<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 Echinococcosis and can you explain it in depth? [/INST] Echinococcosis is a parasitic disease of tapeworms of the Echinococcus type. The two main types of the disease are cystic echinococcosis and alveolar echinococcosis. Less common forms include polycystic echinococcosis and unicystic echinococcosis.The disease often starts without symptoms and this may last for years. The symptoms and signs that occur depend on the cysts location and size. Alveolar disease usually begins in the liver, but can spread to other parts of the body, such as the lungs or brain. When the liver is affected, the patient may experience abdominal pain, weight loss, along with yellow-toned skin discoloration from developed jaundice. Lung disease may cause pain in the chest, shortness of breath, and coughing.The infection is spread when food or water that contains the eggs of the parasite is ingested or by close contact with an infected animal. The eggs are released in the stool of meat-eating animals that are infected by the parasite. Commonly infected animals include dogs, foxes, and wolves. For these animals to become infected they must eat the organs of an animal that contains the cysts such as sheep or rodents. The type of disease that occurs in human patients depends on the type of Echinococcus causing the infection. Diagnosis is usually by ultrasound though computer tomography (CT) or magnetic resonance imaging (MRI) may also be used. Blood tests looking for antibodies against the parasite may be helpful as may biopsy.Prevention of cystic disease is by treating dogs that may carry the disease and vaccination of sheep. Treatment is often difficult. The cystic disease may be drained through the skin, followed by medication. Sometimes this type of disease is just watched. The alveolar form often requires surgical intervention, followed by medications. The medication used is albendazole, which may be needed for years. The alveolar disease may result in death.The disease occurs in most areas of the world and currently affects about one million people. In some areas of South America, Africa, and Asia, up to 10% of the certain populations are affected. In 2015, the cystic form caused about 1,200 deaths; down from 2000 in 1990. The economic cost of the disease is estimated to be around US$3 billion a year. It is classified as a neglected tropical disease (NTD) and belongs to the group of diseases known as helminthiases (worm infections). It can affect other animals such as pigs, cows and horses.Terminology used in this field is crucial, since echinococcosis requires the involvement of specialists from nearly all disciplines. In 2020, an international effort of scientists, from 16 countries, led to a detailed consensus on terms to be used or rejected for the genetics, epidemiology, biology, immunology and clinical aspects of echinococcosis.

Signs and symptoms
In the human manifestation of the disease, E. granulosus, E. multilocularis, E. oligarthrus and E. vogeli are localized in the liver (in 75% of cases), the lungs (in 5–15% of cases) and other organs in the body such as the spleen, brain, heart, and kidneys (in 10–20% of cases). In people who are infected with E. granulosus and therefore have cystic echinococcosis, the disease develops as a slow-growing mass in the body. These slow-growing masses, often called cysts, are also found in people that are infected with alveolar and polycystic echinococcosis.The cysts found in those with cystic echinococcosis are usually filled with a clear fluid called hydatid fluid, are spherical, and typically consist of one compartment and are usually only found in one area of the body. While the cysts found in those with alveolar and polycystic echinococcosis are similar to those found in those with cystic echinococcosis, the alveolar and polycystic echinococcosis cysts usually have multiple compartments and have infiltrative as opposed to expansive growth.Depending on the location of the cyst in the body, the person could be asymptomatic even though the cysts have grown to be very large, or be symptomatic even if the cysts are absolutely tiny. If the person is symptomatic, the symptoms will depend largely on where the cysts are located. For instance, if the person has cysts in the lungs and is symptomatic, they will have a cough, shortness of breath and/or pain in the chest.On the other hand, if the person has cysts in the liver and is symptomatic, they will experience abdominal pain, abnormal abdominal tenderness, hepatomegaly with an abdominal mass, jaundice, fever and/or anaphylactic reaction. In addition, if the cysts were to rupture while in the body, whether during surgical extraction of the cysts or by trauma to the body, the person would most likely go into anaphylactic shock and have high fever, pruritus (itching), edema (swelling) of the lips and eyelids, dyspnea, stridor and rhinorrhea.Unlike intermediate hosts, definitive hosts are usually not hurt very much by the infection. Sometimes, a lack of certain vitamins and minerals can be caused in the host by the very high demand of the parasite.The incubation period for all species of Echinococcus can be months to years, or even decades. It largely depends on the location of the cyst in the body and how fast the cyst is growing.

Cause
Also like many other parasite infections, the course of Echinococcus infection is complex. The worm has a life cycle that requires definitive hosts and intermediate hosts. Definitive hosts are normally carnivores such as dogs, while intermediate hosts are usually herbivores such as sheep and cattle. Humans function as accidental
hosts, because they are usually a dead end for the parasitic infection cycle, unless eaten by dogs or wolves after death.

Hosts
Life cycle
An adult worm resides in the small intestine of a definitive host. A single gravid proglottid releases eggs that are passed in the feces of the definitive host. The egg is then ingested by an intermediate host. The egg then hatches in the small intestine of the intermediate host and releases an oncosphere that penetrates the intestinal wall and moves through the circulatory system into different organs, in particular the liver and lungs. Once it has invaded these organs, the oncosphere develops into a cyst. The cyst then slowly enlarges, creating protoscolices (juvenile scolices), and daughter cysts within the cyst. The definitive host then becomes infected after ingesting the cyst-containing organs of the infected intermediate host. After ingestion, the protoscolices attach to the intestine. They then develop into adult worms and the cycle starts all over again.

Eggs
Echinococcus eggs contain an embryo that is called an oncosphere or hexcanth. The name of this embryo stems from the fact that these embryos have six hooklets. The eggs are passed through the feces of the definitive host and it is the ingestion of these eggs that lead to infection in the intermediate host.

Larval/hydatid cyst stage
From the embryo released from an egg develops a hydatid cyst, which grows to about 5–10 cm within the first year and is able to survive within organs for years. Cysts sometimes grow to be so large that by the end of several years or even decades, they can contain several liters of fluid. Once a cyst has reached a diameter of 1 cm, its wall differentiates into a thick outer, non-cellular membrane, which covers the thin germinal epithelium. From this epithelium, cells begin to grow within the cyst. These cells then become vacuolated, and are known as brood capsules, which are the parts of the parasite from which protoscolices bud. Often, daughter cysts also form within cysts.

Adult worm
Echinococcus adult worms develop from protoscolices and are typically 6 mm or less in length and have a scolex, neck and typically three proglottids, one of which is immature, another of which is mature and the third of which is gravid (or containing eggs). The scolex of the adult worm contains four suckers and a rostellum that has about 25–50 hooks.

Morphological differences
The major morphological difference among different species of Echinococcus is the length of the tapeworm. E. granulosus is approximately 2 to 7 mm while E. multilocularis is often smaller and is 4 mm or less. On the other hand, E. vogeli is found to be up to 5.6 mm long and E. oligarthrus is found to be up to 2.9 mm long. In addition to the difference in length, there are also differences in the hydatid cysts of the different species. For instance, in E. multilocularis, the cysts have an ultra thin limiting membrane and the germinal epithelium may bud externally. Furthermore, E. granulosus cysts are unilocular and full of fluid while E. multilocularis cysts contain little fluid and are multilocular. For E. vogeli, its hydatid cysts are large and are actually polycystic since the germinal membrane of the hydatid cyst actually proliferates both inward, to create septa that divide the hydatid into sections, and outward, to create new cysts. Like E. granulosus cysts, E. vogeli cysts are filled with fluid.

Transmission
As one can see from the life cycles illustrated above, all disease-causing species of Echinococcus are transmitted to intermediate hosts via the ingestion of eggs and are transmitted to definitive hosts by means of eating infected, cyst-containing organs. Humans are accidental intermediate hosts that become infected by handling soil, dirt or animal hair that contains eggs.While there are no biological or mechanical vectors for the adult or larval form of any Echinococcus species, coprophagic flies, carrion birds and arthropods can act as mechanical vectors for the eggs.

Aberrant cases
There are a few aberrant cases in which carnivores play the role of the intermediate hosts. Examples are domestic cats with hydatid cysts of E. granulosus.

Diagnosis
Classification
The most common form found in humans is cystic echinococcosis (also known as unilocular echinococcosis), which is caused by Echinococcus granulosus sensu lato. The second most common form is alveolar echinococcosis (also known as alveolar colloid of the liver, alveolar hydatid disease, alveolococcosis, multilocular echinococcosis, "small fox tapeworm"), which is caused by Echinococcus multilocularis and the third is polycystic echinococcosis (also known as human polycystic hydatid disease, neotropical echinococcosis), which is caused by Echinococcus vogeli and very rarely, Echinococcus oligarthrus. Alveolar and polycystic echinococcosis are rarely diagnosed in humans and are not as widespread as cystic echinococcosis, but polycystic echinococcosis is relatively new on the medical scene and is often left out of conversations dealing with echinococcosis, and alveolar echinococcosis is a serious disease that has a significantly high fatality rate, and may have the potential to become an emerging disease in many countries.

