<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 Cutaneous larva migrans and can you explain it in depth? [/INST] Cutaneous larva migrans (abbreviated CLM) is a skin disease in humans, caused by the larvae of various nematode parasites of the hookworm family (Ancylostomatidae). These parasites live in the intestines of dogs, cats, and wild animals and should not be confused with other members of the hookworm family for which humans are definitive hosts, namely Ancylostoma duodenale and Necator americanus.
Colloquially called creeping eruption due to its presentation, the disease is also somewhat ambiguously known as "ground itch" or (in some parts of the southern United States) "sandworms", as the larvae like to live in sandy soil. Another vernacular name is plumbers itch. The medical term CLM literally means "wandering larvae in the skin".

Symptoms and signs
The infection causes a red, intensely pruritic (itchy) eruption, and may look like twirling lesions. The itching can become very painful and if scratched may allow a secondary bacterial infection to develop. Cutaneous larva migrans usually heals spontaneously over weeks to months and has been known to last as long as one year. However, the severity of the symptoms usually causes those infected to seek medical treatment before spontaneous resolution occurs </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 Hypertensive emergency and can you explain it in depth? [/INST] A hypertensive emergency is very high blood pressure with potentially life-threatening symptoms and signs of acute damage to one or more organ systems (especially brain, eyes, heart, aorta, or kidneys). It is different from a hypertensive urgency by this additional evidence for impending irreversible hypertension-mediated organ damage (HMOD). Blood pressure is often above 200/120 mmHg, however there are no universally accepted cutoff values. Signs of organ damage will be discussed below.

Signs and symptoms
Symptoms may include headache, nausea, or vomiting. Chest pain may occur due to increased workload on the heart resulting in inadequate delivery of oxygen to meet the heart muscles metabolic needs. The kidneys may be affected, resulting in blood or protein in the urine, and acute kidney failure. People can have decreased urine production, fluid retention, and confusion.Other signs and symptoms can include:
Chest pain
Abnormal heart rhythms
Headache
Nosebleeds that are difficult to stop
Dyspnea
Fainting or the sensation of the world spinning around them (vertigo)
Severe anxiety
Agitation
Altered mental status
Abnormal sensationsThe most common presentations of hypertensive emergencies are cerebral infarction (24.5%), pulmonary edema (22.5%), hypertensive encephalopathy (16.3%), and congestive heart failure (12%). Less common presentations include intracranial bleeding, aortic dissection, and  pre-eclampsia or eclampsia.Massive, rapid elevations in blood pressure can trigger any of these symptoms, and warrant further work-up by physicians. Physical exam would include measurement of blood pressure in both arms. Laboratory tests to be conducted include urine toxicology, blood glucose, a basic metabolic panel evaluating kidney function, or a complete metabolic panel evaluating liver function, EKG, chest x-rays, and pregnancy screening.The eyes may show bleeding in the retina, an exudate, cotton-wool spots, scattered splinter hemorrhages, or swelling of the optic disc called papilledema.

Causes
Many factors and causes are contributory in hypertensive crises. The most common cause is patients with diagnosed, chronic hypertension who have discontinued anti hypertensive medications.Other common causes of hypertensive crises are autonomic hyperactivity such as pheochromocytoma, collagen-vascular diseases, drug use particularly stimulants, cocaine and amphetamines and their substituted analogues, monoamine oxidase inhibitors or food-drug interactions, spinal cord disorders, glomerulonephritis, head trauma, neoplasias, preeclampsia and eclampsia, hyperthyroidism and renovascular hypertension. People withdrawing from medications such as clonidine or beta-blockers have been frequently found to develop hypertensive crises. It is important to note that these conditions exist outside of hypertensive emergency, in that patients diagnosed with these conditions are at increased risk of hypertensive emergencies or end organ failure.

Pathophysiology
The pathophysiology of hypertensive emergency is not well understood. Failure of normal autoregulation and an abrupt rise in systemic vascular resistance are typical initial components of the disease process.Hypertensive emergency pathophysiology includes:
Abrupt increase in systemic vascular resistance, likely related to humoral vasoconstrictors
Endothelial injury and dysfunction
Fibrinoid necrosis of the arterioles
Deposition of platelets and fibrin
Breakdown of normal autoregulatory functionThe resulting ischemia prompts further release of vasoactive substances including prostaglandins, free radicals, and thrombotic/mitotic growth factors, completing a vicious cycle of inflammatory changes. If the process is not stopped, homeostatic failure begins, leading to loss of cerebral and local autoregulation, organ system ischemia and dysfunction, and myocardial infarction. Single-organ involvement is found in approximately 83% of hypertensive emergency patients, two-organ involvement in about 14% of patients, and multi-organ failure (failure of at least 3 organ systems) in about 3% of patients.In the brain, hypertensive encephalopathy - characterized by hypertension, altered mental status, and swelling of the optic disc - is a manifestation of the dysfunction of cerebral autoregulation. Cerebral autoregulation is the ability of the blood vessels in the brain to maintain a constant blood flow. People with chronic hypertension can tolerate higher arterial pressure before their autoregulation system is disrupted. Hypertensives also have an increased cerebrovascular resistance which puts them at greater risk of developing cerebral ischemia if the blood flow decreases into a normotensive range. On the other hand, sudden or rapid rises in blood pressure may cause hyperperfusion and increased cerebral blood flow, causing increased intracranial pressure and cerebral edema, with increased risk of intracranial bleeding.In the heart, increased arterial stiffness, increased systolic blood pressure, and widened pulse pressures, all resulting from chronic hypertension, can cause significant damage. Coronary perfusion pressures are decreased by these factors, which also increase myocardial oxygen consumption, possibly leading to left ventricular hypertrophy. As the left ventricle becomes unable to compensate for an acute rise in systemic vascular resistance, left ventricular failure and pulmonary edema or myocardial ischemia may occur.In the kidneys, chronic hypertension has a great impact on the kidney vasculature, leading to pathologic changes in the small arteries of the kidney. Affected arteries develop endothelial dysfunction and impairment of normal vasodilation, which alter kidney autoregulation. When the kidneys autoregulatory system is disrupted, the intraglomerular pressure starts to vary directly with the systemic arterial pressure, thus offering no protection to the kidney during blood pressure fluctuations.  The renin-aldosterone-angiotensin system can be activated, leading to further vasoconstriction and damage. During a hypertensive crisis, this can lead to acute kidney ischemia, with hypoperfusion, involvement of other organs, and subsequent dysfunction. After an acute event, this endothelial dysfunction has persisted for years.

Diagnosis
The term hypertensive emergency is primarily used as a specific term for a hypertensive crisis with a diastolic blood pressure greater than or equal to 120 mmHg or systolic blood pressure greater than or equal to 180 mmHg. Hypertensive emergency differs from hypertensive urgency in that, in the former, there is evidence of acute organ damage. Both of these definitions had collectively been known as malignant hypertension, although this medical term is replaced.In the pregnant patient, the definition of hypertensive emergency (likely secondary to pre-eclampsia or eclampsia) is only a blood pressure exceeding 160 mmHg systolic blood pressure or 110 mmHg diastolic blood pressure.

Treatment
In a hypertensive emergency, treatment should first be to stabilize the patients airway, breathing, and circulation per ACLS guidelines. Patients should have their blood pressure slowly lowered over a period of minutes to hours with an antihypertensive agent. Documented goals for blood pressure include a reduction in the mean arterial pressure by less than or equal to 25% within the first 8 hours of emergency. If blood pressure is lowered aggressively, patients are at increased risk of complications including stroke, blindness, or kidney failure. Several classes of anti hypertensive agents are recommended, with the choice depending on the cause of the hypertensive crisis, the severity of the elevation in blood pressure, and the patients baseline blood pressure prior to a hypertensive emergency. Physicians will attempt to identify a cause of the patients hypertension, including chest radiograph, serum laboratory studies evaluating kidney function, urinalysis, as that will alter the treatment approach for a more patient-directed regimen.Hypertensive emergencies differ from hypertensive urgency in that they are treated parenterally, whereas in urgency it is recommended to use oral anti hypertensives to reduce the risk of hypotensive complications or ischemia. Parenteral agents are classified into beta-blockers, calcium channel blockers, systemic vasodilators, or other (fenoldopam, phentolamine, clonidine). Medications include labetalol, nicardipine, hydralazine, sodium nitroprusside, esmolol, nifedipine, minoxidil, isradipine, clonidine, and chlorpromazine. These medications work through a variety of mechanisms. Labetalol is a beta-blocker with mild alpha antagonism, decreasing the ability of catecholamine activity to increase systemic vascular resistance, while also decreasing heart rate and myocardial oxygen demand. Nicardipine, Nifedipine, and Isradipine are calcium channel blockers that work to decrease systemic vascular resistance and subsequently lower blood pressure. Hydralazine and Sodium nitroprusside are systemic vasodilators, thereby reducing afterload, however can be found to have reflex tachycardia, making them likely second or third line choices. Sodium nitroprusside was previously the first-line choice due to its rapid onset, although now it is less commonly used due to side effects, drastic drops in blood pressure, and cyanide toxicity. Sodium nitroprusside is also contraindicated in patients with myocardial infarction, due to coronary steal. It is again important that the blood pressure is lowered slowly. The initial goal in hypertensive emergencies is to reduce the pressure by no more than 25% the mean arterial pressure. Excessive reduction in blood pressure can precipitate coronary, cerebral, or kidney ischemia and, possibly, infarction.A hypertensive emergency is not based solely on an absolute level of blood pressure, but also on a patients baseline blood pressure before the hypertensive crisis occurs. Individuals with a history of chronic hypertension may not tolerate a "normal" blood pressure, and can therefore present symptomatically with hypotension, including fatigue, light-headedness, nausea, vomiting, or syncope.

