<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 Fibromyalgia and can you explain it in depth? [/INST] Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hypersensitivity.The cause of fibromyalgia is unknown, but is believed to involve a combination of genetic and environmental factors. Environmental factors may include psychological stress, trauma, and certain infections. The pain appears to result from processes in the central nervous system and the condition is referred to as a "central sensitization syndrome".The treatment of fibromyalgia is symptomatic and multidisciplinary. The European Alliance of Associations for Rheumatology strongly recommends aerobic and strengthening exercise. Weak recommendations are given to mindfulness, psychotherapy, acupuncture, hydrotherapy, and meditative exercise such as qigong, yoga, and tai chi. The use of medication in the treatment of fibromyalgia is debated, although antidepressants can improve  quality of life. The medications duloxetine, milnacipran, or pregabalin have been approved by the US Food and Drug Administration (FDA) for the management of fibromyalgia. Other common helpful medications include serotonin-noradrenaline reuptake inhibitors (SNRI), non-steroidal anti-inflammatory drugs (NSAIDs), and muscle relaxants. Q10 coenzyme and vitamin D supplements may improve pain and quality of life. While fibromyalgia is persistent in nearly all patients, it does not result in death or tissue damage.Fibromyalgia is estimated to affect 2–4% of the population. Women are affected about twice as often as men. Rates appear similar in different areas of the world and among different cultures. Fibromyalgia was first defined in 1990, with updated criteria in 2011, 2016, and 2019. The term "fibromyalgia" is from New Latin fibro-, meaning "fibrous tissues", Greek μυο- myo-, "muscle", and Greek άλγος algos, "pain"; thus, the term literally means "muscle and fibrous connective tissue pain".

Classification
Fibromyalgia is classed as a disorder of pain processing due to abnormalities in how pain signals are processed in the central nervous system. The International Classification of Diseases (ICD-11) includes fibromyalgia in the category of "Chronic widespread pain", code MG30.01.

Signs and symptoms
The defining symptoms of fibromyalgia are chronic widespread pain, fatigue, and sleep disturbance. Other symptoms may include heightened pain in response to tactile pressure (allodynia), cognitive problems, musculoskeletal stiffness, environmental sensitivity, hypervigilance, sexual dysfunction, and visual symptoms.

Pain
Fibromyalgia is predominantly a chronic pain disorder. According to the NHS, widespread pain is one major symptom, which could feel like: an ache, a burning sensation, or a sharp, stabbing pain.

Fatigue
Fatigue is one of the defining symptoms of fibromyalgia. Patients may experience physical or mental fatigue. Physical fatigue can be demonstrated by a feeling of exhaustion after exercise or by a limitation in daily activities.

Sleep problems
Sleep problems are a core symptom in fibromyalgia. These include a difficulty to fall asleep or stay asleep, awakening while sleeping and waking up feeling unrefreshed. A meta-analysis compared objective and subjective sleep metrics in people with fibromyalgia and healthy people. Individuals with fibromyalgia had lower sleep quality and efficiency, as well as longer wake time after sleep start, shorter sleep duration, lighter sleep, and greater trouble initiating sleep when objectively assessed, and more difficulty initiating sleep when subjectively assessed. Sleep problems may contribute to pain by decreased release of IGF-1 and human growth hormone, leading to decreased tissue repair. Improving sleep quality can help people with fibromyalgia minimize pain.

Cognitive problems
Many people with fibromyalgia experience cognitive problems (known as "fibrofog" or "brainfog"). One study found that approximately 50% of fibromyalgia patients had subjective cognitive dysfunction and that it was associated with higher levels of pain and other fibromyalgia symptoms. The American Pain Society recognizes these problems as a major feature of fibromyalgia, characterized by trouble concentrating, forgetfulness and disorganized or slow thinking. About 75% of fibromyalgia patients report significant problems with concentration, memory, and multitasking. A 2018 meta-analysis found that the largest differences between fibromyalgia patients and healthy subjects were for inhibitory control, memory, and processing speed. It is hypothesized that the increased pain compromises attention systems, resulting in cognitive problems.

Hypersensitivity
In addition to a hypersensitivity to pain, patients with fibromyalgia show hypersensitivity to other stimuli, such as bright lights, loud noises, perfumes and cold. A review article found that they have a lower cold pain threshold. Other studies documented an acoustic hypersensitivity.

Comorbidity
Fibromyalgia as a stand-alone diagnosis is uncommon, as most fibromyalgia patients often have other chronic overlapping pain problems or mental disorders. Fibromyalgia is associated with mental health issues like anxiety, posttraumatic stress disorder, bipolar disorder, and depression. Patients with fibromyalgia are five times more likely to have major depression than the general population.Fibromyalgia and numerous chronic pain conditions frequently coexist. These include chronic tension headaches, myofascial pain syndrome, and temporomandibular disorders. Multiple sclerosis, post-polio syndrome, neuropathic pain, and Parkinsons disease are four neurological disorders that have been linked to pain or fibromyalgia. Fibromyalgia largely overlaps with chronic fatigue syndrome and may share the same pathogenetic mechanisms.Comorbid fibromyalgia has been reported to occur in 20–30% of individuals with rheumatic diseases. It has been reported in people with noninflammatory musculoskeletal diseases.The prevalence of fibromyalgia in gastrointestinal disease has been described mostly for celiac disease and irritable bowel syndrome (IBS). Fibromyalgia has also been linked with obesity. Other conditions that are associated with fibromyalgia include an overactive bladder.

Risk factors
The cause of fibromyalgia is unknown. However, several risk factors, genetic and environmental,  have been identified.

Genetics
Genetics play a major role in fibromyalgia, and may explain up to 50% of the disease susceptibility. Fibromyalgia is potentially associated with polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems. Several genes have been suggested as candidates for susceptibility to fibromyalgia. These include SLC64A4, TRPV2, MYT1L, NRXN3, and the 5-HT2A receptor 102T/C polymorphism. The heritability of fibromyalgia is estimated to be higher in patients younger than 50.Neuropathic pain and major depressive disorder often co-occur with fibromyalgia – the reason for this comorbidity appears to be due to shared genetic abnormalities, which leads to impairments in monoaminergic, glutamatergic, neurotrophic, opioid and proinflammatory cytokine signaling. In these vulnerable individuals, psychological stress or illness can cause abnormalities in inflammatory and stress pathways that regulate mood and pain. Eventually, a sensitization and kindling effect occurs in certain neurons leading to the establishment of fibromyalgia and sometimes a mood disorder.

Stress
Stress may be an important precipitating factor in the development of fibromyalgia. A 2021 meta-analysis found psychological trauma to be strongly associated with fibromyalgia. People who suffered abuse in their lifetime were three times more likely to have fibromyalgia, people who suffered medical trauma or other stressors in their lifetime were about twice as likely.Some authors have proposed that, because exposure to stressful conditions can alter the function of the hypothalamic-pituitary-adrenal (HPA) axis, the development of fibromyalgia may stem from stress-induced disruption of the HPA axis.

Personality
Although some have suggested that fibromyalgia patients are more likely to have specific personality traits, when depression is statistically controlled for, it appears that their personality is no different than that of people in the general population.

Other risk markers
Other risk markers for fibromyalgia include premature birth, female sex, cognitive influences, primary pain disorders, multiregional pain, infectious illness, hypermobility of joints, iron deficiency and small-fiber polyneuropathy. Metal-induced allergic inflammation has also been linked with fibromyalgia, especially in response to nickel but also inorganic mercury, cadmium, and lead.

Pathophysiology
As of 2022, the pathophysiology of fibromyalgia has not yet been elucidated and several theories have been suggested.

Nervous system
Pain processing abnormalities
Chronic pain can be divided into three categories. Nociceptive pain is pain caused by inflammation or damage to tissues. Neuropathic pain is pain caused by nerve damage. Nociplastic pain (or central sensitization) is less understood and is the common explanation of the pain experienced in fibromyalgia. Because the three forms of pain can overlap, fibromyalgia patients may experience nociceptive (e.g., rheumatic illnesses) and neuropathic (e.g., small fiber neuropathy) pain, in addition to nociplastic pain.

Nociplastic pain (central sensitization)
Fibromyalgia can be viewed as a condition of nociplastic pain. Nociplastic pain is caused by an altered function of pain-related sensory pathways in the periphery and the central nervous system, resulting in hypersensitivity.Nociplastic pain is commonly referred to as "Nociplastic pain syndrome" because it is coupled with other symptoms. These include fatigue, sleep disturbance, cognitive disturbance, hypersensitivity to environmental stimuli, anxiety, and depression. Nociplastic pain is caused by either (1) increased processing of pain stimuli or (2) decreased suppression of pain stimuli at several levels in the nervous system, or both.

Neuropathic pain
An alternative hypothesis to nociplastic pain views fibromyalgia as a stress-related dysautonomia with neuropathic pain features. This view highlights the role of autonomic and peripheral nociceptive nervous systems in the generation of widespread pain, fatigue, and insomnia. The description of small fiber neuropathy in a subgroup of fibromyalgia patients supports the disease neuropathic-autonomic underpinning. However, others claim that small fiber neuropathy occurs only in small groups of those with fibromyalgia.

Autonomic nervous system
Some suggest that fibromyalgia is caused or maintained by a decreased vagal tone, which is indicated by low levels of heart rate variability, signaling a heightened sympathetic response. Accordingly, several studies show that clinical improvement is associated with an increase in heart rate variability. Some examples of interventions that increase the heart rate variability and vagal tone are meditation, yoga, mindfulness and exercise.

Neurotransmitters
Some neurochemical abnormalities that occur in fibromyalgia also regulate mood, sleep, and energy, thus explaining why mood, sleep, and fatigue problems are commonly co-morbid with fibromyalgia. Serotonin is the most widely studied neurotransmitter in fibromyalgia. It is hypothesized that an imbalance in the serotoninergic system may lead to the development of fibromyalgia.  There is also some data that suggests altered dopaminergic and noradrenergic signaling in fibromyalgia. Supporting the monoamine related theories is the efficacy of monoaminergic antidepressants in fibromyalgia.