Cystic
A formal diagnosis of any type of echinococcosis requires a combination of tools that involve imaging techniques, histopathology, or nucleic acid detection and serology. For cystic echinococcosis diagnosis, imaging is the main method—while serology tests (such as indirect hemagglutination, ELISA (enzyme linked immunosorbent assay), immunoblots or latex agglutination) that use antigens specific for E. granulosus verify the imaging results. The imaging technique of choice for cystic echinococcosis is ultrasonography, since it is not only able to visualize the cysts in the bodys organs, but it is also inexpensive, non-invasive and gives instant results. In addition to ultrasonography, both MRI and CT scans can and are often used although an MRI is often preferred to CT scans when diagnosing cystic echinococcosis since it gives better visualization of liquid areas within the tissue.

Alveolar
As with cystic echinococcosis, ultrasonography is the imaging technique of choice for alveolar echinococcosis and is usually complemented by CT scans since CT scans are able to detect the largest number of lesions and calcifications that are characteristic of alveolar echinococcosis. MRIs are also used in combination with ultrasonography though CT scans are preferred. Like cystic echinococcosis, imaging is the major method used for the diagnosis of alveolar echinococcosis while the same types of serologic tests (except now specific for E. multilocularis antigens) are used to verify the imaging results. It is also important to note that serologic tests are more valuable for the diagnosis of alveolar echinococcosis than for cystic echinococcosis since they tend to be more reliable for alveolar echinococcosis since more antigens specific for E. multilocularis are available. In addition to imaging and serology, identification of E. multilocularis infection via PCR or a histological examination of a tissue biopsy from the person is another way to diagnose alveolar echinococcosis.

Polycystic
Similar to the diagnosis of alveolar echinococcosis and cystic echinococcosis, the diagnosis of polycystic echinococcosis uses imaging techniques, in particular ultrasonography and CT scans, to detect polycystic structures within the persons body. However, imaging is not the preferred method of diagnosis since the method that is currently considered the standard is the isolation of protoscoleces during surgery or after the persons death and the identification of definitive features of E. oligarthrus and E. vogeli in these isolated protoscoleces. This is the main way that PE is diagnosed, but some current studies show that PCR may identify E. oligarthrus and E. vogeli in peoples tissues. The only drawback of using PCR to diagnose polycystic echinococcosis is that there arent many genetic sequences that can be used for PCR that are specific only E. oligarthrus or E. vogeli.

Prevention
Cystic echinococcosis
There are several different strategies that are currently being used to prevent and control cystic echinococcosis (CE). Most of these various methods try to prevent and control CE by targeting the major risk factors for the disease and the way it is transmitted. For instance, health education programs focused on cystic echinococcosis and its agents, and improved water sanitation attempt to target poor education and poor drinking water sources, which are both risk factors for contracting echinococcosis. Furthermore, since humans often come into contact with Echinococcus eggs via touching contaminated soil, animal feces and animal hair, another prevention strategy is improved hygiene. In addition to targeting risk factors and transmission, control and prevention strategies of cystic echinococcosis also aim at intervening at certain points of the parasites life cycle, in particular, the infection of hosts (especially dogs) that reside with or near humans. For example, many countries endemic to echinococcosis have researched programs geared at de-worming dogs and vaccinating dogs and other livestock, such as sheep, that also act as hosts for E. granulosus.Proper disposal of carcasses and offal after home slaughter is difficult in poor and remote communities and therefore dogs readily have access to offal from livestock, thus completing the parasite cycle of Echinococcus granulosus and putting communities at risk of cystic echinococcosis. Boiling livers and lungs that contain hydatid cysts for 30 minutes has been proposed as a simple, efficient and energy- and time-saving way to kill the infectious larvae.

Alveolar echinococcosis
A number of strategies are geared towards prevention and control of alveolar echinococcosis—most of which are similar to those for cystic echinococcosis. For instance, health education programs, improved water sanitation, improved hygiene and de-worming of hosts (particularly red foxes) are all effective to prevent and control the spread of alveolar echinococcosis. Unlike cystic echinococcosis, however, where there is a vaccine against E. granulosus, there is currently no canidae or livestock vaccine against E. multilocularis.

Polycystic echinococcosis
While a number of control and prevention strategies deal with cystic and alveolar echinococcosis, there are few methods to control and prevent polycystic echinococcosis. This is probably due to the fact that polycystic echinococcosis is restricted to Central and South America, and that the way that humans become accidental hosts of E. oligarthrus and E. vogeli is still not completely understood.

Human vaccines
Currently there are no human vaccines against any form of echinococcosis. However, there are studies being conducted that are looking at possible vaccine candidates for an effective human vaccine against echinococcosis.

Treatment
Cystic
A number of therapy options are presently available. Treatment with albendazole, whether combined or not with praziquantel, is useful for smaller, uncomplicated cysts (< 5 cm). Only 30% of cysts disappear with medical treatment alone. Noramlly, albendazole is preferred twice a day for 1–5 months. An alternative to albendazole is mebendazole for at least 3 to 6 months.
Surgery is indicated for bigger liver cysts (> 10 cm), and cysts at risk of rupture and/or complicated cysts. The laparoscopic approach is scarcely widespread although  provides excellent cure rates with minimal morbidity and mortality. The radical technique (total cystopericystectomy) is preferable because of its lower risk for postoperative abdominal infection, biliary fistula, and overall morbidity. Conservative techniques are appropriate in endemic areas where surgery is performed by nonspecialist surgeons.PAIR (puncture-aspiration-injection-reaspiration) is an innovative technique representing an alternative to surgery. PAIR is a minimally invasive procedure that involves three steps: puncture and needle aspiration of the cyst, injection of a scolicidal solution for 20–30 min, and cyst-re-aspiration and final irrigation. People who undergo PAIR typically take albendazole or mebendazole from 7 days before the procedure until 28 days after the procedure. It is indicated for inoperable cases and/or patients who reject surgery, for recurrence after surgery, and for lack of response to medical treatment. There have been a number of studies that suggest that PAIR with medical therapy is more effective than surgery in terms of disease recurrence, and morbidity and mortality.There is currently research and studies looking at new treatment involving percutaneous thermal ablation (PTA) of the germinal layer in the cyst by means of a radiofrequency ablation device. This form of treatment is still relatively new and requires much more testing before being widely used.Active surveillance without treatment may be indicated for quiescent or inactive, uncomplicated liver cysts

Alveolar
For alveolar echinococcosis, surgical removal of cysts combined with chemotherapy (using albendazole and/or mebendazole) for up to two years after surgery is the only sure way to completely cure the disease. However, in inoperable cases, chemotherapy by itself can also be used. In treatment using just chemotherapy, one could use either mebendazole in three doses or albendazole in two doses. Since chemotherapy on its own is not guaranteed to completely rid of the disease, people are often kept on the drugs for extended periods of times (i.e. more than 6 months, years). In addition to surgery and chemotherapy, liver transplants are being looked into as a form of treatment for alveolar echinococcosis although it is seen as incredibly risky since it often leads to echinococcosis re-infection in the person afterwards.

Polycystic
Since polycystic echinococcosis is constrained to such a particular area of the world and is not well described or found in many people, treatment of polycystic echinococcosis is less defined than that of cystic and alveolar echinococcosis. While surgical removal of cysts was the treatment of choice for the previous two types of echinococcosis, chemotherapy is the recommended treatment approach for polycystic echinococcosis. While albendazole is the preferred drug, mebendazole can also be used if the treatment is to be for an extended period of time. Only if chemotherapy fails or if the lesions are very small is surgery advised.

Epidemiology
Regions
Very few countries are considered to be completely free of E. granulosus. Areas of the world where there is a high rate of infection often coincide with rural, grazing areas where dogs are able to ingest organs from infected animals.E. multilocularis mainly occurs in the Northern hemisphere, including central Europe and the northern parts of Europe, Asia, and North America. However, its distribution was not always like this. For instance, until the end of the 1980s, E. multilocularis endemic areas in Europe were known to exist only in France, Switzerland, Germany, and Austria. But during the 1990s and early 2000s, there was a shift in the distribution of E. multilocularis as the infection rate of foxes escalated in certain parts of France and Germany.As a result, several new endemic areas were found in Switzerland, Germany, and Austria and surrounding countries such as the Netherlands, Belgium, Luxembourg, Poland, the Czech Republic, the Slovak Republic, and Italy. There is also evidence showing that the Baltic Countries are endemic areas.While alveolar echinococcosis is not extremely common, it is believed that in the coming years it will be an emerging or re-emerging disease in certain countries as a result of E. multilocularis’ ability to spread.Unlike the previous two species of Echinococcus, E. vogeli and E. oligarthrus are limited to Central and South America. Furthermore, infections by E. vogeli and E. oligarthrus (polycystic echinococcosis) are considered to be the rarest form of echinococcosis.