Prognosis
Severe hypertension is a serious and potentially life-threatening medical condition. It is estimated that people who do not receive appropriate treatment only live an average of about three years after the event.The morbidity and mortality of hypertensive emergencies depend on the extent of end-organ dysfunction at the time of presentation and the degree to which blood pressure is controlled afterward. With good blood pressure control and medication compliance, the 5-year survival rate of patients with hypertensive crises approaches 55%.The risks of developing a life-threatening disease affecting the heart or brain increase as the blood flow increases. Commonly, ischemic heart attack and stroke are the causes that lead to death in patients with severe hypertension. It is estimated that for every 20 mm Hg systolic or 10 mm Hg diastolic increase in blood pressures above 115/75 mm Hg, the mortality rate for both ischemic heart disease and stroke doubles.Consequences of hypertensive emergency result after prolonged elevations in blood pressure and associated end-organ dysfunction </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 Overlap syndrome 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 Fifth disease and can you explain it in depth? [/INST] Erythema infectiosum, fifth disease, or slapped cheek syndrome is one of several possible manifestations of infection by parvovirus B19. Fifth disease typically presents as a rash and is more common in children. While parvovirus B19 can affect humans of all ages, only two out of ten individuals will present with physical symptoms.The name "fifth disease" comes from its place on the standard list of rash-causing childhood diseases, which also includes measles (first), scarlet fever (second), rubella (third), Dukes disease (fourth, but is no longer widely accepted as distinct from scarlet fever), and roseola (sixth). Treatment is mostly supportive.

Signs and symptoms
Fifth disease starts with a low-grade fever, headache, rash, and cold-like symptoms, such as a runny or stuffy nose.  These symptoms pass, then a few days later, the rash appears. The bright red rash most commonly appears in the face, particularly the cheeks. This is a defining symptom of the infection in children (hence the name "slapped cheek disease"). Occasionally, the rash will extend over the bridge of the nose or around the mouth. In addition to red cheeks, children often develop a red, lacy rash on the rest of the body, with the upper arms, torso, and legs being the most common locations. The rash typically lasts a few days and may itch; some cases have been known to last for several weeks. Patients are usually no longer infectious once the rash has appeared.Teenagers and adults may present with a self-limited arthritis. It manifests in painful swelling of the joints that feels similar to arthritis. Older children and adults with fifth disease may have difficulty in walking and in bending joints such as wrists, knees, ankles, fingers, and shoulders.The disease is usually mild, but in certain risk groups and rare circumstances, it can have serious consequences:

In pregnant women, infection in the first trimester has been linked to hydrops fetalis, causing spontaneous miscarriage.
In people with sickle-cell disease or other forms of chronic hemolytic anemia such as hereditary spherocytosis, infection can precipitate an aplastic crisis.
Those who are immunocompromised (HIV/AIDS, chemotherapy) may be at risk for complications if exposed.
In less than 5% of women with parvovirus B19 infection, a baby may develop severe anemia leading to miscarriage. This occurs most often during the first half of pregnancy.

Causes
Fifth disease, also known as erythema infectiosum, is caused by parvovirus B19, which only infects humans. Infection by parvovirus B19 can lead to multiple clinical manifestations, but the most common is fifth disease.Parvovirus B19 (B19V) is a small, single-stranded, non-enveloped DNA virus. Binding of B19V capsid to the cellular receptor globoside (Gb4Cer) results in a cascade of structural changes and subsequent signal transduction processes facilitating the entry of parvovirus B19 into the host cell. After gaining access to the host cell, BV19 binds to glycosphingolipid globoside (blood group P antigen) targeting erythroid lineage in the bone marrow. Replication of viral genome and release of virus from infected cells lead to various complex effects on hosts cellular environment such as induction of DNA damage, hijack of cell cycle and apoptosis (killing of infected cells).B19V DNA has been found in a wide range of tissues in healthy and diseased individuals indicates the persistence of B19V infection. According to a clinical microbiology review published by Jianming Qiu "Persistence of viral DNA has been detected in up to 50% of biopsy specimens of the spleen, lymph nodes, tonsils, liver, heart, synovial tissues, skin, brain, and testes, for decades after infection."Recovery from parvovirus B19 infection is achieved by production of IgM antibodies which are specific for virus and are generated 10–12 days after infection. After day 16, when signs of fifth disease (red rashes) and arthralgia (pain in joints) becomes apparent, specific anti B19 IgG is produced by immune cells. Production of serum anti B19 IgG keeps infection under control and facilitates the recovery of erythroid cell production in erythroid lineage cells that were targeted by parvovirus B19.

Diagnosis
The "slapped cheek" appearance of the rash can be suggestive of fifth disease, however, the rash can be mistaken with other skin related disease or infections. Blood samples testing can be definitive in confirming diagnosis. Anti-parvovirus B19 IgM antibody serum assay is the preferred method to detect previous infection. An antibody assay uses antibodies designed to detect parvovirus antigen or protein in blood circulation. The assay can result positive one week after initial infection. Negative results may prompt retesting in the future to rule out early sampling of blood serum.  A positive result can also be indicative of an infection within the past two to six months. People acquire lifetime immunity if IgG antibodies are produced in response to parvovirus B19 exposure. Infection by parvovirus B19 can also be confirmed by isolation of viral DNA detected by PCR or direct hybridization. PCR Is considered significantly more sensitive to detecting viral antigen compared direct DNA hybridization. DNA hybridization assay can better detect variants of the parvovirus B19. There exists 3 biological similar genotypes of parvovirus B19, numbered one through three. The most common genotype circulating is genotype one. Laboratory tests can indicate complications of infection, including anemia, liver damage, and low platelet count.

Transmission
Fifth disease is transmitted primarily by respiratory secretions (saliva, mucus, etc.), but can also be spread by contact with infected blood. The incubation period (the time between the initial infection and the onset of symptoms) is usually between 4 and 21 days. Individuals with fifth disease are most infectious before the onset of symptoms. Typically, school children, day-care workers, teachers, and parents are most likely to be exposed to the virus. When symptoms are evident, the risk of transmission is small; therefore, symptomatic individuals do not need to be isolated. Vertical transmission from maternal infection may also occur, which can lead to hydrops fetalis due to the infections detrimental effects on red blood cell production.

Treatment
Treatment is supportive, as the infection is frequently self-limiting. No specific therapy is recommended. Antipyretics are commonly used to reduce fevers. In cases of arthropathy, such as those with arthritis or arthralgia, non-steroidal anti-inflammatories (NSAIDs) or other ant-inflammatories can be used. The rash usually does not itch, but can be mildly painful. The rash itself is not considered contagious. The infection generally lasts about 5 to 10 days. Stress, hot temperatures, exercise, and exposure to sunlight can contribute to reoccurrence within months of the initial infection. Upon resolution, immunity is considered life-long. Populations at greater risk of complications (see below) may need referral to a specialist. Anemia is a more severe complication that could result from parvovirus B19 infection and requires a blood transfusion as part of therapy.

Epidemiology
Fifth Disease is a viral illness caused by Parvovirus B19. The illness is very common and self-limiting. The modes of transmission include respiratory droplets, blood, or mother to fetus. Fifth Disease is most prevalent in children aged 5 to 15 years old. Fifth disease occurs at lower rates in adults. The virus spreads easily and once contracted, the body will begin developing lasting immunity to reinfection. The prevalence of antibodies is 50% in children and 70% to 85% in adults. The virus affects both men and women equally. During the spring and winter, epidemic outbreaks are most likely to occur. In the summer and fall, sporadic cases and outbreaks occur. The outbreaks most commonly occur in daycares and schools. The periodicity of the outbreak cycle is three-to-seven years. The risk of acquiring the viral illness increases when exposed to an infected person or contaminated blood. Individuals who have an occupation that requires close contact with infected people such as healthcare workers and teachers are at an increased risk of acquiring the viral illness. Another risk factor of fifth disease are immunocompromised individuals, those with anemia are at a higher risk of developing complications. Pregnant women are at risk for acquiring viral illness, especially during the first half of pregnancy. Though, complications are very rare and less than 5% of these cases will experience serious complications. The most common complication among pregnant women is anemia. In rare cases, severe anemia can occur, and a buildup of fluid can develop. A buildup of fluid can cause congestive heart failure or death. A blood infusion or induction may be necessary. No vaccine is available for human parvovirus B19, though attempts have been made to develop one.