Neurophysiology
Neuroimaging studies have observed decreased grey matter of the default mode network in people with fibromyalgia. These deficits are associated with pain processing.

Neuroendocrine system
Studies on the neuroendocrine system and HPA axis in fibromyalgia have been inconsistent. One study found fibromyalgia patients exhibited higher plasma cortisol, more extreme peaks and troughs, and higher rates of dexamethasone non-suppression. However, other studies have only found correlations between a higher cortisol awakening response and pain, and not any other abnormalities in cortisol. Increased baseline ACTH and increase in response to stress have been observed, hypothesized to be a result of decreased negative feedback.

Immune system
Inflammation has been suggested to have a role in the pathogenesis of fibromyalgia. People with fibromyalgia tend to have higher levels of inflammatory cytokines IL-6, and IL-8.  There are also increased levels of the pro-inflammatory cytokines IL-1 receptor antagonist. Increased levels of pro-inflammatory cytokines may increase sensitivity to pain, and contribute to mood problems. Anti-inflammatory interleukins such as IL-10 have also been associated with fibromyalgia.A repeated observation shows that autoimmunity triggers such as traumas and infections are among the most frequent events preceding the onset of fibromyalgia. Neurogenic inflammation has been proposed as a contributing factor to fibromyalgia.

Digestive system
Gut microbiome
Gut bacteria may play a role in fibromyalgia. People with fibromyalgia are more likely to show dysbiosis, a decrease in microbiota diversity. There is a bidirectional interplay between the gut and the nervous system. Therefore, the gut can affect the nervous system, but the nervous system can also affect the gut. Neurological effects mediated via the autonomic nervous system as well as the hypothalamic pituitary adrenal axis are directed to intestinal functional effector cells, which in turn are under the influence of the gut microbiota.

Gut-brain axis
The gut-brain axis, which connects the gut microbiome to the brain via the enteric nervous system, is another area of research. Fibromyalgia patients have less varied gut flora and altered serum metabolome levels of glutamate and serine, implying abnormalities in neurotransmitter metabolism.

Diagnosis
There is no single pathological feature, laboratory finding, or biomarker that can diagnose fibromyalgia and there is debate over what should be considered diagnostic criteria and whether an objective diagnosis is possible. In most cases, people with fibromyalgia symptoms may have laboratory test results that appear normal and many of their symptoms may mimic those of other rheumatic conditions such as arthritis or osteoporosis. The specific diagnostic criteria for fibromyalgia have evolved over time.

American College of Rheumatology 1990
The first widely accepted set of classification criteria for research purposes was elaborated in 1990 by the Multicenter Criteria Committee of the American College of Rheumatology. These criteria, which are known informally as "the ACR 1990", defined fibromyalgia according to the presence of the following criteria:

A history of widespread pain lasting more than three months – affecting all four quadrants of the body, i.e., both sides, and above and below the waist.
Tender points – there are 18 designated possible tender points (although a person with the disorder may feel pain in other areas as well).The ACR criteria for the classification of patients were originally established as inclusion criteria for research purposes and were not intended for clinical diagnosis but have later become the de facto diagnostic criteria in the clinical setting. A controversial study was done by a legal team looking to prove their clients disability based primarily on tender points and their widespread presence in non-litigious communities prompted the lead author of the ACR criteria to question now the useful validity of tender points in diagnosis. Use of control points has been used to cast doubt on whether a person has fibromyalgia, and to claim the person is malingering.

American College of Rheumatology 2010 provisional criteria
In 2010, the American College of Rheumatology approved provisional revised diagnostic criteria for fibromyalgia that eliminated the 1990 criterias reliance on tender point testing. The revised criteria used a widespread pain index (WPI) and symptom severity scale (SSS) in place of tender point testing under the 1990 criteria. The WPI counts up to 19 general body areas in which the person has experienced pain in the preceding week. The SSS rates the severity of the persons fatigue, unrefreshed waking, cognitive symptoms, and general somatic symptoms, each on a scale from 0 to 3, for a composite score ranging from 0 to 12. The revised criteria for diagnosis were:

WPI ≥ 7 and SSS ≥ 5 OR WPI 3–6 and SSS ≥ 9,
Symptoms have been present at a similar level for at least three months, and
No other diagnosable disorder otherwise explains the pain.: 607

American College of Rheumatology 2016 revisions
In 2016, the provisional criteria of the American College of Rheumatology from 2010 were revised. The new diagnosis required all of the following criteria:

"Generalized pain, defined as pain in at least 4 of 5 regions, is present."
"Symptoms have been present at a similar level for at least 3 months."
"Widespread pain index (WPI) ≥ 7 and symptom severity scale (SSS) score ≥ 5 OR WPI of 4–6 and SSS score ≥ 9."
"A diagnosis of fibromyalgia is valid irrespective of other diagnoses. A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses."

American Pain Society 2019
In 2019, the American Pain Society in collaboration with the U.S. Food and Drug Administration developed a new diagnostic system using two dimensions. The first dimension included core diagnostic criteria and the second included common features. In accordance to the 2016 diagnosis guidelines, the presence of another medical condition or pain disorder does not rule out the diagnosis of fibromyalgia. Nonetheless, other conditions should be ruled out as the main explaining reason for the patients symptoms. The core diagnostic criteria are:
Multisite pain defined as six or more pain sites from a total of nine possible sites, for at least three months
Moderate to severe sleep problems or fatigue, for at least three monthsCommon features found in fibromyalgia patients can assist the diagnosis process. These are tenderness (sensitivity to light pressure), dyscognition (difficulty to think), musculoskeletal stiffness, and environmental sensitivity or hypervigilance.

Self-report questionnaires
Some research has suggested using a multidimensional approach taking into consideration somatic symptoms, psychological factors, psychosocial stressors and subjective belief regarding fibromyalgia. These symptoms can be assessed by several self-report questionnaires.

Widespread Pain Index (WPI)
The Widespread Pain Index (WPI) measures the number of painful body regions.

Symptom Severity Scale (SSS)
The Symptom Severity Scale (SSS) assesses the severity of the fibromyalgia symptoms.

Fibromyalgia Impact Questionnaire (FIQ)
The Fibromyalgia Impact Questionnaire (FIQ) and the Revised Fibromyalgia Impact Questionnaire (FIQR) assess three domains: function, overall impact and symptoms. It is considered a useful measure of disease impact.

Other questionnaires
Other measures include the Hospital Anxiety and Depression Scale, Multiple Ability Self-Report Questionnaire, Multidimensional Fatigue Inventory, and Medical Outcomes Study Sleep Scale.

Differential diagnosis
As of 2009, as many as two out of every three people who are told that they have fibromyalgia by a rheumatologist may have some other medical condition instead. Fibromyalgia could be misdiagnosed in cases of early undiagnosed rheumatic diseases such as preclinical rheumatoid arthritis, early stages of inflammatory spondyloarthritis, polymyalgia rheumatica, myofascial pain syndromes and hypermobility syndrome. Neurological diseases with an important pain component include multiple sclerosis, Parkinsons disease and peripheral neuropathy. Other medical illnesses that should be ruled out are endocrine disease or metabolic disorder (hypothyroidism, hyperparathyroidism, acromegaly, vitamin D deficiency), gastro-intestinal disease (celiac and non-celiac gluten sensitivity), infectious diseases (Lyme disease, hepatitis C and immunodeficiency disease) and the early stages of a malignancy such as multiple myeloma, metastatic cancer and leukemia/lymphoma. Other systemic, inflammatory, endocrine, rheumatic, infectious, and neurologic disorders may cause fibromyalgia-like symptoms, such as systemic lupus erythematosus, Sjögren syndrome, ankylosing spondylitis, Ehlers-Danlos syndromes, psoriatic-related polyenthesitis, a nerve compression syndrome (such as carpal tunnel syndrome), and myasthenia gravis. In addition, several medications can also evoke pain (statins, aromatose inhibitors, biophosphonates, and opioids).The differential diagnosis is made during the evaluation on the basis of the persons medical history, physical examination, and laboratory investigations. The patients history can provide some hints to a fibromyalgia diagnosis. A family history of early chronic pain, a childhood history of pain, an emergence of broad pain following physical and/or psychosocial stress, a general hypersensitivity to touch, smell, noise, taste, hypervigilance, and various somatic symptoms (gastrointestinal, urology, gynecology, neurology), are all examples of these signals Extensive laboratory tests are usually unnecessary in the differential diagnosis of fibromyalgia. Common tests that are conducted include complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, C-reactive protein, and thyroid function test.

Management
As with many other medically unexplained syndromes, there is no universally accepted treatment or cure for fibromyalgia, and treatment typically consists of symptom management and improving patient quality of life.  A personalized, multidisciplinary approach to treatment that includes both non-pharmacologic and pharmacologic therapy and begins with effective patient education is most beneficial. Developments in the understanding of the pathophysiology of the disorder have led to improvements in treatment, which include prescription medication, behavioral intervention, and exercise.
A number of associations have published guidelines for the diagnosis and management of fibromyalgia. The European League Against Rheumatism (EULAR; 2017) recommends a multidisciplinary approach, allowing a quick diagnosis and patient education. The recommended initial management should be non-pharmacological, later pharmacological treatment can be added. The European League Against Rheumatism gave the strongest recommendation for aerobic and strengthening exercise. Weak recommendations were given to a number of treatments, based on their outcomes. Qigong, yoga, and tai chi were weakly recommended for improving sleep and quality of life. Mindfulness was weakly recommended for improving pain and quality of life. Acupuncture and hydrotherapy were weakly recommended for improving pain. A weak recommendation was also given to psychotherapy. It was more suitable for patients with mood disorders or unhelpful coping strategies. Chiropractic was strongly recommended against, due to safety concerns. Some medications were weakly recommended for severe pain (duloxetine, pregabalin, tramadol) or sleep disturbance (amitriptyline, cyclobenzaprine, pregabalin). Others were not recommended due to a lack of efficacy (nonsteroidal anti-inflammatory drugs, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors). Growth hormone, sodium oxybate, opioids and steroids were strongly recommended against due to lack of efficacy and side effects.
The guidelines published by the Association of the Scientific Medical Societies in Germany inform patients that self-management strategies are an important component in managing the disease. The Canadian Pain Society also published guidelines for the diagnosis and management of fibromyalgia.