Deaths
As of 2010 it caused about 1200 deaths, down from 2000 in 1990.

History
Echinococcosis is a disease that has been recognized by humans for centuries. There has been mention of it in the Talmud. It was also recognized by ancient scholars such as Hippocrates, Aretaeus, Galen and Rhazes. The recommended treatments were based on herbs like thymus vulgaris and raw garlic. Although echinococcosis has been well known for the past two thousand years, it was not until the past couple of hundred years that real progress was made in determining and describing its parasitic origin. The first step towards figuring out the cause of echinococcosis occurred during the 17th century when Francesco Redi illustrated that the hydatid cysts of echinococcosis were of "animal" origin. Then, in 1766, Pierre Simon Pallas predicted that these hydatid cysts found in infected humans were actually larval stages of tapeworms.A few decades afterwards, in 1782, Goeze accurately described the cysts and the tapeworm heads, while in 1786 E. granulosus was accurately described by Batsch. Half a century later, during the 1850s, Karl von Siebold showed through a series of experiments that Echinococcus cysts do cause adult tapeworms in dogs. Shortly after this, in 1863, E. multilocularis was identified by Rudolf Leuckart. Then, during the early to mid 1900s, the more distinct features of E. granulosus and E. multilocularis, their life cycles and how they cause disease were more fully described as more and more people began researching and performing experiments and studies. While E. granulosus and E. multilocularis were both linked to human echinococcosis before or shortly after the 20th century, it was not until the mid-1900s that E. oligarthrus and E. vogeli were identified as and shown as being causes of human echinococcosis.Two calcified objects recovered from a 3rd- to 4th-century grave of an adolescent in Amiens (Northern France) were interpreted as probable hydatid cysts. A study of remains from two 8,000-year-old cemeteries in Siberia showed presence of echinococcosis.

References
Further reading
Alimuddin I. Zumla; Gordon C. Cook; Patrick Manson (2003). "Section 10: Helminthic Infections 83 </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 Ganser syndrome and can you explain it in depth? [/INST] Ganser syndrome is a rare dissociative disorder characterized by nonsensical or wrong answers to questions and other dissociative symptoms such as fugue, amnesia or conversion disorder, often with visual pseudohallucinations and a decreased state of consciousness. The syndrome has also been called nonsense syndrome, balderdash syndrome, syndrome of approximate answers, hysterical pseudodementia or prison psychosis.
The term prison psychosis is sometimes used because the syndrome occurs most frequently in prison inmates, where it may be seen as an attempt to gain leniency from prison or court officials. Psychological symptoms generally resemble the patients sense of mental illness rather than any recognized category. The syndrome may occur in persons with other mental disorders such as schizophrenia, depressive disorders, toxic states, paresis, alcohol use disorders and factitious disorders. Ganser syndrome can sometimes be diagnosed as merely malingering, but it is more often defined as dissociative disorder.The identification of Ganser syndrome is attributed to German psychiatrist Sigbert Ganser (1853–1931). In 1898, he described the disorder in prisoners awaiting trial in a penal institution in Halle, Germany. He named impaired consciousness and distorted communication, namely in the form of approximate answers (also referred to as Vorbeireden in the literature), as the defining symptoms of the syndrome. Vorbeireden involves the inability to answer questions precisely, although the content of the questions is understood.Ganser syndrome is described as a dissociative disorder not otherwise specified (NOS) in the DSM-IV, and is not currently listed in the DSM-5. It is a rare and an often overlooked clinical phenomenon. In most cases, it is preceded by extreme stress and followed by amnesia for the period of psychosis. In addition to approximate answers, other symptoms include a clouding of consciousness, somatic conversion disorder symptoms, confusion, stress, loss of personal identity, echolalia, and echopraxia.

Cause
To date, no definitive cause or reason of the disorder has been established. The sources that classify the syndrome as a dissociative disorder or a factitious disorder conflict in their proposed aetiologies. As a result, there are differing theories as to why the syndrome develops.
Ganser syndrome was previously classified as a factitious disorder, explaining the symptoms as mimicking of what patients who do not experience psychosis believe is typical of the experience. However, the DSM-IV placed the syndrome under "Dissociative Disorders Not Otherwise Specified". There has been evidence of a strong correlation between approximate answers and amnesia, suggesting that these have an underlying dissociative mechanism.Both Gansers syndrome and the broader category of dissociative disorders have been linked to histories of hysteria, psychosis, conversion, multiple personality and possible feigning. Despite this, the conditions aetiology remains under question due to associations with established psychiatric disorders, as well as organic states.
According to Stern and Whiles (1942), Ganser syndrome is a fundamentally psychotic illness. As evidence, they describe the case of a woman with recurrent mania and a head injury before being submitted to treatment and the report of a man with schizophrenia who suffered from alcoholism and had recently been in prison.Ganser syndrome is also sometimes referred to as "prison psychosis", emphasizing its prevalence among prisoners, generating discussion about whether the disorder only appears in this population. In a study of prisoners, Estes and New concluded that escaping an intolerable situation, such as being incarcerated, prompted the syndromes key symptoms. The study touched on the malingering controversy surrounding the syndrome, as well as the stress component that often precedes the disorder.According to consultant psychiatrist F. A. Whitlock, Ganser syndrome is a hysterical disorder, on par with Gansers description of the disorder. Whitlock pointed to the number of cases in which Ganser syndrome was reported in settings of organic brain disease or functional psychosis as evidence of its hysterical foundations. Kraepelin and Bumke also believed the syndrome to be of a hysterical nature. Bumke thought the syndrome hysterical because amnesia for a traumatic emotional event tends to occur in hysteria more than in other disorders. The giving of approximate answers is thought to be produced in hysterical personalities.According to Mayer-Gross and Bleuler, Ganser syndrome occurs mainly in epileptic or schizophrenic patients.Still others claim that an organic condition that could lead to the manifestation of Ganser syndrome symptoms would have to be at an advanced stage in which a diagnosis could be easily given.There have also been reports of trauma and stroke patients with the syndrome. A study investigating the neurological basis of Ganser syndrome described a patient with symptoms of the disorder who had a history of stroke and bifrontal infarcts. They discovered that hyperglutamatergic states, which are caused by both strokes and stress, share a relationship with dissociative symptoms, suggesting a possible organic pathology that can predispose individuals to the syndrome. Wirtz and colleagues (2008) described a patient with Ganser syndrome after a left-hemispheric middle cerebral artery infarct. A neuropsychological examination revealed atypical lateralisation of cognitive functions, leading to the conclusion that the giving of approximate answers might be related to frontal-executive cerebral dysfunction.

Diagnosis
Ganser syndrome was listed under Factitious Disorder with Psychological Symptoms in the DSM-III. The criteria of this category emphasized symptoms that cannot be explained by other mental disorders, psychological symptoms under the control of the individual, and the goal of assuming a patient role, not otherwise understandable given their circumstances.The DSM-IV-TR classified Ganser syndrome as a dissociative disorder defined by the giving of approximate answers to questions (e.g. 2 plus 2 equals 5 when not associated with dissociative amnesia or dissociative fugue). The ICD-10 and DSM-IV do not specify any diagnostic criteria—apart from approximate answers—as a requirement for a Ganser syndrome diagnosis. Most case studies of the syndrome also depend on the presence of approximate answers and at least one of the other symptoms described by Ganser in his original paper. Usually when giving wrong answers, individuals are only slightly off, showing that the individual understood the question For instance, when asked how many legs a horse has, they might say, "five". Although subjects appear confused in their answers, in other respects they appear to understand their surroundings. Amnesia, loss of personal identity, and clouding of consciousness were among the most common symptoms apart from approximate answers.Although there is currently no uniform way to diagnose the syndrome, a full neurological and mental state examination is recommended to determine its presence as well as tests that assess malingering. In addition to mental examination, other investigations should be done to exclude other underlying causes. These include computer tomography scans (CT) or magnetic resonance imaging (MRI) scans to exclude structural pathology, lumbar puncture to exclude meningitis or encephalitis, and electroencephalography (EEG), to exclude delirium or seizure disorder.Diagnosing Ganser syndrome is challenging because of its rarity and symptom variability. The manifested symptoms may be dependent on the individuals conception of what mental illness entails, creating the possibility of a wide range of combinations of symptoms present in an individual with Ganser syndrome.

Treatment
In many cases, the symptoms seem to dwindle after a few days, and patients are often left with amnesia for the period of psychosis. Hospitalization may be necessary during the acute phase of symptoms, and psychiatric care if the patient is a danger to self or others. A neurological consult is advised to rule out any organic cause. Psychotherapy may also recommended for ensuring and maintaining safety.
Ganser patients typically recover quickly and completely. Since Ganser syndrome can be a response to psychic deterioration, its resolution may be followed by other psychiatric symptoms, such as schizophrenia and depression, hence the rationale behind the recommendation of psychotherapy. Medication is usually not required.