History
Parvovirus, the virus causing the fifth disease, was first discovered in 1975 by Yvonne Cossart. It,  or a disease presenting similarly, was first described by Robert Willan in his book called On Cutaneous Diseases in 1808 as "rubeola, sine catarrho". It was better defined by Anton Tschamer in 1889 as a rubella variant (Ortliche Rotheln) and described it as abortive rubella, identified as a distinct condition in 1896 by Theodor Escherich, and given the name "erythema infectiosum" in 1899. The term "Fifth disease" was coined in 1905 by the Russian-French physician Léon Cheinisse (1871-1924), who proposed a numbered classification of the six most common childhood exanthems. The virus was first described in 1957 at the University of Pennsylvania  by Werner, Brachman et al.

Vulnerable populations
A 2019 systematic review examined the rates of parvovirus B19 infection among daycare workers. Since transmission typically occurs through respiratory secretions, it was thought that daycare workers would be at an increased risk of infection because young children can spread saliva through drool. The systematic review indicates that daycare workers are at an increased risk for infection. Another review also supports the finding that daycare workers have an increased risk of contracting parvovirus B19 infection. A 2019 meta-analysis examined rates of parvovirus B19 infection among those with Sickle Cell Disease (SCD) using IgG and IgM antibody detection. Pooled data from Africa, Asia, and the Americas revealed a 48.8% parvovirus B19 infection prevalence among persons with SCD. Prevalence of infection was also determined by geographic location, where areas with reduced access to adequate housing had higher prevalence (Africa was 55.5%). A 2020 literature review also supports the finding that persons with SCD, as well as those with the blood disorder beta-thalassemia, are at a higher risk of parvovirus B19 infection.

Complications
There are some known complications associated with Fifth Disease relating to pregnancy. While parvovirus B19 is typically transmitted via respiratory secretions or hand to mouth contact, it has also been known to be passed from pregnant mothers to fetuses. Roughly 50-75% of all pregnant women are immune to parvovirus B19 while the remainder of women are susceptible to mild illness. A majority of fetuses who do contract parvovirus B19 show either no significant symptoms or complete resolution of the virus. However, the following serious complications are rare but possible: miscarriage, stillbirth, fetal anemia, hepatic failure, and abnormal neurodevelopment outcome. In some cases, fetuses would develop hydrops fetalis due to congenital parvovirus B19. This condition was studied as a determinant of later fetal outcomes, such as miscarriage or perinatal death, in 2016 systematic review </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 Marfan syndrome and can you explain it in depth? [/INST] Marfan syndrome (MFS) is a multi-systemic genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have overly-flexible joints and scoliosis. The most serious complications involve the heart and aorta, with an increased risk of mitral valve prolapse and aortic aneurysm. The lungs, eyes, bones, and the covering of the spinal cord are also commonly affected. The severity of the symptoms is variable.MFS is caused by a mutation in FBN1, one of the genes that makes fibrillin, which results in abnormal connective tissue. It is an autosomal dominant disorder. In about 75% of cases, it is inherited from a parent with the condition, while in about 25% it is a new mutation. Diagnosis is often based on the Ghent criteria.There is no known cure for MFS. Many of those with the disorder have a normal life expectancy with proper treatment. Management often includes the use of beta blockers such as propranolol or atenolol or, if they are not tolerated, calcium channel blockers or ACE inhibitors. Surgery may be required to repair the aorta or replace a heart valve. Avoiding strenuous exercise is recommended for those with the condition.About 1 in 5,000 to 1 in 10,000 people have MFS. Rates of the condition are similar  in different regions of the world. It is named after French pediatrician Antoine Marfan, who first described it in 1896.

Signs and symptoms
More than 30 signs and symptoms are variably associated with Marfan syndrome. The most prominent of these affect the skeletal, cardiovascular, and ocular systems, but all fibrous connective tissue throughout the body can be affected.

Skeletal system
Most of the readily visible signs are associated with the skeletal system. Many individuals with Marfan syndrome grow to above-average height, and some have disproportionately long, slender limbs with thin, weak wrists and long fingers and toes.
The Steinberg sign, also known as the thumb sign, is one of the clinical examination tests for Marfan disease in the hands. It is a clinical test in which the tip of the thumb extends beyond the palm when the thumb is clasped in the clenched hand.Besides affecting height and limb proportions, people with Marfan syndrome may have abnormal lateral curvature of the spine scoliosis, thoracic lordosis, abnormal indentation (pectus excavatum) or protrusion (pectus carinatum) of the sternum, abnormal joint flexibility, a high-arched palate with crowded teeth and an overbite, flat feet, hammer toes, stooped shoulders, and unexplained stretch marks on the skin. It can also cause pain in the joints, bones, and muscles. Some people with Marfan have speech disorders resulting from symptomatic high palates and small jaws. Early osteoarthritis may occur. Other signs include limited range of motion in the hips due to the femoral head protruding into abnormally deep hip sockets.

Eyes
In Marfan syndrome, the health of the eye can be affected in many ways, but the principal change is partial lens dislocation, where the lens is shifted out of its normal position. This occurs because of weakness in the ciliary zonules, the connective tissue strands which suspend the lens within the eye. The mutations responsible for Marfan syndrome weaken the zonules and cause them to stretch. The inferior zonules are most frequently stretched resulting in the lens shifting upwards and outwards, but it can shift in other directions as well. Nearsightedness (myopia), and blurred vision are common due to connective tissue defects in the eye. Farsightedness can also result particularly if the lens is highly subluxated. Subluxation (partial dislocation) of the lens can be detected clinically in about 60% of people with Marfan syndrome by the use of a slit-lamp biomicroscope. If the lens subluxation is subtle, then imaging with high-resolution ultrasound biomicroscopy might be used.Other signs and symptoms affecting the eye include increased length along an axis of the globe, myopia, corneal flatness, strabismus, exotropia, and esotropia. Those with MFS are also at a high risk for early glaucoma and early cataracts.

Cardiovascular system
The most serious signs and symptoms associated with Marfan syndrome involve the cardiovascular system: undue fatigue, shortness of breath, heart palpitations, racing heartbeats, or chest pain radiating to the back, shoulder, or arm. Cold arms, hands, and feet can also be linked to MFS because of inadequate circulation. A heart murmur, abnormal reading on an ECG, or symptoms of angina can indicate further investigation. The signs of regurgitation from prolapse of the mitral or aortic valves (which control the flow of blood through the heart) result from cystic medial degeneration of the valves, which is commonly associated with MFS (see mitral valve prolapse, aortic regurgitation). However, the major sign that would lead a doctor to consider an underlying condition is a dilated aorta or an aortic aneurysm. Sometimes, no heart problems are apparent until the weakening of the connective tissue (cystic medial degeneration) in the ascending aorta causes an aortic aneurysm or aortic dissection, a surgical emergency. An aortic dissection is most often fatal and presents with pain radiating down the back, giving a tearing sensation.Because underlying connective tissue abnormalities cause MFS, the incidence of dehiscence of prosthetic mitral valve is increased. Care should be taken to attempt repair of damaged heart valves rather than replacement.

Lungs
Individuals with Marfan Syndrome may be affected by various lung-related problems. One study found that only 37% of the patient sample studied (mean age 32±14 years; M 45%) had normal lung function. Spontaneous pneumothorax is common. In spontaneous unilateral pneumothorax, air escapes from a lung and occupies the pleural space between the chest wall and a lung. The lung becomes partially compressed or collapsed. This can cause pain, shortness of breath, cyanosis, and, if not treated, death. Other possible pulmonary manifestations of MFS include sleep apnea and idiopathic obstructive lung disease. Pathologic changes in the lungs have been described such as cystic changes, emphysema, pneumonia, bronchiectasis, bullae, apical fibrosis and congenital malformations such as middle lobe hypoplasia.

Nervous system
Dural ectasia, the weakening of the connective tissue of the dural sac encasing the spinal cord, can result in a loss of quality of life. It can be present for a long time without producing any noticeable symptoms. Symptoms that can occur are lower back pain, leg pain, abdominal pain, other neurological symptoms in the lower extremities, or headaches – symptoms which usually diminish when lying flat. On X-ray, however, dural ectasia is not often visible in the early stages. A worsening of symptoms might warrant an MRI of the lower spine. Dural ectasia that has progressed to this stage would appear in an MRI as a dilated pouch wearing away at the lumbar vertebrae. Other spinal issues associated with MFS include degenerative disc disease, spinal cysts, and dysfunction of the autonomic nervous system.

Genetics
Each parent with the condition has a 50% risk of passing the genetic defect on to any child due to its autosomal dominant nature. Most individuals with MFS have another affected family member.  About 75% of cases are inherited. On the other hand, about 15–30% of all cases are due to de novo genetic mutations; such spontaneous mutations occur in about one in 20,000 births. Marfan syndrome is also an example of dominant negative mutation and haploinsufficiency. It is associated with variable expressivity; incomplete penetrance has not been definitively documented.