Exercise
Exercise is the only fibromyalgia treatment which has been given a strong recommendation by the European Alliance of Associations for Rheumatology (EULAR). There is strong evidence indicating that exercise improves fitness, sleep and quality of life and may reduce pain and fatigue for people with fibromyalgia. Exercise has an added benefit in that it does not cause any serious adverse effects.Exercise may diminish fibromyalgia symptoms through a number of hypothesized biological mechanisms. Exercise may improve pain modulation through serotoninergic pathways. It may reduce pain by altering the hypothalamic-pituitary-adrenal axis and reducing cortisol levels. It also has anti-inflammatory effects that may improve fibromyalgia symptoms. Aerobic exercise can improve muscle metabolism and pain through mitochondrial pathways.When comparing different exercise programs, aerobic exercise is capable of modulating the autonomic nervous function of fibromyalgia patients, whereas resistance exercise does not show such effects. A 2022 meta-analysis found that aerobic training showed a high effect size while strength interventions showed moderate effects. Meditative exercise seems preferable for improving sleep, with no differences between resistance, flexibility and aquatic exercise in their favorable effects on fatigue.Despite its benefits, exercise is a challenge for patients with fibromyalgia, due to the chronic fatigue and pain they experience. They perceive it as more effortful than healthy adults. Exercise may intimidate them, in fear that they will be asked to do more than they are capable of. They may also feel that those who recommend or deliver exercise interventions do not fully understand the possible negative impact of exercise on fatigue and pain. This is especially true for non-personalized exercise programs. Adherence is higher when the exercise program is recommended by doctors or supervised by nurses. A recommended approach to a graded exercise program begins with small, frequent exercise periods and builds up from there. In order to reduce pain, it is recommended to use an exercise program of 13 to 24 weeks, with each session lasting 30 to 60 minutes.

Aerobic
Aerobic exercise for fibromyalgia patients is the most investigated type of exercise. It includes activities such as walking, jogging, spinning, cycling, dancing and exercising in water. A 2017 cochrane summary concluded that aerobic exercise probably improves quality of life, slightly decreases pain and improves physical function and makes no difference in fatigue and stiffness. A 2019 meta-analysis showed that exercising aerobically can reduce autonomic dysfunction and increase heart rate variability. This happens when patients exercise at least twice a week, for 45–60 minutes at about 60%-80% of the maximum heart rate. Aerobic exercise also decreases anxiety and depression and improves the quality of life.

Flexibility
Combinations of different exercises such as flexibility and aerobic training may improve stiffness. However, the evidence is of low-quality. It is not clear if flexibility training alone compared to aerobic training is effective at reducing symptoms or has any adverse effects.

Resistance
In resistance exercise, participants apply a load to their body using weights, elastic band, body weight or other measures.
Two meta-analyses on fibromyalgia have shown that resistance training can reduce anxiety and depression and one found that it improves quality of life.The dosage of resistance exercise for women with fibromyalgia was studied in a 2022 meta-analysis. Effective dosages were found when exercising twice a week, for at least eight weeks. Symptom improvement was found for even low dosages such as 1–2 sets of 4–20 repetitions. Most studies use moderate exercise intensity of 40% to 85% one-repetition maximum. This level of intensity was effective in reducing pain. Some treatment regimes increase the intensity over time (from 40% to 80%), whereas others increase it when the participant is able to perform 12 repetitions.  High-intensity exercises may cause lower treatment adherence.

Meditative
A 2021 meta-analysis found that meditative exercise programs (tai chi, yoga, qigong) were superior to other forms of exercise (aerobic, flexibility, resistance) in improving sleep quality. Other meta-analyses also found positive effects of tai chi for sleep, fibromyalgia symptoms, and pain, fatigue, depression and quality of life. These tai chi interventions frequently included 1-hour sessions practiced 1-3 times a week for 12 weeks. Meditative exercises, as a whole, may achieve desired outcomes through biological mechanisms such as antioxidation, anti-inflammation, reduction in sympathetic activity and modulation of glucocorticoid receptor sensitivity.

Aquatic
Several reviews and meta-analyses suggest that aquatic training can improve symptoms and wellness in people with fibromyalgia.

Other
Limited evidence suggests vibration training in combination with exercise may improve pain, fatigue, and stiffness.

Medications
A few countries have published guidelines for the management and treatment of fibromyalgia. As of 2018, all of them emphasize that medications are not required, only optional. The German guidelines outlined parameters for drug therapy termination and recommended considering drug holidays after six months.

Approved medications
Health Canada and the US Food and Drug Administration (FDA) have approved pregabalin and duloxetine for the management of fibromyalgia. The FDA also approved milnacipran, but the European Medicines Agency refused marketing authority.

Antidepressants
Antidepressants are one of the common drugs for fibromyalgia. A 2021 meta-analysis concluded that antidepressants can improve the quality of life for fibromyalgia patients in the medium-term. As of 2018, the only tricyclic antidepressant (TCA) that has sufficient evidence is amitriptyline.For most people with fibromyalgia, the potential benefits of treatment with the serotonin and noradrenaline reuptake inhibitors (SNRI) duloxetine and milnacipran and the TCAs, such as amitriptyline, are outweighed by significant adverse effects (more adverse effects than benefits), however, a small number of people may experience relief from symptoms with these medications. In addition, while amitriptyline has been used as a first line treatment, the quality of evidence to support this use and comparison between different medications is poor. Very weak evidence indicates that a very small number of people may benefit from treatment with the tetracyclic antidepressant mirtazapine, however, for most, the potential benefits are not great and the risk of adverse effects and potential harm outweighs any potential for benefit.The length of time that antidepressant medications take to be effective at reducing symptoms can vary. Any potential benefits from the antidepressant amitriptyline may take up to three months to take effect and it may take between three and six months for duloxetine, milnacipran, and pregabalin to be effective at improving symptoms. Some medications have the potential to cause withdrawal symptoms when stopping so gradual discontinuation may be warranted particularly for antidepressants and pregabalin.There is tentative evidence that the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) appear to be similar. SSRIs may be used to treat depression in people diagnosed with fibromyalgia.Tentative evidence suggests that monoamine oxidase inhibitors (MAOIs) such as pirlindole and moclobemide are moderately effective for reducing pain. Very low-quality evidence suggests pirlindole as more effective at treating pain than moclobemide. Side effects of MAOIs may include nausea and vomiting.

Central nervous system depressants
Central nervous system depressants include drug categories such as sedatives, tranquilizers, and hypnotics. A 2021 meta-analysis concluded that such drugs can improve the quality of life for fibromyalgia patients in the medium-term.

Anti-seizure medication
The anti-convulsant medications gabapentin and pregabalin may be used to reduce pain. There is tentative evidence that gabapentin may be of benefit for pain in about 18% of people with fibromyalgia. It is not possible to predict who will benefit, and a short trial may be recommended to test the effectiveness of this type of medication. Approximately 6/10 people who take gabapentin to treat pain related to fibromyalgia experience unpleasant side effects such as dizziness, abnormal walking, or swelling from fluid accumulation. Pregabalin demonstrates a benefit in about 9% of people. Pregabalin reduced time off work by 0.2 days per week.

Cannabinoids
Cannabinoids may have some benefits for people with fibromyalgia. However, as of 2022, the data on the topic is still limited. Cannabinoids may also have adverse effects and may negatively interact with common rheumatological drugs.

Opioids
The use of opioids is controversial. As of 2015, no opioid is approved for use in this condition by the FDA. A 2016 Cochrane review concluded that there is no good evidence to support or refute the suggestion that oxycodone, alone or in combination with naloxone, reduces pain in fibromyalgia. The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) in 2014 stated that there was a lack of evidence for opioids for most people. The Association of the Scientific Medical Societies in Germany in 2012 made no recommendation either for or against the use of weak opioids because of the limited amount of scientific research addressing their use in the treatment of FM. They strongly advise against using strong opioids. The Canadian Pain Society in 2012 said that opioids, starting with a weak opioid like tramadol, can be tried but only for people with moderate to severe pain that is not well-controlled by non-opioid painkillers. They discourage the use of strong opioids and only recommend using them while they continue to provide improved pain and functioning. Healthcare providers should monitor people on opioids for ongoing effectiveness, side effects, and possible unwanted drug behaviors.A 2015 review found fair evidence to support tramadol use if other medications do not work. A 2018 review found little evidence to support the combination of paracetamol (acetaminophen) and tramadol over a single medication. Goldenberg et al suggest that tramadol works via its serotonin and norepinephrine reuptake inhibition, rather than via its action as a weak opioid receptor agonist.A large study of US people with fibromyalgia found that between 2005 and 2007 37.4% were prescribed short-acting opioids and 8.3% were prescribed long-acting opioids, with around 10% of those prescribed short-acting opioids using tramadol; and a 2011 Canadian study of 457 people with FM found 32% used opioids and two-thirds of those used strong opioids.

Topical treatment
Capsaicin has been suggested as a topical pain reliever. Preliminary results suggest that it may improve sleep quality and fatigue, but there are not enough studies to support this claim.

Unapproved or unfounded
Sodium oxybate increases growth hormone production levels through increased slow-wave sleep patterns. However, this medication was not approved by the FDA for the indication for use in people with fibromyalgia due to the concern for abuse.The muscle relaxants cyclobenzaprine, carisoprodol with acetaminophen and caffeine, and tizanidine are sometimes used to treat fibromyalgia; however, as of 2015 they are not approved for this use in the United States. The use of NSAIDs is not recommended as first line therapy. Moreover, NSAIDs cannot be considered as useful in the management of fibromyalgia.Very low-quality evidence suggests quetiapine may be effective in fibromyalgia.No high-quality evidence exists that suggests synthetic THC (nabilone) helps with fibromyalgia.