Epidemiology
With about 100 case studies, the incidence of the disorder is not precisely known. Individuals of multiple backgrounds have been reported as having the disorder. The syndrome was historically thought to be more common in men. However, Whitlock speculates that the higher reported rate of Ganser in men might be due to the greater proportion of men who are incarcerated. It has been most frequently seen in individuals ages 15 to 40 and has also been observed in children. This wide age range is derived from case studies, and therefore may not be an accurate estimate. Ganser syndrome has also been observed in groups other than prison populations.

Controversy
There is controversy regarding whether Ganser syndrome is a valid clinical entity. For example, Bromberg (1986) has argued that the syndrome is not due to or related to mental illness, but rather a sort of defense against legal punishment. Some see it as conscious lying, denial and repression, presenting Ganser syndrome symptoms as malingering instead of a dissociative or factitious disorder.One case study of Ganser syndrome presented a middle-aged man who had been in a car crash and wanted disability insurance benefits. Since he had a big incentive, psychologists took careful measures and implemented testing with malingering instruments, which showed that the man performed below chance on simple memory tests and claimed to experience non-existent symptoms. Upon further inspection of the collateral information, they found that the patient took part in high-level sports and other activities that were inconsistent with the cognitive dysfunctions he reported, and they determined it to be a case of malingering.Estes and New (1948) concluded that the motivation for the symptoms of the syndrome was escaping an "intolerable situation". Stern and Whiles proposed an alternative explanation, citing Ganser syndrome presented itself in individuals who, although not psychologically well, do not realize it, and want to appear so. Still others attribute the syndrome to inattention, purposeful evasion, suppression, alcoholic excess, head injury, and to unconscious attempts to deceive others as a means to free themselves from responsibility for their actions </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 Rhabdomyoma 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 Fissured tongue and can you explain it in depth? [/INST] Fissured tongue  is a benign condition characterized by deep grooves (fissures) in the dorsum of the tongue. Although these grooves may look unsettling, the condition is usually painless. Some individuals may complain of an associated burning sensation.It is a relatively common condition, with a prevalence of between 6.8% and 11% found also in children. The prevalence of the condition increases significantly with age, occurring in 40% of the population after the age of 40.

Presentation
The clinical appearance is considerably varied in both the orientation, number, depth and length of the fissure pattern. There are usually multiple grooves/furrows 2–6 mm in depth present. Sometimes there is a large central furrow, with smaller fissures branching perpendicularly </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 Pruritic urticarial papules and plaques of pregnancy and can you explain it in depth? [/INST] Pruritic urticarial papules and plaques of pregnancy (PUPPP), known in United Kingdom as polymorphic eruption of pregnancy (PEP), is a chronic hives-like rash that strikes some women during pregnancy. Some skin changes are known to occur in people who are pregnant while other skin conditions, or dermatoses, that people have prior to getting pregnant will become altered or symptoms will increase. Pruritic urticarial papules and plaques of pregnancy (PUPPP) is one of many skin conditions that is specific to pregnancy and occurs in about 1 in every 160 (0.625%) of pregnancies.It presents no long-term risk for either the woman or fetus as there is no statistical increase of risk of premature labor or fetal loss, despite frequently severe pruritus.PUPPP usually first appears on the abdomen and often spreads to the legs, feet, arms, chest, and neck. The face is usually not affected. Skin distension (stretching) is thought to be a possible trigger for PUPPP as it most commonly affects primigravida (women in their first pregnancy), those with large fundal measurements (distance from the pubic bone to the top of the uterus) and/or those who are carrying large babies or multiples. The papules and plaques often first appear within stretch marks before changing appearance and spreading to other areas of the body.
It is important that those who are pregnant heavily consider the recommendations of their full healthcare team. For those who may be experiencing signs and symptoms of PUPPP, it is strongly recommended they speak with their primary care physician and receive a consult from a dermatologist regarding skin changes during pregnancy.

Signs and Symptoms
PUPPP most commonly presents as a rash that starts within the stretch marks. This rash may then move to other areas of the body, including, but not limited to the trunk of the body, arms, legs, feet, chest, and neck. Very few people experiencing PUPPP have reported the rash spreading to the face, palms of hands, or soles of feet.This rash usually begins with the skin looking abnormally red and feeling itchy, accompanied by notable swelling of skin tissue that appears raised and within the stretch marks. Over time, individual segments of this rash can join to form one whole, larger rash with the same characteristics. As this happens, people report noticing the skin surrounding the rash to appear white in color (blanched) and in the shape of "halos". Multiple features of the disease can continue with time and have been reported as widespread erythema (a red skin rash due to damage of underlying capillaries) and patches of inflamed, itchy, rough, and cracked patches of skin that appear similarly to eczema. Other features have been reported in some cases of those experiencing PUPPP, such as tiny vesicles, however these are not as common and develop after more time.
Certain reports have shown there is a positive correlation between PUPPP and excessive maternal weight gain along with increased newborn birth weight. Additionally, a study from Ghazeeri and al. showed that 89% of people who underwent conception through in vitro fertilization were Rh-positive.The timeline of onset for these symptoms has been reported with some variability. However, most people report experiencing symptoms during the third trimester (last few weeks of pregnancy) where 15% of the women who have PUPPP reported that symptoms actually began immediately after delivery of the baby. As mentioned above, the papules and plaques usually first appear on the abdomen (although not on the umbilicus/belly button) and often spread to the legs, chest, underarms, etc. However, lesions on or above the breasts are rare. Thats why the face is usually spared and does not become affected. As a result of these papules and plaques from PUPPP, it causes the skin to be very itchy (pruritic) and immensely affects the patients sleep quality throughout the night.

Cause
PUPPP is the most common dermatosis of pregnancy and is the most frequent in pregnant women habitating a male fetus, women who had quick and conspicuous weight gain during a short period, and women who ultimately deliver by a c-section. Although the exact cause of the condition is not known and varying amongst individuals, there have been theories linking the cause of PUPPP to hormonal alterations, damage to the connective tissue during pregnancy, and autoimmune disorder where the evidence for these theories is currently low.This skin condition occurs mostly in first pregnancies (primigravida), in the third trimester and is more likely with multiple pregnancies (more so with triplets than twins or singletons). Estimated 75% of people with typical PUPPP people have never given birth. Occasionally, this condition may also occur postpartum, but rarely does this ever occur in the first and second trimester.Other than additional associations with hypertension and induction of labour, there are no observed difference in the outcome of the pregnancy for mothers or babies.

Dermatological Causes
During pregnancy as the abdominal wall rapid stretching, it is hypothesized that there is an inflammatory reaction that occurs due to the exposure of collagen. This reaction has been seen more frequently in those who are having twins or triplets compared to those with single births. This is hypothesized to be due to increased stretching of the abdominal wall while carrying twins or triplets, causing an earlier onset of PUPPP when compared to those undergoing single births.

Hormonal Causes
Throughout pregnancy, there are hormonal changes that occur where it has been hypothesized that these changes may contribute to the onset of PUPPP. Although current research is low on this hypothesis, it has been seen that those who have had multiple gestations can exhibit an increased level of progesterone. With this increase in progesterone, it causes there to be an increased level of progesterone receptors present eliciting an immune reaction seen by skin lesions in PUPPP. With multiple gestations, there is an increase in sex hormones that has been seen those with the condition such as an increase in progesterone as previously discussed but also higher levels of estradiol. Currently evidence is weak in the role that sex hormones play when contributing to PUPPP where further research is needed.

Immunological Causes
Inflammatory Mediated
From those with PUPPP, it has been seen from an immunohistology profile which is used to determine the of tissue components present within an individual via the use of antibodies, that there are certain immune cells that are in greater amount compared to that of those without PUPPP. Immunohistology profile have shown cells consistent with a delayed hypersensitivity with T helper cell infiltrates, dendritic cells and epidermal Langerhans cells.It has been hypothesized that PUPPP appears in response to fetal antigens that circulate throughout the body. For example, a study showed that fetal male DNA was found within the lesions of the mothers skin which was thought to be caused by the fetal cells seen in the mothers blood throughout pregnancy.

Autoimmune
Although this condition has not been determined as an autoimmune condition, from a single study it has been seen that Immunoglobulin M (IgM) deposition at the dermal-epidermal membrane has been associated with a variety of dermatosis including PUPPP. The problem with the hypothesis that has been proposed is that this condition does not reoccur and it does not progressively worsen. Currently there has been no evidence of detecting circulating antibodies that are associated with the onset on PUPPP in an individual.