Pathogenesis
Marfan syndrome is caused by mutations in the FBN1 gene on chromosome 15, which encodes fibrillin 1, a glycoprotein component of the extracellular matrix. Fibrillin-1 is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue, but also serves as a reservoir for growth factors. Elastic fibers are found throughout the body, but are particularly abundant in the aorta, ligaments and the ciliary zonules of the eye; consequently, these areas are among the worst affected. It can also be caused by a range of intravenous crystal treatments in those susceptible to the disorder.A transgenic mouse has been created carrying a single copy of a mutant fibrillin-1, a mutation similar to that found in the human gene known to cause MFS. This mouse strain recapitulates many of the features of the human disease and promises to provide insights into the pathogenesis of the disease. Reducing the level of normal fibrillin 1 causes a Marfan-related disease in mice.Transforming growth factor beta (TGF-β) plays an important role in MFS. Fibrillin-1 directly binds a latent form of TGF-β, keeping it sequestered and unable to exert its biological activity. The simplest model suggests reduced levels of fibrillin-1 allow TGF-β levels to rise due to inadequate sequestration. Although how elevated TGF-β levels are responsible for the specific pathology seen with the disease is not proven, an inflammatory reaction releasing proteases that slowly degrade the elastic fibers and other components of the extracellular matrix is known to occur. The importance of the TGF-β pathway was confirmed with the discovery of the similar Loeys–Dietz syndrome involving the TGFβR2 gene on chromosome 3, a receptor protein of TGF-β. Marfan syndrome has often been confused with Loeys–Dietz syndrome, because of the considerable clinical overlap between the two pathologies.

Marfanoid–progeroid–lipodystrophy syndrome
Marfanoid–progeroid–lipodystrophy syndrome (MPL), also referred to as Marfan lipodystrophy syndrome (MFLS), is a variant of MFS in which Marfan symptoms are accompanied by features usually associated with neonatal progeroid syndrome (also referred to as Wiedemann–Rautenstrauch syndrome) in which the levels of white adipose tissue are reduced. Since 2010, evidence has been accumulating that MPL is caused by mutations near the 3-terminus of the FBN1 gene. It has been shown that these people are also deficient in asprosin, a gluco-regulatory protein hormone which is the C-terminal cleavage product of profibrillin. The levels of asprosin seen in these people were lower than expected for a heterozygous genotype, consistent with a dominant negative effect.

Diagnosis
Diagnostic criteria of MFS were agreed upon internationally in 1996. However, Marfan syndrome is often difficult to diagnose in children, as they typically do not show symptoms until reaching pubescence. A diagnosis is based on family history and a combination of major and minor indicators of the disorder, rare in the general population, that occur in one individual – for example: four skeletal signs with one or more signs in another body system such as ocular and cardiovascular in one individual. The following conditions may result from MFS, but may also occur in people without any known underlying disorder.

Revised Ghent nosology
In 2010, the Ghent nosology was revised, and new diagnostic criteria superseded the previous agreement made in 1996. The seven new criteria can lead to a diagnosis:In the absence of a family history of MFS:

Aortic root Z-score ≥ 2 AND ectopia lentis
Aortic root Z-score ≥ 2 AND an FBN1 mutation
Aortic root Z-score ≥ 2 AND a systemic score* > 7 points
Ectopia lentis AND an FBN1 mutation with known aortic pathologyIn the presence of a family history of MFS (as defined above):

Ectopia lentis
Systemic score* ≥ 7
Aortic root Z-score ≥ 2Points for systemic score:
Wrist AND thumb sign = 3 (wrist OR thumb sign = 1)
Pectus carinatum deformity = 2 (pectus excavatum or chest asymmetry = 1)
Hindfoot deformity = 2 (plain pes planus = 1)
Dural ectasia = 2
Protrusio acetabuli = 2
pneumothorax = 2
Reduced upper segment/lower segment ratio AND increased arm/height AND no severe scoliosis = 1
Scoliosis or thoracolumbar kyphosis = 1
Reduced elbow extension = 1
Facial features (3/5) = 1 (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia)
Skin striae (stretch marks) = 1
Myopia > 3 diopters = 1
Mitral valve prolapse = 1The thumb sign (Steinbergs sign) is elicited by asking the person to flex the thumb as far as possible and then close the fingers over it. A positive thumb sign is where the entire distal phalanx is visible beyond the ulnar border of the hand, caused by a combination of hypermobility of the thumb as well as a thumb which is longer than usual.The wrist sign (Walker-Murdoch sign) is elicited by asking the person to curl the thumb and fingers of one hand around the other wrist. A positive wrist sign is where the little finger and the thumb overlap, caused by a combination of thin wrists and long fingers.

Differential diagnosis
Many other disorders can produce the same type of body characteristics as Marfan syndrome. Genetic testing and evaluating other signs and symptoms can help to differentiate these. The following are some of the disorders that can manifest as "marfanoid":
Congenital contractural arachnodactyly, also known as Beals-Hecht syndrome
Ehlers–Danlos syndrome
Homocystinuria
Loeys–Dietz syndrome
MASS phenotype
Multiple endocrine neoplasia, type 2B
Shprintzen–Goldberg syndrome
Stickler syndrome

Management
There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last few decades and is now similar to that of the average person.Regular checkups are recommended to monitor the health of the heart valves and the aorta. Marfan syndrome is treated by addressing each issue as it arises and, in particular, preventive medication even for young children to slow progression of aortic dilation. The goal of this treatment strategy is to slow the progression of aortic dilation and prevent any damage to heart valves by eliminating heart arrythmias, minimizing the heart rate, and lowering the persons blood pressure.

Physical activity
The American Heart Association made the following recommendations for people with Marfan syndrome with no or mild aortic dilation:
Probably permissible activities: bowling, golf, skating (but not ice hockey), snorkeling, brisk walking, treadmill, stationary biking, modest hiking, and tennis (doubles and singles).
Intermediate risk: basketball (both full- and half-court), racquetball, squash, running (sprinting and jogging), skiing (downhill and cross-country), soccer, touch (flag) football, baseball, softball, biking, lap swimming, motorcycling, and horseback riding.
High risk: bodybuilding, weightlifting (non-free and free weights), ice hockey, rock climbing, windsurfing, surfing, and scuba diving.

Medication
Management often includes the use of beta blockers such as propranolol or if not tolerated calcium channel blockers or ACE inhibitors. Beta blockers are used to reduce the stress exerted on the aorta and to decrease aortic dilation.

Surgery
If the dilation of the aorta progresses to a significant-diameter aneurysm, causes a dissection or a rupture, or leads to failure of the aortic or other valve, then surgery (possibly a composite aortic valve graft or valve-sparing aortic root replacement) becomes necessary. Although aortic graft surgery (or any vascular surgery) is a serious undertaking it is generally successful if undertaken on an elective basis. Surgery in the setting of acute aortic dissection or rupture is considerably more problematic. Elective aortic valve/graft surgery is usually considered when aortic root diameter reaches 50 millimeters (2.0 inches), but each case needs to be specifically evaluated by a qualified cardiologist. New valve-sparing surgical techniques are becoming more common. As people with Marfan syndrome live longer, other vascular repairs are becoming more common, e.g., repairs of descending thoracic aortic aneurysms and aneurysms of vessels other than the aorta.The skeletal and ocular manifestations of Marfan syndrome can also be serious, although not life-threatening. These symptoms are usually treated in an appropriate manner for the condition, such as with pain medications or muscle relaxants. Because Marfan syndrome may cause asymptomatic spinal abnormalities, any spinal surgery contemplated on a person Marfan should only follow detailed imaging and careful surgical planning, regardless of the indication for surgery. The ocular complications of MFS can often be treated with surgery. Ectopia lentis can be treated, as artificial lenses can be surgically implanted. In addition, surgery can address glaucoma and cataracts.Treatment of a spontaneous pneumothorax is dependent on the volume of air in the pleural space and the natural progression of the individuals condition. A small pneumothorax might resolve without active treatment in one to two weeks. Recurrent pneumothoraces might require chest surgery. Moderately sized pneumothoraces might need chest drain management for several days in a hospital. Large pneumothoraces are likely to be medical emergencies requiring emergency decompression.As an alternative approach, custom-built supports for the aortic root are also being used. As of 2020 this procedure has been used in over 300 people with the first case occurring in 2004.