Others
A 2013 review found moderate-level evidence on the usage of acupuncture with electrical stimulation for improvement of the overall well-being. Acupuncture alone will not have the same effects, but will enhance the influence of exercise and medication in pain and stiffness.

Nutrition and dietary supplements
Nutrition is related to fibromyalgia in several ways. Some nutritional risk factors for fibromyalgia complications are obesity, nutritional deficiencies, food allergies and consuming food additives. The consumption of fruits and vegetables, low-processed foods, high-quality proteins, and healthy fats may have some benefits. Low-quality evidence found some benefits of a vegetarian or vegan diet.Although dietary supplements have been widely investigated in relation to fibromyalgia, most of the evidence, as of 2021, is of poor quality. It is therefore difficult to reach conclusive recommendations. It appears that Q10 coenzyme and vitamin D supplements can improve pain and quality of life for fibromyalgia patients. Q10 coenzyme has beneficial effects on fatigue in fibromyalgia patients, with most studies using doses of 300 mg per day for three months. Q10 coenzyme is hypothesized to improve mitochondrial activity and decrease inflammation. Vitamin D has been shown to improve some fibromyalgia measures, but not others.A review article including four studies with 98 patients found that melatonin treatment has several positive effects on fibromyalgia patients, including the improvement of sleep quality, pain, and disease impact. No major adverse events were reported.

Psychotherapy
Due to the uncertainty about the pathogenesis of FM, current treatment approaches focus on management of symptoms to improve quality of life, using integrated pharmacological and non-pharmacological approaches. There is no single intervention shown to be effective for all patients. In a 2020 Cochrane review cognitive behavioral therapy (CBT) was found to have a small but beneficial effect for reducing pain and distress but adverse events were not well evaluated. CBT and related psychological and behavioural therapies have a small to moderate effect in reducing symptoms of fibromyalgia. Effect sizes tend to be small when CBT is used as a stand-alone treatment for FM patients, but these improve significantly when CBT is part of a wider multidisciplinary treatment program.A 2010 systematic review of 14 studies reported that CBT improves self-efficacy or coping with pain and reduces the number of physician visits at post-treatment, but has no significant effect on pain, fatigue, sleep, or health-related quality of life at post-treatment or follow-up. Depressed mood was also improved but this could not be distinguished from some risks of bias. A 2022 meta-analysis found that CBT reduces insomnia in people with chronic pain, including people with fibromyalgia. Sleep hygiene interventions, however, were not as effective.

Patient education
Patient education is recommended by the European League Against Rheumatism (EULAR) as an important treatment component. As of 2022, there is only low-quality evidence showing that patient education can decrease pain and fibromyalgia impact.Sleep hygiene interventions show low effectiveness in improving insomnia.

Manual therapy
A 2021 meta-analysis concluded that massage and myofascial release diminish pain in the medium-term. As of 2015, there was no good evidence for the benefit of other mind-body therapies.

Transcutaneous electrical nerve stimulation (TENS)
Transcutaneous electrical nerve stimulation (TENS) is the delivery of pulsed electrical currents to the skin to stimulate peripheral nerves. TENS is widely used to treat pain and is considered to be a low-cost, safe, and self-administered treatment. As such, it is commonly recommended by clinicians to people suffering from pain. On 2019, an overview of eight Cochrane reviews was conducted, covering 51 TENS-related randomized controlled trials. The review concluded that the quality of the available evidence was insufficient to make any recommendations. A later review concluded that transcutaneous electrical nerve stimulation may diminish pain in the short-term, but there was uncertainty about the relevance of the results.Preliminary findings suggest that electrically stimulating the vagus nerve through an implanted device can potentially reduce fibromyalgia symptoms. However, there may be adverse reactions to the procedure.

Noninvasive brain stimulation
Noninvasive brain stimulation includes methods such as transcranial direct current stimulation and high-frequency repetitive transcranial magnetic stimulation (TMS). Both methods have been found to improve pain scores in neuropathic pain and fibromyalgia.A 2021 meta-analysis of multiple intervention types concluded that magnetic field therapy and transcranial magnetic stimulation may diminish pain in the short-term, but conveyed an uncertainty about the relevance of the result. Several 2022 meta-analyses focusing on transcranial magnetic stimulation found positive effects on fibromyalgia.  Repetitive transcranial magnetic stimulation improved pain in the short-term and quality of life after 5–12 weeks. Repetitive transcranial magnetic stimulation did not improve anxiety, depression, and fatigue. Transcranial magnetic stimulation to the left dorsolateral prefrontal cortex was also ineffective.

Hyperbaric oxygen therapy
Hyperbaric oxygen therapy (HBOT) has shown beneficial effects in treating chronic pain. However, treating fibromyalgia with hyperbaric oxygen therapy is still controversial, in light of the scarcity of large-scale clinical trials. In addition, hyperbaric oxygen therapy raises safety concerns due to the oxidative damage that may follow it.

Prognosis
Although in itself fibromyalgia is neither degenerative nor fatal, the chronic pain of fibromyalgia is pervasive and persistent. Most people with fibromyalgia report that their symptoms do not improve over time. However, most patients learn to adapt to the symptoms over time. The German guidelines for patients explain that:

The symptoms of fibromyalgia are persistent in nearly all patients.
Total relief of symptoms is seldom achieved.
The symptoms do not lead to disablement and do not shorten life expectancy.An 11-year follow-up study on 1,555 patients found that most remained with high levels of self-reported symptoms and distress. However, there was a great deal of patient heterogeneity accounting for almost half of the variance. At the final observation, 10% of the patients showed substantial improvement with minimal symptoms. An additional 15% had moderate improvement. This state, though, may be transient, given the fluctuations in symptom severity.A study of 97 adolescents diagnosed with fibromyalgia followed them for eight years. After eight years, the majority of youth still experienced pain and disability in physical, social, and psychological areas. At the last follow-up, all participants reported experiencing one or more fibromyalgia symptoms such pain, fatigue, and/or sleep problems, with 58% matching the complete ACR 2010 criteria for fibromyalgia. Based on the  WPI and SS score cut-points, the remaining 42% exhibited subclinical symptoms. Pain and emotional symptom trajectories, on the other hand, displayed a variety of longitudinal patterns. The study concluded that while most patients fibromyalgia symptoms endure, the severity of their pain tends to reduce over time.Baseline depressive symptoms in adolescents appear to predict worse pain at follow-up periods.

Epidemiology
Fibromyalgia is estimated to affect 2–4% of the population.Females are affected about twice as often as males based on criteria as of 2014.

History
Chronic widespread pain had already been described in the literature in the 19th century but the term fibromyalgia was not used until 1976 when Dr P.K. Hench used it to describe these symptoms. Many names, including "muscular rheumatism", "fibrositis", "psychogenic rheumatism", and "neurasthenia" were applied historically to symptoms resembling those of fibromyalgia. The term fibromyalgia was coined by researcher Mohammed Yunus as a synonym for fibrositis and was first used in a scientific publication in 1981. Fibromyalgia is from the Latin fibra (fiber) and the Greek words myo (muscle) and algos (pain).Historical perspectives on the development of the fibromyalgia concept note the "central importance" of a 1977 paper by Smythe and Moldofsky on fibrositis. The first clinical, controlled study of the characteristics of fibromyalgia syndrome was published in 1981, providing support for symptom associations. In 1984, an interconnection between fibromyalgia syndrome and other similar conditions was proposed, and in 1986, trials of the first proposed medications for fibromyalgia were published.A 1987 article in the Journal of the American Medical Association used the term "fibromyalgia syndrome" while saying it was a "controversial condition". The American College of Rheumatology (ACR) published its first classification criteria for fibromyalgia in 1990 </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 Persistent thyroglossal duct and can you explain it in depth? [/INST] A persistent thyroglossal duct is a usually benign medical condition in which the thyroglossal duct, a structure usually only found during embryonic development, fails to atrophy. The duct persists as a midline structure forming an open connection between the back of the tongue and the thyroid gland. This opening can lead to fluid accumulation and infection, which necessitate the removal of the duct.

Signs and symptoms
Studies done on cadavers claim persistent thyroglossal ducts can be completely asymptomatic and found in 7% of the human adult population. However, the continued presence of the duct can often lead to complications due to infections and fluid buildup. The glands in the mucosa of the duct will continue their secretions until the fluid forms a cyst or exit the duct via the opening in the foramen cecum. Local infections, such as colds, tonsillitis, or inflammation of the lymph nodes in the area can also lead to the accumulation of fluid within the duct. Even if the cyst forms as secondary to another infection and improved after antibiotics, it will often reoccur and require treatment.

Three-fourths of abnormalities within a persistent thyroglossal duct involve the formation of a cyst. If a persistent thyroglossal duct becomes fluid filled it will form a thyroglossal duct cyst, which accounts for 70% of congenital neck masses and is the most likely diagnosis if the mass is along the midline of the neck. These cysts are often diagnosed in children under the age of ten and have no particular gender prevalence. The cysts are normally asymptomatic at this age and are noticed because of the swelling that will move if the patient swallows. Over 80% of these cysts are located at or below the hyoid bone.Very rarely, the persistent duct can become cancerous, called thyroglossal duct carcinoma. In the case of thyroglossal duct carcinoma, the cancerous cells are ectopic thyroid tissue that has been deposited along the thyroglossal duct and will present as a papillary carcinoma. However, the cells are less likely to metastasize in the cyst, than if they were present in the actual thyroid gland.The other fourth of abnormalities presents as draining abscess. This is from an infection that will rupture through the skin to allow for adequate drainage of the infected area.

Anatomy
The tongue develops after the thyroid primordium so the foramen cecum becomes buried at the base of the tongue. The thyroglossal duct then continues through the neck and lies anterior to the laryngeal cartilage. The duct then passes anteriorly to the developing hyoid bone; however, as the bone continues to grow it can continue to grow posteriorly, become anterior, or even grow to surround the duct. The duct is found very close to the medial line of the neck. The duct continues in front of the thyrohyoid membrane, sternothyroid muscle, and sternohyoid muscle, before terminating in the inferior segment of the neck at the thyroid.Failures of duct removal surgeries have proven that the suprahyoid region of the duct can have many microscopic branches that connect to the base of the tongue. They exhibit variability between different cases; however, it is believed they are associated with the pharyngeal mucosa and muscles of the tongue.