Diagnosis
PUPPP is often a diagnosis of exclusion and may need laboratory testing to rule out other dermatoses. Lab tests may include complete blood count, comprehensive metabolic panel, liver function tests, serum human choriogonadotropin and serum cortisol. Additional specialized tests may include serum for indirect immunofluorescence or biopsy of the lesions for direct immunofluorescence to rule out pemphigoid gestationis.A common misdiagnosis is urticarial pemphigoid gestationis, hence it is needed to exclude it while diagnosing PUPPP as clinical features can overlap. Therefore, histological and immunological studies are necessary to ensure there is no mis-diagnosis. During the case of pemphigoid gestationis, lesions usually occur during the earlier periods of gestation and often involve the umbilicus; as well as, having a positive immunofluorescence of perilesional skin. If there is eczema, people generally have a history of atopy, be it personal or through family. The eruption is identified by pruritic erythematous lesions on flexural areas. Furthermore, other clinical differential diagnosis could be from drug eruptions, urticaria, or viral exanthems.Sometimes, people may require a 3- or 4-mm punch biopsy to exclude herpes gestationis, which is a variant of bullous pemphigoid occurring during or immediately after pregnancy. Usually the biopsy has features that are consistent with PUPPP but there are no pathognomonic symptoms of the particular disorder. Additionally, a biopsy of unaffected perilesional skin could be used for direct immunofluorescence studies to have a more precise exclusion of herpes gestationis.

Treatment
It is important to note that diagnosis should be conducted by a trusted medical professional. In the case that a woman is experiencing symptoms of PUPPP, it is recommended that they contact their primary care physician for referral to a dermatologist for treatment guidance and should not self-treat.In the majority of cases, PUPPP resolves within a few days or weeks upon initial onset or spontaneously within a week of delivery. However, a few women continue to experience symptoms long into the postpartum period.
One of the most recent forms of treatment suggested is the intramuscular injection of autologous whole blood as an alternative treatment option for people affected by PUPPP right after childbirth, as it seems to have both subjective and objective improvements of the symptoms. This is a very good option for the people who are worried about taking medications during pregnancy or breastfeedingAntihistamine tablets may be prescribed to provide relief from the itch, although they are generally considered much less effective than corticosteroid treatments, and may decrease itching through blocking histamine release as well as improving sleep quality.
Furthermore, first-generation antihistamines, such as chlorpheniramine, have proven to be safe in pregnancy and can be a supplement treatment for pruritus </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 Sphincter of Oddi dysfunction and can you explain it in depth? [/INST] Sphincter of Oddi dysfunction refers to a group of functional disorders leading to abdominal pain due to dysfunction of the Sphincter of Oddi: functional biliary sphincter of Oddi and functional pancreatic sphincter of Oddi disorder. The sphincter of Oddi is a sphincter muscle, a circular band of muscle at the bottom of the biliary tree which controls the flow of pancreatic juices and bile into the second part of the duodenum. The pathogenesis of this condition is recognized to encompass stenosis or dyskinesia of the sphincter of Oddi (especially after cholecystectomy); consequently the terms biliary dyskinesia, papillary stenosis, and postcholecystectomy syndrome have all been used to describe this condition.  Both stenosis and dyskinesia can obstruct flow through the sphincter of Oddi and can therefore cause retention of bile in the biliary tree and pancreatic juice in the pancreatic duct.
Individuals with sphincter of Oddi dysfunction present with abdominal pain resembling that of structural or inflammatory disorders of the gallbladder, biliary tree or pancreas. Among other characteristics, the pain is typically in the upper part of the abdomen or in the right upper quadrant of the abdomen, lasts 30 minutes or longer, and is not associated with a structural abnormality that could lead to these symptoms. The disorder is classified into two subtypes: functional biliary sphincter of Oddi disorder, where there is no disturbance in pancreatic enzyme measurements, such as amylase and lipase; and, functional pancreatic sphincter of Oddi disorder, where pancreatic enzyme measurements are elevated.
Attacks can be precipitated by opioid analgesics, particularly in patients having undergone a cholecystectomy or bariatric surgery.

Classification
Functional disorders of the gallbladder, bile duct and pancreas have been defined and classified by the Rome criteria for functional gastrointestinal disorders. The criteria outline three variants of functional disorders of the gallbladder, bile duct and pancreas, termed functional gallbladder disorder, functional biliary sphincter of Oddi disorder and functional pancreatic sphincter of Oddi disorder. All of the following criteria need to be met for as part of the definition of a functional disorder of the gallbladder:
the pain must be located in the upper part of the abdomen and/or the right upper quadrant of the abdomen
episodes of pain must last at least 30 minutes
the symptoms must be recurrent, and occur at differing intervals
the pain must incrementally increase to a "steady level"
the pain must be severe enough the patients daily activities are affected, or that the patient must attend the emergency department
the pain must not be relieved by any of bowel movements, change in posture, or antacids; and,
other structural disorders that could explain the symptoms must be excluded.

Functional gallbladder disorder
Individuals are classified as having a functional gallbladder disorder if the above criteria are met, if the gallbladder is present, and if the testing of liver enzymes, conjugated bilirubin, and pancreatic enzymes (amylase and lipase) are normal.

Functional biliary sphincter of Oddi disorder
If all of the above criteria are met, individuals are classified as having a functional biliary sphincter of Oddi disorder, if the testing of pancreatic enzymes (amylase and lipase) is normal.The old Milwaukee classification of biliary sphincter of Oddi dysfunction (SOD) used to divide the condition into three subtypes: but it is no longer in use. Type I included patients with biliary-type abdominal pain, with all of altered liver enzymes on blood testing, dilated biliary ducts on ultrasound or ERCP, and delayed bile clearance on HIDA scan. Type II included patients with biliary-type abdominal pain associated with at least one of the following: altered liver enzymes on blood testing, dilated biliary ducts on imaging tests, and delayed bile clearance on HIDA scan. Biliary-type pain in the absence of any sign of biliary or pancreatic alteration was the so-called Type III biliary SOD. The hypothesis that this pain could be linked to SOD has been studied in a large trial published in JAMA (2014)  where patients were randomized to sphincterotomy or sham surgery. Contrary to expectations, patients who were not subjected to sphincterotomy fared better </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 Subconjunctival bleeding and can you explain it in depth? [/INST] Subconjunctival bleeding, also known as subconjunctival hemorrhage or subconjunctival haemorrhage, is bleeding from a small blood vessel over the whites of the eye. It results in a red spot in the white of the eye. There is generally little to no pain and vision is not affected. Generally only one eye is affected.Natural causes can include coughing, vomiting, heavy lifting, straining to pass hard stools during acute constipation or the act of "pushing" or "bearing down" during labour/childbirth as these activities can increase the blood pressure in the vascular systems supplying the retina. There are up to four vascular retinal plexuses that are supplied by tiny, delicate capillaries whose walls if encountered with a sudden amount of force from blood will rupture. External causes can include direct impact/injury from an accidental bump or a physical altercation resulting in blunt force trauma. Risk factors include hypertension, diabetes, old age, and blood thinners. They occur in about 2% of newborns following a vaginal delivery. The blood occurs between the conjunctiva and the episclera </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 Grisels syndrome and can you explain it in depth? [/INST] Grisels syndrome is a non-traumatic subluxation of the atlanto-axial joint caused by inflammation of the adjacent tissues. This is a rare disease that usually affects children. Progressive throat and neck pain and neck stiffness can be followed by neurologic symptoms such as pain or numbness radiating to arms (radiculopathies). In extreme cases, the condition can lead to quadriplegia and even death from acute respiratory failure.  The condition often follows soft tissue inflammation in the neck such as in cases of upper respiratory tract infections, peritonsillar or retropharyngeal abscesses </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 Pelvic congestion syndrome and can you explain it in depth? [/INST] Pelvic congestion syndrome, also known as pelvic vein incompetence, is a long term condition believed to be due to enlarged veins in the lower abdomen. The condition may cause chronic pain, such as a constant dull ache, which can be worsened by standing or sex. Pain in the legs or lower back may also occur.While the condition is believed to be due to blood flowing back into pelvic veins as a result of faulty valves in the veins, this hypothesis is not certain. The condition may occur or worsen during pregnancy. The presence of estrogen is believed to be involved in the mechanism. Diagnosis may be supported by ultrasound, CT scan, MRI, or laparoscopy.Early treatment options include medroxyprogesterone or nonsteroidal anti-inflammatory drugs (NSAIDs). Surgery to block the varicose veins may also be done. About 30% of women of reproductive age are affected. It is believed to be the cause of about a third of chronic pelvic pain cases </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 Diaphragmatic rupture and can you explain it in depth? [/INST] Diaphragmatic rupture (also called diaphragmatic injury or tear) is a tear of the diaphragm, the muscle across the bottom of the ribcage that plays a crucial role in breathing. Most commonly, acquired diaphragmatic tears result from physical trauma. Diaphragmatic rupture can result from blunt or penetrating trauma and occurs in about 0.5% of all people with trauma.Diagnostic techniques include X-ray, computed tomography, and surgical techniques such as an explorative surgery. Diagnosis is often difficult because signs may not show up on X-ray, or signs that do show up appear similar to other conditions. Signs and symptoms include chest and abdominal pain, difficulty breathing, and decreased lung sounds. When a tear is discovered, surgery is needed to repair it.
Injuries to the diaphragm are usually accompanied by other injuries, and they indicate that more severe injury may have occurred. The outcome often depends more on associated injuries than on the diaphragmatic injury itself. Since the pressure is higher in the abdominal cavity than the chest cavity, rupture of the diaphragm is almost always associated with herniation of abdominal organs into the chest cavity, which is called a diaphragmatic hernia. This herniation can interfere with breathing.