Pregnancy
During pregnancy, even in the absence of preconception cardiovascular abnormality, women with Marfan syndrome are at significant risk of aortic dissection, which is often fatal even when rapidly treated. Women with Marfan syndrome, then, should receive a thorough assessment prior to conception, and echocardiography should be performed every six to 10 weeks during pregnancy, to assess the aortic root diameter. For most women, safe vaginal delivery is possible.Prenatal testing can be performed in females with Marfan syndrome to determine if the condition has been inherited in their child. At 10 to 12 weeks of pregnancy, examining a piece of placental tissue through a test called chorionic villus sampling can be performed to make a diagnosis. Another prenatal test can be performed called amniocentesis at 16 to 18 weeks of pregnancy.Marfan syndrome is expressed dominantly. This means a child with one parent a bearer of the gene has a 50% probability of getting the syndrome. In 1996, the first preimplantation genetic testing (PGT) therapy for Marfan was conducted; in essence PGT means conducting a genetic test on early-stage IVF embryo cells and discarding those embryos affected by the Marfan mutation.

Prognosis
Prior to modern cardiovascular surgical techniques and medications such as losartan, and metoprolol, the prognosis of those with Marfan syndrome was not good: a range of untreatable cardiovascular issues was common. Lifespan was reduced by at least a third, and many died in their teens and twenties due to cardiovascular problems. Today, cardiovascular symptoms of Marfan syndrome are still the most significant issues in diagnosis and management of the disease, but adequate prophylactic monitoring and prophylactic therapy offers something approaching a normal lifespan, and more manifestations of the disease are being discovered as more patients live longer. Women with Marfan syndrome live longer than men.

Epidemiology
Marfan syndrome affects males and females equally, and the mutation shows no ethnic or geographical bias. Estimates indicate about 1 in 5,000 to 10,000 individuals have Marfan syndrome.

History
Marfan syndrome is named after Antoine Marfan, the French pediatrician who first described the condition in 1896 after noticing striking features in a five-year-old girl. The gene linked to the disease was first identified by Francesco Ramirez at the Mount Sinai Medical Center in New York City in 1991.

Famous patients
Famous people who have had Marfan syndrome include:

Isaiah Austin
Javier Botet
Austin Carlile
Bradford Cox
Euell Gibbons
Flo Hyman
Jonathan Jeanne
Vincent Schiavelli
Troye Sivan
John TavenerIn addition the following historical figures and celebrities often appear on lists of people with Marfan syndrome, but from case to case the evidence is speculative, questionable, or even refuted.

See also
Ehlers–Danlos syndrome
Kashin–Beck disease
Loeys–Dietz syndrome
Nail-Patella syndrome
Mitral valve prolapse

Bibliography
Lorenz, Megaera. "Lorenz, Maegara "The Mystery of Akhenaton: Genetics or Aesthetics"" </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 Coccydynia and can you explain it in depth? [/INST] Coccydynia is a medical term meaning pain in the coccyx or tailbone area, often brought on by a fall onto the coccyx or by persistent irritation usually from sitting.

Synonyms
Coccydynia is also known as coccygodynia, coccygeal pain, coccyx pain, or coccalgia.

Anatomy
Structure
Coccydynia occurs in the lowest part of the spine, the coccyx, which is believed to be a vestigial tail, or in other words the “tail bone”. The name coccyx is derived from the Greek word for cuckoo due to its beak like appearance. The coccyx itself is made up of 3 to 5 vertebrae, some of which may be fused together. The ventral side of the coccyx is slightly concave whereas the dorsal aspect is slightly convex. Both of these sides have transverse grooves that show where the vestigial coccygeal units had previously fused. The coccyx attaches to the sacrum from the dorsal grooves, with the attachment being either a symphysis or as a true synovial joint, and also to the gluteus maximus muscle, the coccygeal muscle, and the anococcygeal ligament.

Orientations of the coccyx
There are four different orientations for the coccyx, as described by Postacchini and Massobrio. In type I the coccyx is curved anteriorly with its apex facing downward and caudally. In type II this forward curvature is more dramatic and the apex extends forward. Type III is where the coccyx angles forward sharply. Lastly, type IV is characterized by the coccyx being subluxated at the sacrococcygeal joint.

Pathophysiology
There are common pathophysiological ways that a person may develop coccydynia. The two main causes for this condition are sudden impact due to fall, and coccydynia caused by childbirth pressure in women. Other ways that coccydynia develops are partial dislocation of the sacrococcygeal synchondrosis that can possibly result in abnormal movement of the coccyx from excessive sitting, and repetitive trauma of the surrounding ligaments and muscles, resulting in inflammation of tissues and pain.

Diagnosis
A number of different conditions can cause pain in the general area of the coccyx, but not all involve the coccyx and the muscles attached to it. The first task of diagnosis is to determine whether the pain is related to the coccyx. Physical rectal examination, high resolution x-rays and MRI scans can rule out various causes unrelated to the coccyx, such as Tarlov cysts and pain referred from higher up the spine. Note that, contrary to most anatomical textbooks, most coccyxes consist of several segments: fractured coccyx is often diagnosed when the coccyx is in fact normal or just dislocated at an intercoccygeal joint.A simple test to determine whether the coccyx is involved is injection of local anesthetic into the area. If the pain relates to the coccyx, this should produce immediate relief.If the anesthetic test proves positive, then a dynamic (sit/stand) x-ray or MRI scan may show whether the coccyx dislocates when the patient sits.Use of dynamic x-rays on 208 patients who gave positive results with the anesthetic test showed:

31% Not possible to identify the cause of pain
27% Hypermobility (excessive flexing of the coccyx forwards and upwards when sitting)
22% Posterior luxation (partial dislocation of the coccyx backwards when sitting)
14% Spicule (bony spur) on the coccyx
5%  Anterior luxation (partial dislocation of the coccyx forwards when sitting)This study found that the pattern of lesions was different depending on the obesity of the patients: obese patients were most likely to have posterior luxation of the coccyx, while thin patients were most likely to have coccygeal spicules.

Angle of incidence
Sagittal coccygeal movement is measured using the angle of incidence—or the angle at which the coccyx strikes the seat when an individual sits down.  A smaller angle indicates the coccyx being more parallel to the seat, resulting in flexion (or “normal” movement) of the coccyx. A larger angle indicates the coccyx being more perpendicular to the seat, causing posterior subluxation (or “backward” movement) of the coccyx.

Causes
One way of classifying coccydynia is whether the onset was traumatic versus non-traumatic. In many cases the exact cause is unknown and is referred to as idiopathic coccydynia.
Coccydynia is a fairly common injury which can often result from falls, particularly in leisure activities such as cycling and skateboarding.
Coccydynia is often reported following a fall or after childbirth. In some cases, persistent pressure from activities like bicycling may cause the onset of coccyx pain.  Coccydynia due to these causes usually is not permanent, but it may become very persistent and chronic if not controlled. Coccydynia may also be caused by sitting improperly thereby straining the coccyx.
Rarely, coccydynia is due to the undiagnosed presence of a sacrococcygeal teratoma or other tumor in the vicinity of the coccyx.

Prevalence
A study of 2000 cases of back pain referred to hospital found that 2.7% were diagnosed as coccydynia. This type of pain occurs five times more frequently in women than in men. It can occur at any age, the mean age of onset being around 40.  There are no ethnicity or race associations with coccydynia.

Clinical features
Activities that put pressure on the affected area are bicycling, horseback riding, and other activities such as increased sitting that put direct stress on the coccyx. The medical condition is often characterized by pain that worsens with constipation and may be relieved with bowel movement. Rarely, even sexual intercourse can aggravate symptoms.

Non-surgical treatment
Since sitting on the affected area may aggravate the condition, a cushion with a cutout at the back under the coccyx is recommended. If there is tailbone pain with bowel movements, then stool softeners and increased fiber in the diet may help. Anti-inflammatory medications such as NSAIDS may be prescribed.If the pain persists, other treatments may be applied. Manual treatment is carried out by repeated massage of the muscles attached to the coccyx, via the anus. Such treatment is usually given by an intimate partner, chiropractor, osteopath or physical therapist. Thiele applied this treatment to a series of 169 coccydynia patients, and reported 63% cured.Orthopaedic surgeons commonly inject corticosteroids into the painful joint. Maigne and Tamalet applied this treatment to 86 patients under fluoroscopic guidance. Two months after the injection, 50% of the patients with luxation or hypermobility were improved or healed, but only 27% of the patients with no visible abnormality improved. Where an abnormality had been found, and injection relieved the pain, the abnormality remained but ceased to be painful.
Temporary or permanent nerve blocks are sometimes applied in cases of coccydynia. Foye et al reported that repeated temporary nerve blocks by injection at the ganglion impar could give relief in a number of cases, and occasionally a single injection was sufficient.

Surgical treatment
If non-surgical treatments fail to relieve the pain, or in cases of cancer, surgery to remove the coccyx (coccygectomy) may be required. In cases where pain persists after surgery, standard drugs for chronic pain, such as tri-cyclic anti-depressants, may help alleviate the pain.