Embryological origin
During the third week of development, the thyroid gland begins to develop from the floor of the pharynx. This primordium begins as an evagination between the first and second pharyngeal grooves, relatively where the anterior two-thirds of the tongue ends. This area is known as the foramen cecum and marks the origin of the thyroglossal duct. As the developing thyroid begins to travel to its intended destination, it remains connected to the tongue via the thyroglossal duct. By the seventh week of fetal development, the thyroid reaches its final position in the neck after growing through the mesoderm and musculature of the tongue, mouth, and neck. During the eighth to tenth week, the cells of the duct normally begin growing inwards and fill the previously hollow tube, beginning from the inferior end. This inferior end of the duct will then become the pyramidal lobe of the thyroid gland </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 Mycobacterium avium-intracellulare infection and can you explain it in depth? [/INST] Mycobacterium avium-intracellulare infection (MAI) is an atypical mycobacterial infection, i.e. one with nontuberculous mycobacteria or NTM, caused by Mycobacterium avium complex (MAC), which is made of two Mycobacterium species, M. avium and M. intracellulare. This infection causes respiratory illness in birds, pigs, and humans, especially in immunocompromised people. In the later stages of AIDS, it can be very severe. It usually first presents as a persistent cough. It is typically treated with a series of three antibiotics for a period of at least six months.
M. avium, M. intracellulare, and M. chimaera are each saprotrophic organisms present in soil and water; entry into hosts is usually via the gastrointestinal tract, but also can be via the lungs.
MAC infections can cause fevers, diarrhea, malabsorption, as well as loss of appetite and weight loss, and can disseminate to the bone marrow. MAI is typically resistant to standard mycobacterial therapies.

Signs and symptoms
Pulmonary involvement symptoms are similar to tuberculosis (TB), and include fever, fatigue, weight loss, and coughing up blood. Diarrhea and abdominal pain are associated with gastrointestinal involvement.

Children
M. avium and M. haemophilum infections in children form a distinct clinical entity, not associated with abnormalities of the immune system. M. avium typically causes unilateral swelling of one of the lymph nodes of the neck. This node is firm at the beginning, but a collar-stud abscess is formed eventually, which is a characteristic blue-purple in colour with multiple discharging sinuses. The treatment of choice is surgical excision of the affected lymph nodes, with antibiotic treatment (usually clarithromycin and rifabutin for 18 to 24 months) reserved for those patients who cannot have surgery.

Cause
MAC bacteria are common in the environment and cause infection when inhaled or swallowed. Recently, M. avium has been found to deposit and grow in bathroom shower heads from which it may be easily aerosolized and inhaled.

Bacteria
Mycobacterium avium complex (MAC), also called Mycobacterium avium-intracellulare complex, is a microbial complex of three Mycobacterium species (i.e. M. avium, M. intracellulare, and M. chimaera). It causes Mycobacterium avium-intracellulare infection. Some sources also include Mycobacterium avium subspecies paratuberculosis (MAP).

Risk factors
MAI is common in immunocompromised individuals, including senior citizens and those with HIV/AIDS or cystic fibrosis. Bronchiectasis, the bronchial condition which causes pathological enlargement of the bronchial tubes, is commonly found with MAI infection. Whether the bronchiectasis leads to the MAC infection or is the result of it is not always known.The Mycobacterium avium complex (MAC) includes common atypical bacteria, i.e. nontuberculous mycobacteria (NTM), found in the environment which can infect people with HIV and low CD4 cell count (below 100/microliter); mode of infection is usually inhalation or ingestion.MAC causes disseminated disease in up to 40% of people with HIV in the United States, producing fever, sweats, weight loss, and anemia. Disseminated MAC (DMAC) characteristically affects people with advanced HIV disease and peripheral CD4 cell counts less than 50 cells/uL. Effective prevention and therapy of MAC has the potential to contribute substantially to improved quality of life and duration of survival for HIV-infected persons.

Pathophysiology
MAC is the most commonly found form of NTM.Immunodeficiency is not a requirement for MAI.MAC usually affects patients with abnormal lungs or bronchi. However, Jerome Reich and Richard Johnson describe a series of six patients with MAC infection of the right middle lobe or lingula who did not have any predisposing lung disorders.The right middle lobe and lingula of the lungs are served by bronchi that are oriented downward when a person is in the upright position. As a result, these areas of the lung may be more dependent upon vigorous voluntary expectoration (cough) for clearance of bacteria and secretions.Since the six patients in their retrospective case series were older females, Reich and Johnson proposed that patients without a vigorous cough may develop right middle lobe or left lingular infection with MAC. They proposed this syndrome be named Lady Windermere syndrome, after the character Lady Windermere in Oscar Wildes play Lady Windermeres Fan. However, little research has confirmed this speculative cause.

Diagnosis
Diagnosis can be achieved through blood cultures or cultures of other bodily fluids such as sputum. Bone marrow culture can often yield an earlier diagnosis but is usually avoided as an initial diagnostic step because of its invasiveness. Many people will have anemia and neutropenia if the bone marrow is involved. MAC bacteria should always be considered in a person with HIV infection presenting with diarrhea.The diagnosis requires consistent symptoms with two additional signs:
Chest X-ray or CT scan showing evidence of right middle lobe (or left lingular lobe) lung infection
Sputum culture or bronchoalveolar lavage culture demonstrating the infection is caused by MACDisseminated MAC is most readily diagnosed by one positive blood culture. Blood cultures should be performed in patients with symptoms, signs, or laboratory abnormalities compatible with mycobacterium infection. Blood cultures are not routinely recommended for asymptomatic persons, even for those who have CD4+ T-lymphocyte counts less than 100 cells/uL.

HIV infection
MAC in patients with HIV disease is theorized to represent recent acquisition rather than latent infection reactivating (which is the case in many other opportunistic infections in immunocompromised patients).The risk of MAC is inversely related to the patients CD4 count and increases significantly when the CD4 count decreases below 50 cells/mm³. Other risk factors for acquisition of MAC infection include using an indoor swimming pool, consumption of raw or partially cooked fish or shellfish, bronchoscopy and treatment with granulocyte stimulating factor. Disseminated disease was previously the common presentation prior to the advent of highly active antiretroviral therapy (HAART). Today, in regions where HAART is the standard of care, localized disease presentation is more likely. This generally includes a focal lymphadenopathy/lymphadenitis.

Prevention
People with AIDS are given macrolide antibiotics such as azithromycin for prophylactic treatment.People with HIV infection and less than 50 CD4 cells/uL should be administered prophylaxis against MAC. Prophylaxis should be continued for the patients lifetime unless multiple drug therapy for MAC becomes necessary because of the development of MAC disease.Clinicians must weigh the potential benefits of MAC prophylaxis against the potential for toxicities and drug interactions, the cost, the potential to produce resistance in a community with a high rate of tuberculosis, and the possibility that the addition of another drug to the medical regimen may adversely affect patients compliance with treatment. Because of these concerns, therefore, in some situations rifabutin prophylaxis should not be administered.Before prophylaxis is administered, patients should be assessed to ensure that they do not have the active disease due to MAC, M. tuberculosis, or any other mycobacterial species. This assessment may include a chest radiograph and tuberculin skin test.Rifabutin, by mouth daily, is recommended for the peoples lifetime unless disseminated MAC develops, which would then require multiple drug therapy. Although other drugs, such as azithromycin and clarithromycin, have laboratory and clinical activity against MAC, none has been shown in a prospective, controlled trial to be effective and safe for prophylaxis. Thus, in the absence of data, no other regimen can be recommended at this time. The 300-mg dose of rifabutin has been well tolerated. Adverse effects included neutropenia, thrombocytopenia, rash, and gastrointestinal disturbances.

Treatment
Postinfection treatment involves a combination of antituberculosis antibiotics, including rifampicin, rifabutin, ciprofloxacin, amikacin, ethambutol, streptomycin, clarithromycin or azithromycin.NTM infections are usually treated with a three-drug regimen of either clarithromycin or azithromycin, plus rifampicin and ethambutol. Treatment typically lasts at least 12 months.Although studies have not yet identified an optimal regimen or confirmed that any therapeutic regimen produces sustained clinical benefit for patients with disseminated MAC, the Task Force concluded that the available information indicated the need for treatment of disseminated MAC. The Public Health Service, therefore, recommends that regimens be based on the following principles:
Treatment regimens outside a clinical trial should include at least two agents.
Every regimen should contain either azithromycin or clarithromycin; many experts prefer ethambutol as a second drug. Many clinicians have added one or more of the following as second, third, or fourth agents: clofazimine, rifabutin, rifampin, ciprofloxacin, and in some situations amikacin. Isoniazid and pyrazinamide are not effective for the therapy of MAC.
Therapy should continue for the lifetime of the patient if the clinical and microbiologic improvement is observed.Clinical manifestations of disseminated MAC—such as fever, weight loss, and night sweats—should be monitored several times during the initial weeks of therapy. The microbiologic response, as assessed by blood culture every 4 weeks during initial therapy, can also be helpful in interpreting the efficacy of a therapeutic regimen. Most patients who ultimately respond show substantial clinical improvement in the first 4–6 weeks of therapy. Elimination of the organism from blood cultures may take somewhat longer, often requiring 4–12 weeks.

HIV-infected children
HIV-infected children less than 12 years of age also develop disseminated MAC. Some age adjustment is necessary when clinicians interpret CD4+ T-lymphocyte counts in children less than 2 years of age. Diagnosis, therapy, and prophylaxis should follow recommendations similar to those for adolescents and adults.