Signs and symptoms
Symptoms may include pain, orthopnea, (shortness of breath when lying flat), and coughing. In people with herniation of abdominal organs, signs of intestinal blockage or sepsis in the abdomen may be present. Bowel sounds may be heard in the chest, and shoulder or epigastric pain may be present. When the injury is not noticed right away, the main symptoms are those that indicate bowel obstruction.

Causes
Diaphragmatic rupture may be caused by blunt trauma, penetrating trauma, and by iatrogenic causes (as a result of medical intervention), for example during surgery to the abdomen or chest. It has also occurred spontaneously at the time of pregnancy or for no discernible reason. Injury to the diaphragm is reported to be present in 8% of cases of blunt chest trauma. In cases of blunt trauma, vehicle accidents and falls are the most common causes. Penetrating trauma has been reported to cause 12.3–20% of cases, but it has also been proposed as a more common cause than blunt trauma; discrepancies could be due to varying regional, social, and economic factors in the areas studied. Stab and gunshot wounds can cause diaphragmatic injuries. Clinicians are trained to suspect diaphragmatic rupture particularly if penetrating trauma has occurred to the lower chest or upper abdomen. With penetrating trauma, the contents of the abdomen may not herniate into the chest cavity right away, but they may do so later, causing the presentation to be delayed. Since the diaphragm moves up and down during breathing, penetrating trauma to various parts of the torso may injure the diaphragm; penetrating injuries as high as the third rib and as low as the twelfth have been found to injure the diaphragm. Iatrogenic cases have occurred as a complication of medical procedures involving the thorax or abdomen. It has occurred as a complication of thoracentesis and radiofrequency ablation.

Mechanism
Although the mechanism is unknown, it is proposed that a blow to the abdomen may raise the pressure within the abdomen so high that the diaphragm ruptures. Blunt trauma creates a large pressure gradient between the abdominal and thoracic cavities; this gradient, in addition to causing the rupture, can also cause abdominal contents to herniate into the thoracic cavity. Abdominal contents in the pleural space interfere with heart function and lung function. High intrathoracic pressure results in an increase in right atrial pressure, disrupting the filling of the heart and venous return of blood. As venous return determines cardiac output, this results in a reduction of cardiac output. If ventilation of the lung on the side of the tear is severely inhibited, hypoxemia (low blood oxygen) results. Usually, the rupture is on the same side as an impact. A blow to the side is three times more likely to cause diaphragmatic rupture than a blow to the front.

Diagnosis
Physical examinations are not accurate, as there is usually no specific physical sign that can be used to diagnose this condition. Thoracoscopic and laparoscopic methods can be accurate. Chest X-ray is known to be unreliable in diagnosing diaphragmatic rupture; it has low sensitivity and specificity for the injury. Often another injury such as pulmonary contusion masks the injury on the X-ray film. Half the time, initial X-rays are normal; in most of those that are not, hemothorax or pneumothorax is present. A nasogastric tube from the stomach may appear on the film in the chest cavity; this sign is pathognomonic for diaphragmatic rupture, but it is rare. The X-ray is better able to detect the injury when taken from the back with the person upright, but this is not usually possible because the person is usually not stable enough; thus it is usually taken from the front with the person lying supine. Positive pressure ventilation helps keep the abdominal organs from herniating into the chest cavity, but this also can prevent the injury from being discovered on an X-ray.A CT scan has an increased accuracy of diagnosis over X-ray, but no specific findings on a CT scan exist to establish a diagnosis. The free edge of a ruptured diaphragm may curl and become perpendicular to the chest wall, a sign known as a dangling diaphragm. A herniated organ may constrict at the location of a rupture, a sign known as the collar sign. If the liver herniates through a rupture on the right side, it may produce two signs known as the hump and band signs. The hump sign is a form of the collar sign on the right. The band sign is a bright line that intersects the liver.  it is believed to result due to the ruptured diaphragm compressing.  Although CT scanning increases chances that diaphragmatic rupture will be diagnosed before surgery, the rate of diagnosis before surgery is still only 31–43.5%. Another diagnostic method is laparotomy, but this misses diaphragmatic ruptures up to 15% of the time. Often diaphragmatic injury is discovered during a laparotomy that was undertaken because of another abdominal injury. Because laparotomies are more common in those with penetrating trauma than compared to those who experienced a blunt force injury, diaphragmatic rupture is found more often in these people. Thoracoscopy is more reliable in detecting diaphragmatic tears than laparotomy and is especially useful when chronic diaphragmatic hernia is suspected.

Location
Between 50 and 80% of diaphragmatic ruptures occur on the left side. It is possible that the liver, which is situated in the right upper quadrant of the abdomen, cushions the diaphragm. However, injuries occurring on the left side are also easier to detect in X-ray films. Half of diaphragmatic ruptures that occur on the right side are associated with liver injury. Injuries occurring on the right are associated with a higher rate of death and more numerous and serious accompanying injuries. Bilateral diaphragmatic rupture, which occurs in 1–2% of ruptures, is associated with a much higher death rate (mortality) than injuries that occur on just one side.

Treatment
Since the diaphragm is in constant motion with respiration, and because it is under tension, lacerations will not heal on their own. The injury usually becomes larger with time if not repaired. The main goals of surgery are to repair any injuries to the diaphragm and to move any herniated abdominal organs back to their original place. This is done be debriding nonviable tissue and closing the rupture. Most of the time, the injury is repaired during laparotomy. Early surgery is important, as diaphragmatic atrophy and adhesions occur over time. Sutures are used in the repair. Other injuries, such as hemothorax, may present a more immediate threat and may need to be treated first if they accompany diaphragmatic rupture. Video-assisted thoracoscopy may be used.

Prognosis
In most cases, isolated diaphragmatic rupture is associated with good outcome if it is surgically repaired. The death rate (mortality) for diaphragmatic rupture after blunt and penetrating trauma is estimated to be 15–40% and 10–30% respectively, but other injuries play a large role in determining outcome. Herniation of abdominal organs is present in 3–4% of people with abdominal trauma who present to a trauma center.

Epidemiology
Diaphragmatic injuries are present in 1–7% of people with significant blunt trauma and an average of 3% of abdominal injuries. A high body mass index may be associated with a higher risk of diaphragmatic rupture in people involved in vehicle accidents. Over 90% occur due to trauma from vehicle accidents. Due to the great force needed to rupture the diaphragm, it is rare for the diaphragm alone to be injured, especially in blunt trauma; other injuries are associated in as many as 80–100% of cases. In fact, if the diaphragm is injured, it is an indication that more severe injuries to organs may have occurred. Thus, the mortality after a diagnosis of diaphragmatic rupture is 17%, with most deaths due to lung complications. Common associated injuries include head injury, injuries to the aorta, fractures of the pelvis and long bones, and lacerations of the liver and spleen. Associated injuries occur in over three quarters of cases.

History
In 1579, Ambroise Paré made the first description of diaphragmatic rupture in a French artillery captain who had been shot eight months before his death.  He died from complications of the rupture. Using autopsies, Paré also described diaphragmatic rupture in people who had suffered blunt and penetrating trauma </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 Drug withdrawal and can you explain it in depth? [/INST] Drug withdrawal, drug withdrawal syndrome, or substance withdrawal syndrome, is the group of symptoms that occur upon the abrupt discontinuation or decrease in the intake of pharmaceutical or recreational drugs.
In order for the symptoms of withdrawal to occur, one must have first developed a form of drug dependence. This may occur as physical dependence, psychological dependence or both. Drug dependence develops from consuming one or more substances over a period of time.
Dependence arises in a dose-dependent manner and produces withdrawal symptoms that vary with the type of drug that is consumed. For example, prolonged use of an antidepressant medication is likely to cause a rather different reaction when discontinued compared to discontinuation of an opioid, such as heroin. Withdrawal symptoms from opiates include anxiety, sweating, vomiting, and diarrhea. Alcohol withdrawal symptoms include irritability, fatigue, shaking, sweating, and nausea. Withdrawal from nicotine can cause irritability, fatigue, insomnia, headache, and difficulty concentrating. Many prescription and legal nonprescription substances can also cause withdrawal symptoms when individuals stop consuming them, even if they were taken as directed by a physician.
The route of administration, whether intravenous, intramuscular, oral or otherwise, can also play a role in determining the severity of withdrawal symptoms. There are different stages of withdrawal as well; generally, a person will start to feel bad (crash or come down), progress to feeling worse, hit a plateau, and then the symptoms begin to dissipate. However, withdrawal from certain drugs (barbiturates, benzodiazepines, alcohol, glucocorticoids) can be fatal. While it is seldom fatal to the user, withdrawal from opiates (and some other drugs) can cause miscarriage, due to fetal withdrawal. The term "cold turkey" is used to describe the sudden cessation use of a substance and the ensuing physiologic manifestations.
The symptoms from withdrawal may be even more dramatic when the drug has masked prolonged malnutrition, disease, chronic pain, infections (common in intravenous drug use), or sleep deprivation, conditions that drug abusers often develop as a secondary consequence of the drug. When the drug is removed, these conditions may resurface and be confused with withdrawal symptoms </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 Lichen aureus 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 Luteal phase and can you explain it in depth? [/INST] The menstrual cycle is on average 28 days in length. It begins with menses (day 1–7) during the follicular phase (day 1–14) and followed by ovulation (day 14) and ending with the luteal phase (day 14–28). Unlike the follicular phase which can vary in length among individuals, the luteal phase is typically fixed at approximately 14 days (i.e. days 14–28) and is characterized by changes to hormone levels, such as an increase in progesterone and estrogen levels, decrease in gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), changes to the endometrial lining to promote implantation of the fertilized egg, and development of the corpus luteum. In the absence of fertilization by sperm, the corpus luteum atrophies leading to a decrease in progesterone and estrogen, an increase in FSH and LH, and shedding of the endometrial lining (menses) to begin the menstrual cycle again.