Prevention or to ease coccyx pain
Body positioning and alignment is significant for producing less stress in the coccyx region. Bad posture can influence coccyx pain. People may not realize that they are over stressing their coccyx while doing daily activities. Pain in the coccyx can be caused from many incidents like falling, horseback riding, or even sitting on hard surfaces for a long period of time. The main focus is to prevent coccyx pain from occurring, by correcting everyday activities that contribute to tailbone pain. You can take hot or cold water baths. Have a stream of hot or cold water run down your back continuously if pain becomes unbearable. Use cold water if pain persists </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 Zika fever and can you explain it in depth? [/INST] Zika fever, also known as Zika virus disease or simply Zika, is an infectious disease caused by the Zika virus. Most cases have no symptoms, but when present they are usually mild and can resemble dengue fever. Symptoms may include fever, red eyes, joint pain, headache, and a maculopapular rash. Symptoms generally last less than seven days. It has not caused any reported deaths during the initial infection. Mother-to-child transmission during pregnancy can cause microcephaly and other brain malformations in some babies. Infections in adults have been linked to Guillain–Barré syndrome (GBS).Zika fever is mainly spread via the bite of mosquitoes of the Aedes type. It can also be sexually transmitted and potentially spread by blood transfusions. Infections in pregnant women can spread to the baby. Diagnosis is by testing the blood, urine, or saliva for the presence of the viruss RNA when the person is sick, or the blood for antibodies after symptoms are present more than a week.Prevention involves decreasing mosquito bites in areas where the disease occurs and proper use of condoms. Efforts to prevent bites include the use of insect repellent, covering much of the body with clothing, mosquito nets, and getting rid of standing water where mosquitoes reproduce. There is no effective vaccine. Health officials recommended that women in areas affected by the 2015–16 Zika outbreak consider putting off pregnancy and that pregnant women not travel to these areas. While there is no specific treatment, paracetamol (acetaminophen) may help with the symptoms. Admission to hospital is rarely necessary.The virus that causes the disease was first isolated in Africa in 1947. The first documented outbreak among people occurred in 2007 in the Federated States of Micronesia. An outbreak started in Brazil in 2015, and spread to the Americas, Pacific, Asia, and Africa. This led the World Health Organization to declare it a Public Health Emergency of International Concern in February 2016. The emergency was lifted in November 2016, but 84 countries still reported cases as of March 2017. The last proven case of Zika spread in the Continental United States was in 2017.

Signs and symptoms
Most people who are infected have no or few symptoms. Otherwise the most common signs and symptoms of Zika fever are fever, rash, conjunctivitis (red eyes), muscle and joint pain, and headache, which are similar to signs and symptoms of dengue and chikungunya fever. The time from a mosquito bite to developing symptoms is not yet known, but is probably a few days to a week. The disease lasts for several days to a week and is usually mild enough that people do not have to go to a hospital.Due to being in the same family as dengue, there has been concern that it could cause similar bleeding disorders. However that has only been documented in one case, with blood seen in semen, also known as hematospermia.

Guillain–Barré syndrome
Zika virus infections have been strongly associated with Guillain–Barré syndrome (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. Though Zika virus has been shown to infect human Schwann cells. Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak.

Pregnancy
The disease spreads from mother to child in the womb and can cause multiple problems, most notably microcephaly, in the baby. The full range of birth defects caused by infection during pregnancy is not known, but they appear to be common, with large scale abnormalities seen in up to 42% of live births. The most common observed associations have been abnormalities with brain and eye development such as microcephaly and chorioretinal scarring. Less commonly there have been systemic abnormalities such as hydrops fetalis, where there is abnormal accumulation of fluid in the fetus. These abnormalities can lead to intellectual problems, seizures, vision problems, hearing problems, problems feeding and slow development.Whether the stage of pregnancy at which the mother becomes infected affects the risk to the fetus is not well understood, nor is whether other risk factors affect outcomes. One group has estimated the risk of a baby developing microcephaly at about 1% when the mother is infected during the first trimester, with the risk of developing microcephaly becoming uncertain beyond the first trimester. Affected babies might appear normal but actually have brain abnormalities; infection in newborns could also lead to brain damage.

Cause
Reservoir
Zika virus is a mosquito-borne flavivirus closely related to the dengue and yellow fever viruses. While mosquitoes are the vector, the main reservoir species remains unknown, though serological evidence has been found in both West African monkeys and rodents.

Transmission
Transmission is via the bite of mosquitoes from the genus Aedes, primarily Aedes aegypti in tropical regions. It has also been isolated from Ae. africanus, Ae. apicoargenteus, Ae. luteocephalus, Ae. albopictus, Ae. vittatus and Ae. furcifer. During the 2007 outbreak on Yap Island in the South Pacific, Aedes hensilli was the vector, while Aedes polynesiensis spread the virus in French Polynesia in 2013.Zika virus can also spread by sexual transmission from infected men to their partners. Zika virus has been isolated from semen samples, with one person having 100,000 times more virus in semen than blood or urine, two weeks after being infected. It is unclear why levels in semen can be higher than other body fluids, and it is also unclear how long infectious virus can remain in semen. There have also been cases of men with no symptoms of Zika virus infection transmitting the disease. The CDC has recommended that all men who have travelled to affected areas should wait at least 6 months before trying to attempt conception, regardless of whether they were ill. To date there have been no reported sexual transmissions from women to their sexual partners. Oral, anal or vaginal sex can spread the disease.Cases of vertical perinatal transmission have been reported. The CDC recommends that women with Zika fever should wait at least 8 weeks after they start having symptoms of disease before attempting to conceive. There have been no reported cases of transmission from breastfeeding, but infectious virus has been found in breast milk.Like other flaviviruses it could potentially be transmitted by blood transfusion and several affected countries have developed strategies to screen blood donors. The U.S. FDA has recommended universal screening of blood products for Zika. The virus is detected in 3% of asymptomatic blood donors in French Polynesia.

Pathophysiology
In fruit flies microcephaly appears to be caused by the flavivirid virus protein NS4A, which can disrupt brain growth by hijacking a pathway which regulates growth of new neurons.

Diagnosis
It is difficult to diagnose Zika virus infection based on clinical signs and symptoms alone due to overlaps with other arboviruses that are endemic to similar areas. The US Centers for Disease Control and Prevention (CDC) advises that "based on the typical clinical features, the differential diagnosis for Zika virus infection is broad. In addition to dengue, other considerations include leptospirosis, malaria, rickettsia, group A streptococcus, rubella, measles, and parvovirus, enterovirus, adenovirus, and alphavirus infections (e.g., chikungunya, Mayaro, Ross River, Barmah Forest, Onyongnyong, and Sindbis viruses)."In small case series, routine chemistry and complete blood counts have been normal in most patients. A few have been reported to have mild leukopenia, thrombocytopenia, and elevated liver transaminases.Zika virus can be identified by reverse transcriptase PCR (RT-PCR) in acutely ill patients. However, the period of viremia can be short and the World Health Organization (WHO) recommends RT-PCR testing be done on serum collected within 1 to 3 days of symptom onset or on saliva samples collected during the first 3 to 5 days. When evaluating paired samples, Zika virus was detected more frequently in saliva than serum.  Urine samples can be collected and tested up to 14 days after the onset of symptoms, as the virus has been seen to survive longer in the urine than either saliva or serum. The longest period of detectable virus has been 11 days and Zika virus does not appear to establish latency.Later on, serology for the detection of specific IgM and IgG antibodies to Zika virus can be used. IgM antibodies can be detectable within 3 days of the onset of illness. Serological cross-reactions with closely related flaviviruses such as dengue and West Nile virus as well as vaccines to flaviviruses are possible. As of 2019, the FDA has authorized two tests to detect Zika virus antibodies.

Screening in pregnancy
The CDC recommends screening some pregnant women even if they do not have symptoms of infection. Pregnant women who have traveled to affected areas should be tested between two and twelve weeks after their return from travel. Due to the difficulties with ordering and interpreting tests for Zika virus, the CDC also recommends that healthcare providers contact their local health department for assistance. For women living in affected areas, the CDC has recommended testing at the first prenatal visit with a doctor as well as in the mid-second trimester, though this may be adjusted based on local resources and the local burden of Zika virus. Additional testing should be done if there are any signs of Zika virus disease. Women with positive test results for Zika virus infection should have their fetus monitored by ultrasound every three to four weeks to monitor fetal anatomy and growth.

Infant testing
For infants with suspected congenital Zika virus disease, the CDC recommends testing with both serologic and molecular assays such as RT-PCR, IgM ELISA and plaque reduction neutralization test (PRNT). RT-PCR of the infants serum and urine should be performed in the first two days of life. Newborns with a mother who was potentially exposed and who have positive blood tests, microcephaly or intracranial calcifications  should have further testing including a thorough physical investigation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions. Other recommended tests are cranial ultrasound, hearing evaluation, and eye examination. Testing should be done for any abnormalities encountered as well as for other congenital infections such as syphilis, toxoplasmosis, rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus. Some tests should be repeated up to 6 months later as there can be delayed effects, particularly with hearing.