Society and culture
Terminology
"Lady Windermere syndrome" is one term to describe infection in the lungs due to MAC. It is named after a character in Oscar Wildes 1892 play Lady Windermeres Fan.In recent years, some have described the eponym as inappropriate, and some have noted that it would have been unlikely that Lady Windermere had the condition to which her name was assigned.The more commonly used term is nontuberculous mycobacteria (NTM) infection, or non-tuberculous mycobacterial infection (NMI). There is no evidence that a persons reluctance to spit has any causal role in NTM infection, the chief reason for the term having been applied to older women presenting with the condition.Lady Windermere syndrome is a type of mycobacterial lung infection.

Literary reference
The original Chest article proposing the existence and pathophysiology of the Lady Windermere syndrome suggested the character Lady Windermere in Oscar Wildes Victorian-era play Lady Windermeres Fan is a good example of the fastidious behavior believed to cause the syndrome. The article states:
We offer the term, Lady Windermeres Syndrome, from the Victorian-era play, Lady Windermeres Fan, to convey the fastidious behavior hypothesized: "How do you do, Lord Darlington. No, I cant shake hands with you. My hands are all wet with the roses."Victorian women presumably believed "ladies dont spit," and consequently might have been predisposed to develop lung infection.
Shortly after the Lady Windermere syndrome was proposed, a librarian wrote a letter to the editor of Chest challenging the use of Lady Windermere as the eponymous ancestor of the proposed syndrome.  In the play, Lady Windermere is a vivacious young woman, married only two years, who never coughs or displays any other signs of illness </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 Sucrose intolerance and can you explain it in depth? [/INST] Sucrose intolerance or genetic sucrase-isomaltase deficiency (GSID) is the condition in which sucrase-isomaltase, an enzyme needed for proper metabolism of sucrose (sugar) and starch (e.g., grains), is not produced or the enzyme produced is either partially functional or non-functional in the small intestine. All GSID patients lack fully functional sucrase, while the isomaltase activity can vary from minimal functionality to almost normal activity. The presence of residual isomaltase activity may explain why some GSID patients are better able to tolerate starch in their diet than others with GSID.

Signs and symptoms
Abdominal cramps and bloating
Diarrhea and constipation
Vomiting
Hypoglycemia and headaches
Poor weight gain and growth
Upper respiratory tract and viral diseases
Anxiety and heart palpitations
Excess gas production

Cause
Sucrose intolerance can be caused by genetic mutations in which both parents must contain this gene for the child to carry the disease (so-called primary sucrose intolerance). Sucrose intolerance can also be caused by irritable bowel syndrome, aging, or small intestine disease (secondary sucrose intolerance). There are specific tests used to help determine if a person has sucrose intolerance. The most accurate test is the enzyme activity determination, which is done by biopsying the small intestine. This test is a diagnostic for GSID. Other tests which can aid in the diagnosis of GSID but which are not truly diagnostic for the disease are the sucrose breath test, and a genetic test which tests for the absence of certain genes which are thought to be responsible for GSID.Sucrose (also called saccharose) is a disaccharide and is a two-sugar chain composed of glucose and fructose which are bonded together. A more familiar name is table, beet, or cane sugar. It was believed that most cases of sucrose intolerance were due to an autosomal recessive, genetic, metabolic disease. Based on new data patients with heterozygous and compound heterozygous genotypes can have symptom presentation as well. GSID involves deficiency in the enzyme sucrase-isomaltase, which breaks the bond between the glucose and fructose molecules. When disaccharides are consumed, they must be broken down into monosaccharides by enzymes in the intestines before they can be absorbed. Monosaccharides, or single sugar units, are absorbed directly into the blood.A deficiency of sucrase may result in malabsorption of sugar, which can lead to potentially serious symptoms. Since sucrase-isomaltase is involved in the digestion of starches, some GSID patients may not be able to absorb starches as well. It is important for those with sucrose intolerance to minimize sucrose consumption as much as possible. Dietary supplements or medications may be taken as a substitute for the missing enzyme or to introduce healthy bacteria into the immune system.

Diagnosis
Chronic gastrointestinal symptoms that are fairly common but difficult to diagnose may be caused by congenital sucrase-isomaltase deficiency (CSID). CSID is an inherited condition characterized by a dysfunctional digestive enzyme.The purpose of the digestive enzyme, sucrase-isomaltase, is to break down the compound sugars sucrose (table sugar) and starch sugars so they will be small enough to be absorbed from the gastrointestinal tract.In addition to CSID, a primary gastrointestinal disorder such as a gastrointestinal infection, celiac disease or Crohn’s disease, can transiently suppress the digestive function of sucrase-isomaltase, causing an acquired form of sucrase-isomaltase deficiency (SID). Once the underlying disorder is treated and resolved, the symptoms of SID usually go away.A deficiency or absence of sucrase-isomaltase function is likely to cause chronic gastrointestinal symptoms whenever a person eats food containing sucrose or starch sugars, which are very common in carbohydrates. In fact, the sucrase-isomaltase enzyme is responsible for the digestion of all foods containing sucrose and approximately 60% to 80% of all foods containing starch sugars. When sucrose or starch sugars are not absorbed from the gastrointestinal tract, they travel to the large intestine (colon) where two things happen:
The food draws in excess water by a process called osmosis, creating watery diarrhea.
The food is broken down by the normal bacteria that reside in the colon by a process called fermentation; byproducts of all fermentation include the production of excess gas and an acidic environment.The timing of gastrointestinal symptoms associated with CSID is distinctive. CSID symptoms are frequent, daily events; they are lifelong, and they are postprandial (occurring after eating food). These symptoms can range from mild to severe and include chronic, watery, acidic diarrhea; intestinal gas and bloating; nausea; and abdominal pain.Infants may not show symptoms of CSID until they begin to eat sucrose- and starch-containing foods such as juices, solid foods, and medications sweetened with sucrose. Chronic, watery diarrhea and failure to thrive are the most common symptoms in infants and toddlers. Other symptoms include abdominal distention, gassiness, colic, irritability, excoriated buttocks, severe diaper rash due to acidic diarrhea, indigestion, and vomiting.Adults with CSID are usually lean, with a low body-mass index and an aversion to eating carbohydrates and “sweets.” Because CSID is an inherited condition, patients with CSID often have close relatives who also experience chronic diarrhea.
Determining the cause of chronic gastrointestinal symptoms may take a long time because the symptoms can be common to many gastrointestinal conditions. One diagnostic method, considered the gold standard for diagnosing CSID, measures the level of activity of four intestinal enzymes that digest compound sugars, also called disaccharides. The four disaccharides digested in the small intestine are lactose, sucrose, maltose, and isomaltose.This diagnostic method, called a disaccharidase assay, is conducted on tissue samples taken from the small intestine during an endoscopic procedure, also called an upper GI (gastrointestinal) examination. If the level of sucrase activity is below the level considered necessary for normal sucrase function, the patient will be diagnosed with CSID.Noninvasive diagnostic methods include two breath tests, which can be useful screening tools but are not specific enough for a confirmed diagnosis of CSID.The first of these is the hydrogen/methane breath test, which measures the amount of hydrogen and methane gases a person exhales after consuming sugary water. The exhaled breath is collected in sealed test tubes at 30-minute intervals over a three-hour period after drinking the sugary water. If a person has CSID and there are little or no working sucrase-isomaltase enzymes in the intestines, greater than normal levels of hydrogen and/or methane are generated and exhaled in the breath. However, there may be other reasons why the person is exhaling excess hydrogen and/or methane gas, such as an overgrowth of bacteria in the small intestine, called small intestinal bacterial overgrowth (SIBO).The second breath test is called the carbon-13 (13C) breath test. Carbon-13 is a stable isotope of carbon that occurs naturally in sucrose, making it possible to track a person’s ability to digest and absorb sucrose by measuring the amount of 13CO2 exhaled after drinking a sugar-water solution. In this breath test, the exhaled breath is collected in sealed test tubes at 30-minute intervals over a 90-minute period after drinking the sugar-water solution. If the cumulative amount of 13CO2 exhaled is below the normal level that occurs when sucrose is digested by sucrase, the person may have CSID and the person should undergo further examination by their doctor.The findings from a 13C-breath test are believed to be more definitive for CSID than the hydrogen/methane breath test although neither test is validated to provide, by themselves, a diagnosis for CSID. In both breath tests, the consumption of sugar may cause severe gastrointestinal symptoms in those who have CSID. For this reason, these breath tests should be conducted under the supervision of a healthcare professional.
A relatively new, noninvasive test that shows promise is a genetic test for the gene SI, which codes for the enzyme sucrase-isomaltase. This test requires a swab of tissue from the inside of the cheek. So far, 37 aberrant variations of the SI gene have been found in patients who have been diagnosed with CSID.A positive genetic test for one or more of the 37 SI gene variations known to cause CSID can help confirm a diagnosis of CSID. However, a negative genetic test cannot rule out a diagnosis of CSID. There are more than 2,000 different variations of the SI gene, and many of these variations have not yet been investigated for their ability to cause CSID.  Therefore, a negative genetic test only means that the person does not carry one of the 37 SI gene variations that are known to be associated with CSID, but they may have an SI gene variation that has not yet been identified as one that can cause CSID.
While the breath tests and genetic test have not been validated to be diagnostic for CSID, they may become important tests that help in identifying patients with CSID. As with all diagnoses, a diagnosis of CSID depends on combining a doctor’s clinical findings with results from objective tests </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 Pachydermodactyly 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 Schneckenbecken dysplasia 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 Pneumocephalus 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 Acute megakaryoblastic leukemia and can you explain it in depth? [/INST] Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.AMKL is commonly regarded as a subtype of acute myeloid leukemia (AML). More formally, it is classified under the AML-M7 category of the French-American-British classification and by the World Health Organization of 2016 in the AML-Not Otherwise Specified subcategory.Acute megakaryoblastic leukemia falls into three distinct groups which differ in underlying causes, ages of presentation, responses to therapy, and prognoses. These groups are: AMKL occurring in young children with Down syndrome, i.e. DS-AMKL; AMKL occurring in children who do not have Down syndrome, i.e. non-DS-AMKL (also termed pediatric acute megakaryoblastic leukemia or pediatric AMKL); and AMKL occurring in non-DS adults, i.e. adult-AMKL. AMKL, while rare, is the most common form of AML in DS-AMKL, occurring ~500-fold more commonly in Down syndrome children than in children without Down syndrome; non-DS-AMKL and adult-AMLK are rare, accounting for <1% of all individuals diagnosed as in the AML-M7 category of leukemia.