Hormonal events
After ovulation and release of the oocyte, the anterior pituitary hormones–follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are released and cause the remaining parts of the dominant follicle to transform into the corpus luteum. It continues to grow during the luteal phase after ovulation and produces significant amounts of hormones, particularly progesterone, and, to a lesser extent, estrogen and inhibin. Progesterone plays a vital role in making the endometrium receptive to implantation of the embryo and supportive of early pregnancy. High levels of progesterone inhibit the follicular growth. The increase in estrogen and progesterone also lead to increased basal body temperature during the luteal phase.The LH surge that occurs during ovulation triggers the release of the oocyte and its cumulus oophorus from the ovary and into the fallopian tube and triggers the oocyte to divide and enter metaphase of meiosis II (46 or 2n chromosome) and extrude its first polar body. The oocyte will only continue through meiosis and extrude its second polar body once it is fertilized. Ovulation occurs ~35 hours after the beginning of the LH surge or ~10 hours following the LH surge. Several days after ovulation, the increasing amount of estrogen produced by the corpus luteum may cause one or two days of fertile cervical mucus, lower basal body temperatures, or both. This is known as a "secondary estrogen surge".The hormones released by the corpus luteum suppress production of the FSH and LH from the anterior pituitary gland. The corpus luteum relies on LH activation on its receptors in order to survive. The loss of the corpus luteum can be prevented by implantation of an embryo: after implantation, human embryos produce human chorionic gonadotropin (hCG), which is structurally similar to LH and can preserve the corpus luteum </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 Brunner syndrome and can you explain it in depth? [/INST] Brunner syndrome is a rare genetic disorder associated with a mutation in the MAOA gene. It is characterized by lower than average IQ (typically about 85), problematic impulsive behavior (such as pyromania, hypersexuality and violence), sleep disorders and mood swings. It was identified in fourteen males from one family in 1993.  It has since been discovered in  additional families.

Signs and symptoms
Causes
Brunner syndrome is caused by a monoamine oxidase A (MAOA) deficiency, which leads to an excess of monoamines in the brain, such as serotonin, dopamine, and norepinephrine (noradrenaline) </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 Dural arteriovenous fistula and can you explain it in depth? [/INST] A dural arteriovenous fistula (DAVF) or malformation is an abnormal direct connection (fistula) between a meningeal artery and a meningeal vein or dural venous sinus.

Signs and symptoms
The most common signs/symptoms of DAVFs are:
Pulsatile tinnitus
Occipital bruit
Headache
Visual impairment
PapilledemaPulsatile tinnitus is the most common symptom in patients, and it is associated with transverse-sigmoid sinus DAVFs. Carotid-cavernous DAVFs, on the other hand, are more closely associated with pulsatile exophthalmos. DAVFs may also be asymptomatic (e.g. cavernous sinus DAVFs).

Location
Most commonly found adjacent to dural sinuses in the following locations:
Transverse (lateral) sinus, left-sided slightly more common than right
Intratentorial
From the posterior cavernous sinus, usually draining to the transverse or sigmoid sinuses
Vertebral artery (posterior meningeal branch)

Causes
It is still unclear whether DAVFs are congenital or acquired. Current evidence supports transverse-sigmoid sinus junction dural malformations are acquired defects, occurring in response to thrombosis and collateral revascularization of a venous sinus.

Diagnosis
Cerebral angiography is the diagnostic standard. MRIs are typically normal but can identify venous hypertension as a result of arterial-venous shunting.

Classification
Borden Classification
The Borden Classification of dural arteriovenous malformations or fistulas, groups into three types based upon their venous drainage:
Type I: dural arterial supply drains anterograde into venous sinus.
Type II: dural arterial supply drains into venous sinus. High pressure in sinus results in both anterograde drainage and retrograde drainage via subarachnoid veins.
Type III: dural arterial supply drains retrograde into subarachnoid veins.

Type I
Type I dural arteriovenous fistulas are supplied by meningeal arteries and drain into a meningeal vein or dural venous sinus. The flow within the draining vein or venous sinus is anterograde.

Type Ia – simple dural arteriovenous fistulas have a single meningeal arterial supply
Type Ib – more complex arteriovenous fistulas are supplied by multiple meningeal arteriesThe distinction between Types Ia and Ib is somewhat specious as there is a rich system of meningeal arterial collaterals. Type I dural fistulas are often asymptomatic, do not have a high risk of bleeding and do not necessarily need to be treated.

Type II
The high pressure within a Type II dural AV fistula causes blood to flow in a retrograde fashion into subarachnoid veins which normally drain into the sinus. Typically this is because the sinus has outflow obstruction. Such draining veins form venous varices or aneurysms which can bleed. Type II fistulas need to be treated to prevent hemorrhage. The treatment may involve embolization of the draining sinus as well as clipping or embolization of the draining veins.

Type III
Type III dural AV fistulas drain directly into subarachnoid veins. These veins can form aneurysms and bleed. Type III dural fistulas need to be treated to prevent hemorrhage. Treatment can be as simple as clipping the draining vein at the site of the dural sinus </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 Testicular dysgenesis syndrome and can you explain it in depth? [/INST] Testicular dysgenesis syndrome is a male reproduction-related condition characterized by the presence of symptoms and disorders such as hypospadias, cryptorchidism, poor semen quality, and testicular cancer. The concept was first introduced by N.E. Skakkaebaek in a research paper along with the department of Growth and Reproduction in Copenhagen University. The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system.

Causes
Central to the cause of irreversible TDS are disruptions to early fetal testes development. This has genetic, environmental, and lifestyle components, however the rapid increase in the incidence of the disorders associated with TDS in the last decades indicates that it is under a powerful environmental influence. The fetal origins of TDS are reinforced by the high incidence of TDS disorders found occurring together in one individual.
Associated with mutation of Insulin like Factor 3 (INSL3)

Genetic
Many genes have been implicated in the disorders of TDS, with genome wide association studies (GWAS) regularly identifying new gene variants that play a role in abnormal testes development. Some of these are specific to certain disorders, and some are part of a risk factor network that connect TGCC, hypospadias, cryptorchidism, poor semen quality. The majority of these genes are involved in fetal gonad development. Mutations in androgen receptor genes are highly implicated, as these are involved in penile development, testes descent, and testes development. Testicular germ cell cancer (TGCC) shows a strong genetic disposition, with the most significant gene variants being those linked to gonad formation and germ cell function.

Environmental
Exposure of a male fetus to substances that disrupt hormone systems, particularly chemicals that inhibit the action of androgens (male sex hormones) during the development of the reproductive system, has been shown to cause many of the characteristic TDS disorders. These include environmental estrogens and anti-androgens found in food and water sources that have been contaminated with synthetic hormones and pesticides used in agriculture. In historical cases, medicines given to pregnant women, like diethylstilbestrol (DES), have caused many of the features of TDS in fetuses exposed to this chemical during gestation. The impact of environmental chemicals is well documented in animal models. If a substance affects Sertoli and Leydig cell differentiation (a common feature of TDS disorders) at an early developmental stage, germ cell growth and testosterone production will be impaired. These processes are essential for testes descent and genitalia development, meaning that genital abnormalities like cryptorchidism or hypospadias may be present from birth, and fertility problems and TGCC become apparent during adult life. Severity or number of disorders may therefore be dependent on the timing of the environmental exposure. Environmental factors can act directly, or via epigenetic mechanisms, and it is likely that a genetic susceptibility augmented by environmental factors is the primary cause of TDS.