Infant feeding in areas of Zika virus transmission
In response to the widespread transmission of Zika virus during the 2016 outbreak and concerns of viral genetic material detected in breast milk the World Health Organization (WHO) released a Guideline of infant feeding in areas of Zika virus transmission, first in 2016 and updated in 2021, where the evidence showed that despite the detection of Zika virus in breast milk, there is unclear evidence of transmission to the infant, and considering that Zika virus infection among infants is mild, the balance between desirable and undesirable effects favours breastfeeding versus not breastfeeding. According to the 2021WHO guidelines:
Infants born to mothers with suspected, probable or confirmed Zika virus infection or who reside in or have travelled to areas of ongoing Zika virus transmission should be fed according to normal infant feeding guidelines. They should start breastfeeding within one hour of birth, be exclusively breastfed for six months and have timely introduction of adequate, safe and properly fed complementary foods, while continuing breastfeeding up to two years of age or beyond.
Infants fed with expressed breast-milk from mothers with suspected, probable or confirmed Zika virus infection or who reside in or have travelled to areas of ongoing Zika virus transmission should be fed according to normal infant feeding guidelines (strong recommendation, very-low certainty of evidence).
Among infants (0–12 months) affected by complications associated with Zika virus infection, infant feeding practices should be modified (such as adjusting the environment, postural correction or thickening feeds) to achieve and maintain optimal possible infant growth and development (strong recommendation, very- low certainty of evidence).
Mothers and caregivers of infants affected by complications associated with Zika virus (such as feeding difficulties) should receive skilled support from health-care workers to initiate and sustain optimal infant feeding practices

Prevention
The virus is spread by mosquitoes, making mosquito avoidance an important element to disease control. The CDC recommends that individuals:
Cover exposed skin by wearing long-sleeved shirts and long pants treated with permethrin.
Use an insect repellent containing DEET, picaridin, oil of lemon eucalyptus (OLE), or ethyl butylacetylaminopropionate (IR3535)
Always follow product directions and reapply as directed
If you are also using sunscreen, apply sunscreen first, let it dry, then apply insect repellent
Follow package directions when applying repellent on children. Avoid applying repellent to their hands, eyes, or mouth
Stay and sleep in screened-in or air-conditioned rooms
Use a bed net if the area where you are sleeping is exposed to the outdoors
Cover cribs, strollers and carriers with mosquito netting for babies under 2 months old.The CDC also recommends strategies for controlling mosquitoes such as eliminating standing water, repairing septic tanks and using screens on doors and windows. Spraying insecticide is used to kill flying mosquitoes and larvicide can be used in water containers.Because Zika virus can be sexually transmitted, men who have gone to an area where Zika fever is occurring should be counseled to either abstain from sex or use condoms for 6 months after travel if their partner is pregnant or could potentially become pregnant. Breastfeeding is still recommended by the WHO, even by women who have had Zika fever. There have been no recorded cases of Zika transmission to infants through breastfeeding, though the replicative virus has been detected in breast milk.When returning from travel, with or without symptoms, it is suggested that prevention of mosquito bites continue for 3 weeks in order reduce the risk of virus transmission to uninfected mosquitos.

CDC travel alert
Because of the "growing evidence of a link between Zika and microcephaly", in January 2016, the CDC issued a travel alert advising pregnant women to consider postponing travel to countries and territories with ongoing local transmission of Zika virus. Later, the advice was updated to caution pregnant women to avoid these areas entirely if possible and, if travel is unavoidable, to protect themselves from mosquito bites. Male partners of pregnant women and couples contemplating pregnancy who must travel to areas where Zika is active are advised to use condoms or abstain from sex. The agency also suggested that women thinking about becoming pregnant should consult with their physicians before traveling.In September 2016, the CDC travel advisories included:
Cape Verde
Many parts of the Caribbean: Anguilla, Antigua and Barbuda, Aruba, The Bahamas, Barbados, Bonaire, British Virgin Islands, Cayman Islands, Cuba, Curaçao, Dominica, Dominican Republic, Grenada, Guadeloupe, Haiti, Jamaica, Martinique, Puerto Rico, Saba, Saint Saint Barthélemy, Saint Lucia, Saint Martin, Saint Vincent and the Grenadines, Sint Eustatius, Sint Maarten, Trinidad and Tobago, and the U.S. Virgin Islands
Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama
Mexico
Most of South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Peru, Suriname, and Venezuela
Several Pacific Islands: American Samoa, Fiji, Marshall Islands, Micronesia, New Caledonia, Papua New Guinea, Samoa, and Tonga
In Asia: Singapore, Malaysia, BruneiIn December 2020, no active Zika outbreaks were reported by the CDC.

WHO response
Both the regional Pan American Health Organization (PAHO) as well as the WHO have issued statements of concern about the widespread public health impact of the Zika virus and its links to GBS and microcephaly. The WHO Director-General, Margaret Chan, issued a statement in February 2016 "declaring that the recent cluster of microcephaly cases and other neurological disorders reported in Brazil, following a similar cluster in French Polynesia in 2014, constitutes a Public Health Emergency of International Concern." The declaration allowed the WHO to coordinate international response to the virus as well as gave its guidance the force of international law under the International Health Regulations. The declaration was ended in November 2016.

Vaccine
As of 2016 there was no available vaccine. Development was a priority of the US National Institutes of Health (NIH), but officials stated that development of a vaccine could take years. To speed new drug development regulatory strategies were proposed by the WHO and NIH. Animal and early human studies were underway as of September 2016. As of December 2019, there were several vaccine candidates in various stages of development.

Mosquito control
Disease control in the affected countries currently centres around mosquito control. Several approaches are available for the management of Aedes aegypti mosquito populations, including the destruction of larval breeding sites (the aquatic pools in which eggs are laid and larvae hatch prior to mosquito development into flying adults); and, insecticides targeting either the larval stages, adult mosquitoes or both. Additionally, a whole host of novel technologies are under current development for mosquito control and the World Health Organization has recently lent its support for the accelerated development of modern methods for mosquito control such as the use of Wolbachia bacteria to render mosquitoes resistant to the virus, and, the release of sterilized male mosquitoes that breed with wild female mosquitoes to give rise to non-viable offspring (offspring that do not survive to the biting, adult stage).Oxitec’s genetically modified OX513A mosquito was approved by Brazils National Biosecurity Technical Commission (CTNBio) in April 2014 and it was being used to try to combat mosquitoes carrying the Zika virus in the town of Piracicaba, São Paulo in 2016.In the 1940s and 1950s, the Aedes aegypti mosquito was eradicated on some Caribbean islands and in at least eighteen Latin American countries.  Decreasing political will and presumably available money, mosquito resistance to insecticide, and a pace of urbanization which exceeded eradication efforts led to this mosquitos comeback.

Treatment
There is currently no specific treatment for Zika virus infection. Care is supportive with treatment of pain, fever, and itching. Some authorities have recommended against using aspirin and other NSAIDs as these have been associated with hemorrhagic syndrome when used for other flaviviruses. Additionally, aspirin use is generally avoided in children when possible due to the risk of Reye syndrome.Zika virus had been relatively little studied until the major outbreak in 2015, and no specific antiviral treatments are available as yet. Advice to pregnant women is to avoid any risk of infection so far as possible, as once infected there is little that can be done beyond supportive treatment.

Outcomes
Most of the time, Zika fever resolves on its own in two to seven days, but rarely, some people develop Guillain–Barré syndrome.   The fetus of a pregnant woman who has Zika fever may die or be born with congenital central nervous system malformations, like microcephaly.

Epidemiology
In April 1947, as part of studies sponsored by the Rockefeller Foundation into yellow fever, 6 caged rhesus monkeys were placed in the canopy of the Zika Forest of Uganda. On April 18 one of the monkeys (no. 776) developed a fever and blood samples revealed the first known case of Zika fever. Population surveys at the time in Uganda found 6.1% of individuals to be seropositive for Zika. The first human cases were reported in Nigeria in 1954. A few outbreaks have been reported in tropical Africa and in some areas in Southeast Asia. Until recently there were no documented cases of Zika virus in the Indian subcontinent, however, the first cases were reported in 2017 from Gujarat state and Tamil Nadu,  more cases were reported in Rajasthan state involving an outbreak of 153 reported cases and in a pregnant women living in Kerala state. A 1954 study assessing blood samples from several people from different states found antibodies to Zika in healthy people in India which could indicate past exposure, though it could also be due to cross-reaction with other flaviviruses.By using phylogenetic analysis of Asian strains, it was estimated that Zika virus had moved to Southeast Asia by 1945. In 1977–1978, Zika virus infection was described as a cause of fever in Indonesia. Before 2007, there were only 13 reported natural infections with Zika virus, all with a mild, self-limited febrile illness. As of July 2019, evidence of local transmission from mosquitoes to humans has been reported in a total of 87 countries from four of six WHO Regions; African, Americas, South-East Asia and Western Pacific.