DS-AMKL
Pathophysiology
Individuals with Down syndrome almost always have three instead of the normal two copies of chromosome 21. The extra copies of key chromosome 21 genes underlie their increased susceptibility to AMKL by promoting the development of a certain type of inactivating mutation in the GATA1 gene. The GATA1 gene resides on the X chromosome and codes for two transcription factors, GATA1 and a shorter version, GATA1-S. GATA1 and GATA1-S contribute to regulating the expression of genes that control the maturation of megakaryoblasts to promegakaryocytes, megakaryocytes, and platelets as well as the maturation of erythroblasts to red blood cells. GATA1-S appears less active than GATA1 in controlling some of the genes that promote megakaryoblast maturation but more active than GATA1 in stimulating megakaryoblast proliferation. Various GATA1 mutations that cause this gene to make GATA1-S but unable to make GATA1 result in the excessive proliferation of platelet precursor cells, reductions in the levels of circulating blood platelets, mild reductions in the levels of circulating red blood cells, and the development of transient myeloproliferative disease (TMD). TMD is a disorder involving the excessive proliferation of non-malignant megakaryoblasts and descendent cells due to the cited truncating mutations in the GATA1 gene. TMD is a necessary predecessor to DS-AMKL.Down syndrome fetuses and neonates with one of the cited types of GATA1 truncating mutations are in rare cases asymptomatic (i.e. silent TMD) but more commonly exhibit in utero or during the first months of live accumulations of immature megakaryoblasts in, and sometimes life-threatening injury to, the fetal blood-forming organ, the liver, and other tissues. While fatal in up to 20% of cases, ~80 of infants with TMD fully recover from the diseases within 4 months. However, ~10% of individuals with a history of symptomatic or silent TMD develop DS-AMKL within 4 years. During this interval, these individuals may acquire somatic mutations in those of their megakaryoblasts that bear the original truncating GATA1 mutation. These newly acquired mutations appear to result from the interactions of GATAT1 truncating mutations with excessive copies of chromosome 21 genes. The genes with these mutations include TP53, FLT3, ERG, DYRK1A, CHAF1B, HLCS, RUNX1, MIR125B2 (which is the gene for microRNA MiR125B2CTCF, STAG2, RAD21, SMC3, SMC1A, NIPBL, SUZ12, PRC2, JAK1, JAK2, JAK3, MPL, KRAS, NRAS, and SH2B3. At least one but probably several of these mutations, whether occurring in individuals with silent or symptomatic TMD, are presumed responsible for or to contribute to the development of DS-AMKL.Rare cases of transient myeloproliferative disease and DS-AMKL occur in individuals who do not have Down syndrome. These individuals usually have a history of TMD and invariably have megakaryoblasts which bear extra copies of key chromosome 21 genes, truncating mutations in GATA1, and somatic mutations in one or more of the genes listed in the previous section. These individuals have extra copies of only a portion of the genes on chromosome 21. This duplication of only some chromosome 21 genes results from: a) Robertsonian translocations, wherein part of chromosome 21 is duplicated on another chromosome; b) partial trisomy 21, wherein only part of chromosome 21 is duplicated); c) an isochromosome, wherein chromosome 21 contains two long but no short arms); or d) duplications, wherein extra chromosome 21 genes are on this or other chromosomes. AMKL occurring in these individuals is classified as DS-AMKL.

Presentation
DS-AMKL most often presents in children 1–2 years old but almost always less than 4 years old who have a history of TMD. Given this history, these children are usually followed-up medically with complete blood count tests. and therefore often present with elevated blood levels of abnormally appearing platelets and platelet precursor cells, particularly megakaryoblasts, and reduced blood levels of red blood cells. DS-AMKL usually progresses slowly with affected children gradually developing increasingly more severe changes in their blood counts as well as slowly developing symptoms of these developments such as fatigue and shortness of breath due to anemia. In cases of advanced disease, individuals with DS-AMKL may present with signs and symptoms that are more typical of acute myeloid leukemic diseases such as liver enlargement, spleen enlargement, leukemia cutis (i.e. skin nodules caused by leukemic infiltrates), or leukostasis (i.e. an emergency situation in which excessive elevations in circulating blast (i.e. early precursor) cells plug the microcirculation to cause life-threatening heart, lung, and neurological dysfunctions).

Diagnosis
The diagnosis of DS-AMKL in young children is indicated by: a history of TMD; findings of increased presence of blast cells (e.g. ≥20% of nucleated cells) that have the megakaryoblast phenotype in blood and/or bone marrow as defined by the morphology of these cells in blood or bone marrow smears; failure to obtain a bone marrow aspirate because of marrow fibrosis; and immunophenotyping analyses of platelet precursor cells lineage as determined by flow cytometry and immunohistochemistry.  Malignant megakaryoblasts are usually medium-sized to large cells with a high nuclear-cytoplasmic ratio. Nuclear chromatin is dense and homogeneous. There is scanty, variable basophilic cytoplasm which may be excessively vacuolated. An irregular cytoplasmic border is often noted in some of the megakaryoblasts and occasionally projections resembling budding atypical platelets are present. Megakaryoblasts lack myeloperoxidase (MPO) activity and stain negatively with Sudan Black B. They are alpha naphthyl butyrate esterase negative and manifest variable alpha naphthyl acetate esterase activity usually in scattered clumps or granules in the cytoplasm. PAS diastase staining varies from negative to focal or granular positivity to strongly positive. Immunochemical analyses, often conducted by flow cytometry, of the surface antigens on leukemic blast cells are positive for CD41, CD42b, CD51, and Von Willebrand factor in AMKL but not leukemia involving non-platelet malignant cells.Where indicated and available, the diagnosis of DS-AMKL is further supported by; immunophenotyping analysis using monoclonal antibody directed against megakaryocyte restricted antigen (CD41 and CD61) and DNA sequencing to detect GATA1  mutations that are projected to cause the gene to make GATA1-S but not GATA1 transcription factors.

Treatment
The chemotherapy regimens used for all types of AMKL are similar to those used for AML. A final confirmation of safety and efficacy phase 3 study consisted of 4 cycles of induction therapy with cytarabine and daunorubicin followed by a single course of intensification therapy consisting of cytarabine and L-asparaginase, and concluded with a central nervous system consolidation course of 3 additional doses of intrathecal cytarabine. The dosages of cytarabine in this study were kept low because DS-AMKL patients proved highly susceptible to the toxic effects of the regimen which used a higher cytarabine dosage to treat AML. The low-dose cytarabine regimen achieved excellent results in DS-AMKL with relatively reduced overall toxicity and is currently recommended as a preferred treatment regimen for the disease.Autologous hematopoietic stem cell transplantation (i.e. transplantation of stem cells derived from the individual being transplanted) did not improve relapse-free survival in one large study of DS-AMKL. Allogenic hematopoietic stem cell transplantation (i.e. transplantation of stem cells derived another individual) has given better disease-free survival results than autologous transplantation and, based on recent uncontrolled studies, should be considered in DS-AMKL cases that have relapsed after their first chemotherapy-induced complete remission.

Prognosis
The 5-year event free survival, disease-free survival, and overall survival rate in the phase 3 clinical study in DS-AMKL were 79, 89, 84 percent, respectively. Other studies that use a treatment regimen similar to that used in the phase 3 clinical study report overall survival rates of ~80% and long-term survivals of 74-91%. However, DS-AMKL patients who relapse following chemotherapy have a far poorer outlook with 3 year overall survival rate in one study of only 26%. There also appears to be little role for stem cell transplantation in DS-AMKL given the success of initial chemotherapy and the relatively poor results in DS-AMKL patients given this transplantation.

Non-DS-AMKL
Pathophysiology
The most common genetic abnormality occurring in non-Down-AMKL is a nonreciprocal translocation between the short or p arm at position 13 on chromosome 1 (i.e. 1p13) and the p arm at position 13 on chromosome 22 (i.e. 22p13). Nonreciprocal translocations are exchanges of genes between two chromosomes that are not homologs, i.e. that are not maternal and paternal copies of the same chromosome. This particular translocation, designated t(1;22)(p13;q13), occurs mainly in infants but also is seen in children up to the age of 7 years with non-DS-AMKL. This translocation involves the RBM15 gene on chromosome 1 and the MKL1 gene (also termed MRTFA) on chromosome 22 to create a RBM15-MKL1 fusion gene. Studies in mice indicate that the Mkl1 gene (only the first letter of a mouse gene is capitalized)  product, MKL1, interacts with the transcription factor SRF to stimulate the expression of various genes. MKLl is required for the maturation of mouse megakaryoblasts: in its absence, megakaryoblasts and promegakaryocytes proliferate abnormally while megakaryocytes are few in number and have an abnormal morphology. Mouse studies also indicate that the product of Rbm15, RMB15, interacts with Nuclear receptor co-repressor 1, Nuclear receptor co-repressor 2 (also termed SMRT), and RBPJ nuclear proteins to suppress the expression of various genes that are involved in the maturation of platelet, myeloid and lymphocyte precursor cells. In consequence, the RBM15-MKL1 fusion protein acts in an unregulated fashion to suppress MKL1 targeted genes while  stimulating RPBJ target genes. This causes an over-active Notch signaling pathway and, among other abnormalities, expansion of fetal hematopoiesis and development of AMKL in a small percentage of adult mice. It is assumed that these events must be accompanied by other, as yet undefined, oncogenic (i.e., cancer causing) events to explain the development of human non-Down AMKL. A large number of other genetic abnormalities are associated with the development of non-DS-AMLK. These include complex chromosomal rearrangements and increases in copy number of various genes. Besides the t(1;22)(p13;q13) translocation, common genetic abnormalities in a study of 372 individuals diagnosed with non-DS-AMKL include: rearrangements of genes at position 23 on the long (i.e. q) arm of chromosome 11; inversion of chromosome 16 occurring between p13.3 and q24.3 denoted as inv(16)(p13.3q24.3) that results in the production of a CBFA2T3-GLIS2 fusion protein; and increases in chromosome numbers from a normal of 46 to anywhere from 47 to >50. The relationships of these and the many other genetic abnormalities detected in non-Down-AMKL to the diseases development require further investigations.

