2021, a review published in Plastic And Reconstructive Surgery found that less than 1% of people who undergo gender-affirming surgery regret the decision.

Comorbidities
Among youth, around 20% to 30% of individuals attending gender clinics meet the DSM criteria for an anxiety disorder. Gender dysphoria is also associated with an increased risk of eating disorders in transgender youth.A widely held view among clinicians is that there is an over-representation of neurodevelopmental conditions amongst individuals with GD, although this view has been questioned due to the low quality of evidence. Studies on children and adolescents with gender dysphoria have found a high prevalence of autism spectrum disorder (ASD) traits or a confirmed diagnosis of ASD. Adults with gender dysphoria attending specialist gender clinics have also been shown to have high rates of ASD traits or an autism diagnosis as well. It has been estimated that children with ASD were over four times as likely to be diagnosed with GD, with ASD being reported from 6% to over 20% of teens referring to gender identity services.

Epidemiology
Different studies have arrived at different conclusions about the prevalence of gender dysphoria. The DSM-5 estimates that about 0.005% to 0.014% of people assigned male at birth and 0.002% to 0.003% of people assigned female at birth are diagnosable with gender dysphoria.According to Blacks Medical Dictionary, gender dysphoria "occurs in one in 30,000 male births and one in 100,000 female births." Studies in European countries in the early 2000s found that about 1 in 12,000 natal male adults and 1 in 30,000 natal female adults seek out sex reassignment surgery. Studies of hormonal treatment or legal name change find higher prevalence than sex reassignment, with, for example a 2010 Swedish study finding that 1 in 7,750 adult natal males and 1 in 13,120 adult natal females requested a legal name change to a name of the opposite gender.Studies that measure transgender status by self-identification find even higher rates of gender identity different from sex assigned at birth (although some of those who identify as transgender or gender nonconforming may not experience clinically significant distress and so do not have gender dysphoria). A study in New Zealand found that 1 in 3,630 natal males and 1 in 22,714 natal females have changed their legal gender markers.  A survey of Massachusetts adults found that 0.5% identify as transgender. A national survey in New Zealand of 8,500 randomly selected secondary school students from 91 randomly selected high schools found 1.2% of students responded "yes" to the question "Do you think you are transgender?". Outside of a clinical setting, the stability of transgender or non-binary identities is unknown.Research indicates people who transition in adulthood are up to three times more likely to be male assigned at birth, but that among people transitioning in childhood the sex ratio is close to 1:1. The prevalence of gender dysphoria in children is unknown due to the absence of formal prevalence studies.

History
Neither the DSM-I (1952) nor the DSM-II (1968) contained a diagnosis analogous to gender dysphoria. Gender identity disorder first appeared as a diagnosis in the DSM-III (1980), where it appeared under "psychosexual disorders" but was used only for the childhood diagnosis. Adolescents and adults received a diagnosis of transsexualism (homosexual, heterosexual, or asexual type). The DSM-III-R (1987) added "Gender Identity Disorder of Adolescence and Adulthood, Non-Transsexual Type" (GIDAANT). DSM-V (2013) replaced gender identity disorder (GID) with gender dysphoria (GD) to avoid the stigma of the term disorder.

Society and culture
Researchers disagree about the nature of distress and impairment in people with GD. Some authors have suggested that people with GD suffer because they are stigmatized and victimized; and that, if society had less strict gender divisions, transgender people would suffer less.Some controversy surrounds the creation of the GD diagnosis, with Davy et al. stating that although the creators of the diagnosis state that it has rigorous scientific support, "it is impossible to scrutinize such claims, since the discussions, methodological processes, and promised field trials of the diagnosis have not been published."Some cultures have three or more defined genders.  The existence of accepted social categories other than man or woman may alleviate the distress associated with cross-gender identity. For example, in Samoa, the faafafine, a group of feminine males, are mostly socially accepted. The faafafine appear similar to transgender women in terms of their lifelong identities and gendered behavior, but experience far less distress than do transgender women in Western cultures. This suggests that the distress of gender dysphoria is mostly not caused by the cross-gender identity itself, but by difficulties encountered from social disapproval by ones culture. Overall, it is unclear whether or not gender dysphoria persists in cultures with third gender categories.