Yap Islands
The first major outbreak, with 185 confirmed cases, was reported in 2007 in the Yap Islands of the Federated States of Micronesia. A total of 108 cases were confirmed by PCR or serology and 72 additional cases were suspected. The most common symptoms were rash, fever, arthralgia, and conjunctivitis, and no deaths were reported. The mosquito Aedes hensilli, which was the predominant species identified in Yap during the outbreak, was probably the main vector of transmission. While the way of introduction of the virus on Yap Island remains uncertain, it is likely to have happened through introduction of infected mosquitoes or a human infected with a strain related to those in Southeast Asia. This was also the first time Zika fever had been reported outside Africa and Asia. Before the Yap Island outbreak, only 14 human cases had ever been reported.

Oceania
In 2013–2014, several outbreaks of Zika were reported in French Polynesia, New Caledonia, Easter Island and the Cook Islands. The source of the virus was thought to be an independent introduction of the virus from Southeast Asia, unrelated to the Yap Islands outbreak.

Americas
Genetic analyses of Zika virus strains suggest that Zika first entered the Americas between May and December 2013. It was first detected in the Western Hemisphere in February 2014, and rapidly spread throughout South and Central America, reaching Mexico in November 2015. In 2016 it established local transmission in Florida and Texas. The first death in the United States due to Zika occurred in February 2016.In May 2015, Brazil officially reported its first 16 cases of the illness. Although, a case of illness was reported in March 2015 in a returning traveller. According to the Brazilian Health Ministry, as of November 2015 there was no official count of the number of people infected with the virus in Brazil, since the disease is not subject to compulsory notification. Even so, cases were reported in 14 states of the country. Mosquito-borne Zika virus is suspected to be the cause of 2,400 possible cases of microcephaly and 29 infant deaths in Brazil in 2015 (of the 2400 or so notified cases in 2015, 2165 were under investigation in December 2015, 134 were confirmed and 102 were ruled out for microcephaly).The Brazilian Health Ministry has reported at least 2,400 suspected cases of microcephaly in the country in 2015 as of 12 December, and 29 fatalities. Before the Zika outbreak, only an average of 150 to 200 cases per year were reported in Brazil. In the state of Pernambuco the reported rates of microcephaly in 2015 are 77 times higher than in the previous 5 years. A model using data from a Zika outbreak in French Polynesia estimated the risk of microcephaly in children born to mothers who acquired Zika virus in the first trimester to be 1%.On 24 January 2016, the WHO warned that the virus is likely to spread to nearly all countries of the Americas, since its vector, the mosquito Aedes aegypti, is found in all countries in the region, except for Canada and continental Chile. The mosquito and dengue fever have been detected in Chiles Easter Island, some 3,500 km (2,200 mi) away from its closest point in mainland Chile, since 2002.In February 2016, WHO declared the outbreak a Public Health Emergency of International Concern as evidence grew that Zika is a cause of birth defects and neurological problems. In April 2016, WHO stated there is a scientific consensus, based on preliminary evidence, that Zika is a cause of microcephaly in infants and Guillain–Barré syndrome in adults. Studies of this and prior outbreaks have found Zika infection during pregnancy to be associated with early pregnancy loss and other pregnancy problems. In the Americas the number of cases peaked during the first half of 2016 and declined through 2017–2018, with a total of 31,587 suspected, probable, and confirmed cases of ZIKV disease were reported in the Region of the Americas. Of these, 3,473 (11%) were laboratory confirmed. In general, transmission persists at low levels in some areas and is not uniformly distributed within countries.

Asia
In 2016 imported or locally transmitted Zika was reported in all the countries of Asia except Brunei, Hong Kong, Myanmar and Nepal. Serological surveys have indicated that Zika virus is endemic in most areas of Asia, though at a low level. While there was a sharp rise in the number of cases of Zika detected in Singapore after the 2016 Summer Olympics in Brazil, genetic analysis revealed that the strains were more closely related to strains from Thailand than from those causing the epidemic in the Americas.

History
Origin of the name
It is named after the Zika Forest near Entebbe, Uganda, where the Zika virus was first identified.

Microcephaly and other infant disorders
Zika virus was first identified in the late 1940s in Kampala, Uganda, Africa but was first confirmed in Brazil. Since it was first identified, Zika has been found in more than 27 countries and territories. Following the initial Zika outbreak in Northeastern Brazil in May 2015, physicians observed a very large surge of reports of infants born with microcephaly, with 20 times the number of expected cases. Many of these cases have since been confirmed, leading WHO officials to project that approximately 2,500 infants will be found to have born in Brazil with Zika-related microcephaly.Proving that Zika causes these effects was difficult and complex for several reasons. For example, the effects on an infant might not be seen until months after the mothers initial infection, long after the time when Zika is easily detected in the body. In addition, research was needed to determine the mechanism by which Zika produced these effects.Since the initial outbreak, studies that use several different methods found evidence of a link, leading public health officials to conclude that it appears increasingly likely the virus is linked to microcephaly and miscarriage. On 1 February 2016, the World Health Organization declared recently reported clusters of microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC). On 8 March 2016, the WHO Committee reconfirmed that the association between Zika and neurological disorders is of global concern.The Zika virus was first linked with newborn microcephaly during the Brazil Zika virus outbreak. In 2015, there were 2,782 suspected cases of microcephaly compared with 147 in 2014 and 167 in 2013. Confirmation of many of the recent cases is pending, and it is difficult to estimate how many cases went unreported before the recent awareness of the risk of virus infections.

In November 2015, the Zika virus was isolated in a newborn baby from the northeastern state of Ceará, Brazil, with microcephaly and other congenital disorders. The Lancet medical journal reported in January 2016 that the Brazilian Ministry of Health had confirmed 134 cases of microcephaly "believed to be associated with Zika virus infection" with an additional 2,165 cases in 549 counties in 20 states remaining under investigation. An analysis of 574 cases of microcephaly in Brazil during 2015 and the first week of 2016, reported in March 2016, found an association with maternal illness involving rash and fever during the first trimester of pregnancy. During this period, 12 Brazilian states reported increases of at least 3 standard deviations (SDs) in cases of microcephaly compared with 2000–14, with the northeastern states of Bahia, Paraíba and Pernambuco reporting increases of more than 20 SDs.In January 2016, a baby in Oahu, Hawaii, was born with microcephaly, the first case in the United States of brain damage linked to the virus. The baby and mother tested positive for a past Zika virus infection. The mother, who had probably acquired the virus while traveling in Brazil in May 2015 during the early stages of her pregnancy, had reported her bout of Zika. She recovered before relocating to Hawaii. Her pregnancy had progressed normally, and the babys condition was not known until birth.In February 2016, ocular disorders in newborns have been linked to Zika virus infection. In one study in Pernambuco state in Brazil, about 40 percent of babies with Zika-related microcephaly also had scarring of the retina with spots, or pigment alteration. On 20 February 2016, Brazilian scientists announced that they had successfully sequenced the Zika virus genome and expressed hope that this would help in both developing a vaccine and in determining the nature of any link to birth defects.Also in February 2016, rumors that microcephaly is caused by the use of the larvicide pyriproxyfen in drinking water were refuted by scientists. "Its important to state that some localities that do not use pyriproxyfen also had reported cases of microcephaly", read a Brazilian government statement. The Brazilian government also refuted conspiracy theories that chickenpox and rubella vaccinations or genetically modified mosquitoes were causing increases in microcephaly.Researchers also suspected that Zika virus could be transmitted by a pregnant woman to her babies ("vertical transmission"). This remained unproven until February 2016, when a paper by Calvet et al. was published, showing not only was the Zika virus genome found in the amniotic fluid but also IgM antibodies against the virus. This means that not only can the virus cross the placental barrier, but also the antibodies produced by the mother can reach the fetus, which suggests that vertical transmission is plausible in these cases. One other study published in March 2016 by Mlakar and colleagues analyzed autopsy tissues from a fetus with microcephaly that was probably related to Zika virus; researchers found ZIKV in the brain tissue and suggested that the brain injuries were probably associated with the virus, which also shed a light on the vertical transmission theory. Also in March 2016, first solid evidence was reported on how the virus affects the development of the brain, indicating that it appears to preferentially kill developing brain cells.The first cases of birth defects linked to Zika in Colombia and in Panama were reported in March 2016. In the same month, researchers published a prospective cohort study that found profound impacts in 29 percent of infants of mothers infected with Zika, some of whom were infected late in pregnancy. This study did not suffer from some of the difficulties of studying Zika: the study followed women who presented to a Rio de Janeiro clinic with fever and rash within the last five days. The women were then tested for Zika using PCR, then the progress of the pregnancies were followed using ultrasound.

Guillain–Barré syndrome
A high rate of the autoimmune disease Guillain–Barré syndrome (GBS), noted in the French Polynesia outbreak, has also been found in the outbreak that began in Brazil. Laboratory analysis found Zika infections in some patients with GBS in Brazil, El Salvador, Suriname and Venezuela, and the WHO declared on 22 March 2016 that Zika appeared to be "implicated" in GBS infection and that if the pattern was confirmed it would represent a global public health crisis.

Research
Mechanism
Research has been ongoing to better understand how Zika virus causes microcephaly and other neurological disorders.It may involve infection of the primary neural stem cells of the fetal brain, known as neural progenitor cells </s>