Presentation
Non-DS-AMKL occurs in neonates, infants, and children of all ages. Except for the lack of Down syndrome, no history of TMD, and occurrences in children that can be >4 years of age, individuals with non-DS-AMKL present with many of the symptoms, signs, and hematological findings seen in DS-AMKL. However, non-DS-AMKL is a more aggressive and rapidly progressing disorder than DS-AMKL. Nonetheless, the presentation of non-DS-AMKL is also like DS-AMKL in that it is not often accompanied by one or more extramedullary signs or symptoms of the disease such as liver enlargement, spleen enlargement, leukemia cutis, and leukostasis.

Diagnosis
The diagnosis of non-DS-AMKL is made in children who do not have Down syndrome but exhibit the same clinical symptoms, signs, hematological abnormalities, and specialized laboratory findings seen in DS-AMKL. These children should bear one or more of the genetic aberrations associated with the disease but not the inactivating GATA1 mutations, extra copies of chromosome 21 genes, or other genetic abnormalities associated with DS-AMKL. Non-DS-AMKL has many clinical and laboratory features similar to and must be distinguished from Acute panmyelosis with myelofibrosis, a disorder characterized by bone marrow fibrosis, abnormal megakaryocytes, macrocytic erythropoiesis, defects in neutrophil production, reduced blood levels of most circulating cells (i.e. pancytopenia), and low levels of circulating blast cells. Analyses of circulating and bone marrow blast cells for features of AMKL (see Diagnosis section of DS-AMKL) and genetic aberrations is helpful in distinguishing the two diseases.

Treatment
In a review of 153 patients treated for non-DS-AMKL between 1990 and 2014 with various intensive chemotherapy protocols that included cytarabine, an anthracycline (e.g. daunorubicin, doxorubicin), and in 25% of cases human stem cell transplantation, the probability of overall 4 year survival rate, probability of 4 year event-free survival, and probability of 4 year cumulative relapse rate were 56, 51, and 29%, respectively. A more recent treatment regimen that is similar to that used to treat DS-AMKL as described above (except it employs the high dose of cytarabine used to treat AML) gives better results and has been recommended for non-DS-AMKL. The response to this regimen approached that seen in non-DS-AMKL, i.e. its complete remission and estimated 10 year survival rates were both 76%. Similar to DS-AMKL treatment regimens, allogenic rather than autologous stem cell bone marrow transplantation should be considered in non-DS-AMKL cases that have relapsed following their first chemotherapy-induced complete remission. Further studies may indicate that this recent cancer chemotherapy regimen plus allogenic bone marrow transplantation in cases which relapse after the first remission are the preferred treatment for non-DS-AMKL.

Prognosis
In a review of 153 patients treated for non-DS-AMKL between 1990 and 2014 with various intensive chemotherapy protocols that included cytarabine, an anthracycline (e.g. daunorubicin, doxorubicin), and in 25% of cases human stem cell transplantation, the probability of overall 4 year survival rate, probability of 4 year event-free survival, and probability of 4 year cumulative relapse rate were 56, 51, and 29%, respectively. Patients with non-DS-AMKL given the treatment regimen described for DS-AMKL above had a much better prognosis than patients treated with earlier-devised treatment regimens: their overall survival rate using these regimen was estimated to be 76%.

Adult-AMKL
Pathophysiology
Adult-AMKL can result from the progression of other myeloproliferative neoplasms (MPN) viz., chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, and primary myelofibrosis. In one review of adult-AMKL, 25% of 49 cases were considered as secondary to one of these MPN. The mechanism behind these cases of secondary AMKL are unknown although an inversion in chromosome 3 at positions q21 and q26, i.e. inv(3)(q21q26), is often seen in these secondary cases of adult-AMKL.Rare cases of adult-AMKL also have mediastinal germ cell tumors. These tumors are malignancies of germ cells, i.e. primitive cells that give rise to sperm and ovum cells. In adult-AMKL, mediastinal germ cell tumors that are associated with adult-AMKL are not seminomas (i.e. do not originate from the sperm cell line) and occur before or concomitantly with but not after the diagnosis AMKL is made. The three most common genetic aberrations in the bone marrow cells of these individuals (representing ~65% of all cases) were inversions in the p arm of chromosome 12, trisomy 8, and an extra X chromosome. In several of these cases, the genetic aberrations in the malignant platelet precursor cells were similar to those in the malignant mediastinal germ cells. These results and those of other analyses suggest that the two malignancies derive from a common founding clone of cells (i.e. a set of genetically identical cells).Overall, the most common genetic aberrations occurring in adult-AMKL are the previously described inv((3)(q21q26) inversion, translocation between the q arm of chromosome 9 at position 34 and the q arm of chromosome 22 at position 11, i.e. (t(9:22)(q34:q11), and various aberrations in chromosome 5 or chromosome 7. Aberrations in the latter two chromosomes are also commonly seen in an AML that is associated with myelodydplastic-related changes (i.e. predominance of immature blood cells in the bone marrow). The underlying malignancy-causing mechanism, if any, behind these genetic aberrations requires further study.

Presentation
Adult-AMKL may occur in individuals who have a prior diagnosis of and/or present with chronic myelogenous leukemia, polycythemia vera, essential thrombocytosis, primary myelofibrosis, or mediastinal germ cell tumor. AMKL associated with mediastinal germ cell tumors typically occurs in younger adults, i.e. ages 13–36 (average age 24). Cases occurring in children aged ≤18 years, which represent ~20% of all cases, could be regarded in the non-DS-AMKL category </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 Paruresis and can you explain it in depth? [/INST] Paruresis, also known as shy bladder syndrome, is a type of phobia in which a person is unable to urinate in the real or imaginary presence of others, such as in a public restroom. The analogous condition that affects bowel movement is called parcopresis or shy bowel.

Signs and symptoms
Some people have brief, isolated episodes of urinary difficulty in situations where other people are in close proximity.  Paruresis, however, goes beyond simple shyness, embarrassment, fear of exposure, or fear of being judged for not being able to urinate. Other people may find that they are unable to urinate while in moving vehicles, or are fixated on the sounds of their urination in quiet restrooms or residential settings. In severe cases, a person with paruresis can urinate only when alone at home or through the process of catheterization.

Causes
A possible cause of paruresis is undergoing a voiding cystourethrography (VCUG) in the past. "Complications that can occur in both sexes include UTI, hematuria, cystitis as well as urinary dysfunction following a catheterization, phobia of urination, nocturia, and stopping urination. In the literature, psychological trauma resulting from VCUG was considered the same as from a violent rape, especially in girls."

Pathophysiology
It appears that paruresis involves a tightening of the sphincter or bladder neck due to a sympathetic nervous system response. The adrenaline rush that produces the involuntary nervous system response probably has peripheral and central nervous system involvement. The internal urethral sphincter (smooth muscle tissue) or the external urethral sphincter (striated muscle), levator ani (especially the pubococcygeus) muscle area, or some combination of the above, may be involved. It is possible that there is an inhibition of the detrusor command through a reflex pathway as well. The pontine micturition center (Barringtons nucleus) also may be involved, as its inhibition results in relaxation of the detrusor and prevents the relaxation of the internal sphincter.

Diagnosis
The condition is catered for in the rules for mandatory urine testing for drugs in UK prisons, and UK Incapacity Benefit tribunals also recognise it.  It is listed in the NHS on-line encyclopaedia of conditions and disorders. It is now reported to have been accepted as a valid reason for jury service excusal. From 1 August 2005, the guidance on the rules relating to the testing of those on probation in the UK cites paruresis as a valid reason for inability to produce a sample which is not to be construed as a refusal.The condition is recognised by the American Urological Association, who include it in their on-line directory of conditions.Paruresis was described in section 300.23 of the DSM-IV-TR as "performance fears . . . using a public restroom" but it was not mentioned by name. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) mentions paruresis by name.Kaplan & Sadocks Synopsis of Psychiatry states, "Persons with social phobias (also called social anxiety disorder) have excessive fears of humiliation or embarrassment in various social settings, such as in speaking in public, urinating in a public rest room (also called shy bladder), and speaking to a date." The Synopsis describes shy bladder as "inability to void in a public bathroom" and notes that relaxation exercises are an application of behavior therapy for dealing with this disorder. Some paruretics experience delayed urination and must wait for their need to void to overcome their anxiety, while others are unable to urinate at all.

Treatment
In terms of treating the mental aspect of paruresis, such treatment can be achieved by graduated exposure therapy and cognitive behavioral therapy. In graduated exposure therapy, the subject has a trusted person stand outside the restroom at first, and once the fear is overcome the observer is brought closer in, until step by step the phobia is vanquished. The International Paruresis Association provides a detailed discussion of this method on its website.
In addition to gradual exposure therapy, cognitive behavioral therapy is used to change a patients mental approach to the condition, from one of a person who cannot urinate, to a person who can urinate or is not overly fearful when they cant publicly urinate.

History
The term paruresis was coined by Williams and Degenhart (1954) in their paper "Paruresis: a survey of a disorder of micturition" in the Journal of General Psychology 51:19-29. They surveyed 1,419 college students and found 14.4% had experienced paruresis, either incidentally or continuously.

Other names
Paruresis is also known by many colloquial terms, including bashful bladder, bashful kidneys, stage fright, pee-shyness, and shy bladder syndrome.

Society and culture
Drug testing
Some drug testing authorities find paruresis a nuisance, and some implement "shy bladder procedures" which pay no more than lip service to the condition, and where there is no evidence that they have conducted any real research into the matter. In the U.S. Bureau of Prisons, the Code of Federal Regulations provides that "An inmate is presumed to be unwilling if the inmate fails to provide a urine sample within the allotted time period </s>