Classification as a disorder
The psychiatric diagnosis of gender identity disorder (now gender dysphoria) was introduced in DSM-III in 1980. Arlene Istar Lev and Deborah Rudacille have characterized the addition as a political maneuver to re-stigmatize homosexuality. (Homosexuality was declassified as a mental disorder in the DSM-II in 1974.) By contrast, Kenneth Zucker and Robert Spitzer argue that gender identity disorder was included in DSM-III because it "met the generally accepted criteria used by the framers of DSM-III for inclusion." Some researchers, including Spitzer and Paul J. Fink, contend that the behaviors and experiences seen in transsexualism are abnormal and constitute a dysfunction. The American Psychiatric Association stated that gender nonconformity is not the same thing as gender dysphoria, and that "gender nonconformity is not in itself a mental disorder. The critical element of gender dysphoria is the presence of clinically significant distress associated with the condition."Individuals with gender dysphoria may or may not regard their own cross-gender feelings and behaviors as a disorder. Advantages and disadvantages exist to classifying gender dysphoria as a disorder. Because gender dysphoria had been classified as a disorder in medical texts (such as the previous DSM manual, the DSM-IV-TR, under the name "gender identity disorder"), many insurance companies are willing to cover some of the expenses of sex reassignment therapy. Without the classification of gender dysphoria as a medical disorder, sex reassignment therapy may be viewed as a cosmetic treatment, rather than medically necessary treatment, and may not be covered. In the United States, transgender people are less likely than others to have health insurance, and often face hostility and insensitivity from healthcare providers. Gender dysphoria being a disorder also means it is covered by the Americans with Disabilities Act, which may aid transgender people in accessing legal protections they otherwise may be unable to. Some researchers and transgender people support declassification of the condition because they say the diagnosis pathologizes gender variance and reinforces the binary model of gender.An analysis of the Samoan third gender faafafine suggests that the DSM-IV-TR diagnostic component of distress is not inherent in the cross-gender identity; rather, it is related to social rejection and discrimination suffered by the individual. Psychology professor Darryl Hill insists that gender dysphoria is not a mental disorder, but rather that the diagnostic criteria reflect psychological distress in children that occurs when parents and others have trouble relating to their childs gender variance. Transgender people have often been harassed, socially excluded, and subjected to discrimination, abuse and violence, including murder.In December 2002, the British Lord Chancellors office published a Government Policy Concerning Transsexual People document that categorically states, "What transsexualism is not ... It is not a mental illness." In May 2009, the government of France declared that a transsexual gender identity will no longer be classified as a psychiatric condition, but according to French trans rights organizations, beyond the impact of the announcement itself, nothing changed. Denmark made a similar statement in 2016.In the ICD-11, GID is reclassified as "gender incongruence", a condition related to sexual health. The working group responsible for this recategorization recommended keeping such a diagnosis in ICD-11 to preserve access to health services.

Gender euphoria
Gender euphoria (GE) is a proposed term for the opposite of gender dysphoria. It is the satisfaction, enjoyment, or relief felt by trans people when they feel their body matches their personal gender identity. Healthline defines it as "feelings of alignment or joy about [ones] gender identity or expression," while Psych Centrals definition is "deep joy when your internal gender identity matches your gender expression."In 1986, the term was first published in a trans context, as part of an interview with a trans person: "gender dysphoria, and a term of which he seems inordinately proud, gender euphoria." Similar uses were published in 1988. (The same term had been used as early as 1979, but to describe male privilege present in Black men.)In a 1988 interview with a trans man, the subject states, "I think that day [Dr. Charles Ilhenfeld] administered my first shot of the wonder-drug must have been one of the peak-experiences of my life -- talk about gender euphoria!" The interview indicates he is referring to testosterone.In 1989, Mariette Pathy Allen published an unnamed transgender persons quote in her photography book Transformations: "The shrinks may call it gender dysphoria, but for some of us, its gender euphoria, and were not going to apologize anymore!"In 1990, Virginia Prince used the phrase in trans magazine Femme Mirror, ending an article with, "...from here on you can enjoy GENDER EUPHORIA - HAVE A GOOD LIFE!"Starting in 1991, a monthly newsletter named Gender Euphoria was released, featuring articles about transgender topics; Leslie Feinberg read the newsletter to better understand the transgender community. In 1993, the blurb of Nan Goldins The Other Side read, "The pictures in this book are not of people suffering dysphoria but rather expressing gender euphoria."In 1994, Scottish "TV/TS" periodical The Tartan Skirt wrote, "Lets accentuate the positive, discard the negative, and promote the new condition of Gender Euphoria."In 1997, Patrick Califia described transgender activists picketing using signs that read "Gender Euphoria NOT Gender Dysphoria" and handing out "thousands of leaflets" at protests.
The following year, in 1998, Second Skins: The Body Narratives of Transsexuality reported:The transactivist group Transexual Menace is campaigning to have the diagnosis "Gender Identity Disorder" removed entirely from the Diagnostic and Statistical Manual of Mental Disorders. "Gender Euphoria NOT Gender Dysphoria"; its slogans invert the pathologizing of transgender, offering pride in queer difference as an alternative to the psychiatric story.Transgender congruence is also used to ascribe transgender individuals feeling genuine, authentic, and comfortable with their gender identity and external appearance.In 2019, the Midsumma festival in Australia hosted "Gender Euphoria," a cabaret focusing on "bliss" in transgender experiences, including musical, ballet, and burlesque performances. A reviewer described it as "triumphant – honest, unpretentious, touching, and a vital celebration."

See also
List of transgender-related topics
Transmedicalism
Gender transitioning
Detransition
Rapid-onset gender dysphoria controversy
ICD-11 § Gender incongruence

References
Further reading
Conway, Lynn (June 26, 2014). "Successful TransMen: Links and Photos". ai.eecs.umich.edu. Retrieved December 2, 2014.
Conway, Lynn (February 5, 2011). "Transsexual Womens Successes: Links and Photos". ai.eecs.umich.edu </s>