Lifestyle
Links between maternal smoking and TDS are tenuous, but there are stronger associations between maternal alcohol consumption and incidences of cryptorchidism in sons. Smoking does however affect the growth of a fetus, and low birth weight is shown to increase the likelihood of all the disorders encompassed by TDS. Maternal obesity, resulting in gestational diabetes, has also been shown to be a risk factor for impaired testes development and TDS symptoms in sons.

Pathogenesis
The TDS hypothesis proposes that testicular dysgenesis, which has various primary causes, can lead to abnormalities in Sertoli and/or Leydig cell function. This leads to both impaired germ cell development and hormonal changes during male sexual differentiation. For instance, insufficient production of testosterone can result in incomplete masculinisation, whilst reduced expression of insulin-like factor 3 can lead to incomplete testes descent.  The downstream disorders of such abnormalities can include both genital malformations (e.g. hypospadias and cryptorchidism) and delayed reproductive disorders (e.g. testicular cancer and poor semen quality) which comprise TDS.

Diagnosis
Hypospadias
Hypospadias presents as an abnormal location for the end of the urethra which is typically found on the distal end of the penis. It is generally diagnosed at birth from visual confirmation of the hallmark features. As well as an unusual location of the urethra, the prepuce (foreskin) is typically incomplete as well. The abnormal ‘hooded’ prepuce is what often draws attention to the condition but can occur separately to hypospadias.

Cryptorchidism
In Cryptorchidism a diagnosis is made from a physical examination which is performed when the baby is lacking one or both testes in the dependant portion of the scrotal sac. 70% of cryptorchid testes can be felt and are unable to be pulled into the scrotum or retreats quickly after being pulled into a higher position </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 Keshan disease and can you explain it in depth? [/INST] Keshan disease is a congestive cardiomyopathy caused by a combination of dietary deficiency of selenium and the presence of a mutated strain of Coxsackievirus, named after Keshan County of Heilongjiang province, Northeast China, where symptoms were first noted. These symptoms were later found prevalent in a wide belt extending from northeast to southwest China, all due to selenium-deficient soil. The disease peaked in 1960–1970, killing thousands of people.Often fatal, the disease affects children and women of child-bearing age, characterized by heart failure and pulmonary edema. Over decades, supplementation with selenium reduced this condition.It had been linked to the coxsackie B virus. Current research suggests that the lack of selenium results in a more virulent strain of the coxsackievirus becoming the dominant viral species present in the population of virus, but the mechanism of this selection event is unclear.Keshan disease can also lead to higher rates of cancer, cardiovascular disease, hypertension, and strokes. In addition, an individual can experience eczema, psoriasis, arthritis, cataracts, alcoholism, and infections.

Signs and symptoms
Cardiac arrythmias,dizziness,fast breathing,shortness of breath(PULMONARY EDEMA)

Diagnosis
Prevention
It is hard to consider Keshan disease extremely preventable because the only way to ensure that the individual is getting enough selenium would be to test the soil in the area. However, one way that selenium intake can be improved is to increase intake of foods that are rich with selenium. Examples include Brazil nuts, onions, canned tuna, beef, cod, turkey, chicken breast, enriched pasta, egg, cottage cheese, oatmeal, white or brown rice, and garlic. If the individual lives in an area that does not have selenium enriched soil, dietary supplementation should be considered. To determine whether or not an individual is selenium deficient, blood testing is performed.

Treatments
The treatment for Keshan disease is selenium supplementation </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 Adverse drug reaction and can you explain it in depth? [/INST] An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term differs from the term "side effect" because side effects can be beneficial as well as detrimental. The study of ADRs is the concern of the field known as pharmacovigilance. An adverse drug event (ADE) refers to any unexpected and inappropriate occurrence at the time a drug is used, whether or not associated with the administration of the drug. An ADR is a special type of ADE in which a causative relationship can be shown.  ADRs are only one type of medication-related harm, as harm can also be caused by omitting to take indicated medications.

Classification
ADRs may be classified by e.g. cause and severity.

Cause
Type A: Augmented pharmacologic effects - dose dependent and predictableType A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drugs primary pharmacological effect (e.g. bleeding when using the anticoagulant warfarin) or a low therapeutic index of the drug (e.g. nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term side effects is often applied to minor type A reactions.Type B: IdiosyncraticTypes A and B were proposed in the 1970s, and the other types were proposed subsequently when the first two proved insufficient to classify ADRs.

Seriousness
The U.S Food and Drug Administration defines a serious adverse event as one when the patient outcome is one of the following:
Death
Life-threatening
Hospitalization (initial or prolonged)
Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patients body function/structure, physical activities or quality of life.
Congenital abnormality
Requires intervention to prevent permanent impairment or damageSeverity is a point on an arbitrary scale of intensity of the adverse event in question.  The terms "severe" and "serious", when applied to adverse events, are technically very different. They are easily confused but can not be used interchangeably, requiring care in usage.
A headache is severe if it causes intense pain. There are scales like "visual analog scale" that help clinicians assess the severity. On the other hand, a headache is not usually serious (but may be in case of subarachnoid haemorrhage, subdural bleed, even a migraine may temporally fit criteria), unless it also satisfies the criteria for seriousness listed above.

Location
Adverse effects may be local, i.e. limited to a certain location, or systemic, where medication has caused adverse effects throughout the systemic circulation.
For instance, some ocular antihypertensives cause systemic effects, although they are administered locally as eye drops, since a fraction escapes to the systemic circulation.

Mechanisms
As research better explains the biochemistry of drug use, fewer ADRs are Type B and more are Type A. Common mechanisms are:

Abnormal pharmacokinetics due to
genetic factors
comorbid disease states
Synergistic effects between either
a drug and a disease
two drugs
Antagonism effects between either
a drug and a disease
two drugs

Abnormal pharmacokinetics
Comorbid disease states
Various diseases, especially those that cause renal or hepatic insufficiency, may alter drug metabolism. Resources are available that report changes in a drugs metabolism due to disease states.The Medication Appropriateness Tool for Comorbid Health Conditions in Dementia (MATCH-D) criteria warns that people with dementia are more likely to experience adverse effects, and that they are less likely to be able to reliably report symptoms.

Genetic factors
Abnormal drug metabolism may be due to inherited factors of either Phase I oxidation or Phase II conjugation. Pharmacogenomics is the study of the inherited basis for abnormal drug reactions.

Phase I reactions
Inheriting abnormal alleles of cytochrome P450 can alter drug metabolism. Tables are available to check for drug interactions due to P450 interactions.Inheriting abnormal butyrylcholinesterase (pseudocholinesterase) may affect metabolism of drugs such as succinylcholine

Phase II reactions
Inheriting abnormal N-acetyltransferase which conjugated some drugs to facilitate excretion may affect the metabolism of drugs such as isoniazid, hydralazine, and procainamide.Inheriting abnormal thiopurine S-methyltransferase may affect the metabolism of the thiopurine drugs mercaptopurine and azathioprine.

Interactions with other drugs
The risk of drug interactions is increased with polypharmacy.

Protein binding
These interactions are usually transient and mild until a new steady state is achieved. These are mainly for drugs without much first-pass liver metabolism. The principal plasma proteins for drug binding are:
albumin
α1-acid glycoprotein
lipoproteinsSome drug interactions with warfarin are due to changes in protein binding.

Cytochrome P450
Patients have abnormal metabolism by cytochrome P450 due to either inheriting abnormal alleles or due to drug interactions. Tables are available to check for drug interactions due to P450 interactions.

Synergistic effects
An example of synergism is two drugs that both prolong the QT interval.

Assessing causality
Causality assessment is used to determine the likelihood that a drug caused a suspected ADR. There are a number of different methods used to judge causation, including the Naranjo algorithm, the Venulet algorithm and the WHO causality term assessment criteria. Each have pros and cons associated with their use and most require some level of expert judgement to apply.
An ADR should not be labeled as certain unless the ADR abates with a challenge-dechallenge-rechallenge protocol (stopping and starting the agent in question). The chronology of the onset of the suspected ADR is important, as another substance or factor may be implicated as a cause; co-prescribed medications and underlying psychiatric conditions may be factors in the ADR.Assigning causality to a specific agent often proves difficult, unless the event is found during a clinical study or large databases are used. Both methods have difficulties and can be fraught with error. Even in clinical studies some ADRs may be missed as large numbers of test individuals are required to find that adverse drug reaction. Psychiatric ADRs are often missed as they are grouped together in the questionnaires used to assess the population.

Monitoring bodies
Many countries have official bodies that monitor drug safety and reactions. On an international level, the WHO runs the Uppsala Monitoring Centre, and the European Union runs the European Medicines Agency (EMA). In the United States, the Food and Drug Administration (FDA) is responsible for monitoring post-marketing studies.
In Canada, the Marketed Health Products Directorate of Health Canada is responsible for the surveillance of marketed health products. In Australia, the Therapeutic Goods Administration (TGA) conducts postmarket monitoring of therapeutic products </s>