<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 Nasal septum perforation and can you explain it in depth? [/INST] A nasal septum perforation is a medical condition in which the nasal septum, the bony/cartilaginous wall dividing the nasal cavities, develops a hole or fissure.
This may be brought on directly, as in the case of nasal piercings, or indirectly, as by long-term topical drug application, including intranasal ethylphenidate, methamphetamine, cocaine, crushed prescription pills, or decongestant nasal sprays, chronic epistaxis, excessive nose picking and as a complication of nasal surgery like septoplasty or rhinoplasty. Much less common causes for perforated nasal septums include rare granulomatous inflammatory conditions like granulomatosis with polyangiitis. It has been reported as a side effect of anti-angiogenesis drugs like bevacizumab.

Signs and symptoms
A perforated septum can vary in size and location, and is usually found deep inside the nose. It may be asymptomatic, or cause a variety of signs and symptoms. Small perforations can cause a whistling noise when breathing. Larger perforations usually have more severe symptoms. These can be a combination of crusting, blood discharge, difficulty breathing, nasal pressure and discomfort. The closer the perforation is to the nostrils, the more likely it is to cause symptoms.

Cause
Infective causes include syphilis, leprosy, and rhinoscleroma. Non-infective causes include cocaine abuse, an in situ foreign body, chronic use of topical nasal decongestants, methamphetamine, facial trauma, or may develop as a consequence of nasal surgery.

Treatment
Septal perforations are managed with a multitude of options. The treatment often depends on the severity of symptoms and the size of the perforations. Generally speaking anterior septal perforations are more bothersome and symptomatic. Posterior septal perforations, which mainly occur iatrogenically, are often managed with simple observation and are at times intended portions of skull base surgery. Septal perforations that are not bothersome can be managed with simple observation. While no septal perforation will spontaneously close, for the majority of septal perforations that are unlikely to get larger observation is an appropriate form of management. For perforations that bleed or are painful, initial management should include humidification and application of salves to the perforation edges to promote healing. Mucosalization of the perforation edges will help prevent pain and recurrent epistaxis and majority of septal perforations can be managed without surgery.
For perforations in which anosmia, or the loss of smell, and a persistent whistling are a concern, the use of a silicone septal button is a treatment option. These can be placed while the patient is awake and usually in the clinic setting. While complications of button insertion are minimal, the presence of the button can be bothersome to most patients.
For patients who desire definitive close, surgery is the only option. Prior to determining candidacy for surgical closure, the etiology of the perforation must be determined. Often this requires a biopsy of the perforation to rule out autoimmune causes. If a known cause such as cocaine is the offending agent, it must be ensured that the patient is not still using the irritant.
For those that are determined to be medically cleared for surgery, the anatomical location and size of the perforation must be determined. This is often done with a combination of a CT scan of the sinuses without contrast and an endoscopic evaluation by an Ear Nose and Throat doctor. Once dimensions are obtained the surgeon will decide if it is possible to close the perforation. Multiple approaches to access the septum have been described in the literature. While sublabial and midfacial degloving approaches have been described, the most popular today is the rhinoplasty approach. This can include both open and closed methods </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 Robinow syndrome and can you explain it in depth? [/INST] Robinow syndrome is an extremely rare genetic disorder characterized by short-limbed dwarfism, abnormalities in the head, face, and external genitalia, as well as vertebral segmentation. The disorder was first described in 1969 by human geneticist Meinhard Robinow, along with physicians Frederic N. Silverman and Hugo D. Smith, in the American Journal of Diseases of Children. By 2002, over 100 cases had been documented and introduced into medical literature.Two forms of the disorder exist, dominant and recessive, of which the former is more common. Patients with the dominant version often suffer moderately from the aforementioned symptoms. Recessive cases, on the other hand, are usually more physically marked, and individuals may exhibit more skeletal abnormalities. The recessive form is particularly frequent in Turkey. However, this can likely be explained by a common ancestor, as these patients families can be traced to a single town in Eastern Turkey. Clusters of the autosomal recessive form have also been documented in Oman and Czechoslovakia.The syndrome is also known as Robinow-Silverman-Smith syndrome, Robinow dwarfism, fetal face, fetal face syndrome, fetal facies syndrome, acral dysostosis with facial and genital abnormalities, or mesomelic dwarfism-small genitalia syndrome.  The recessive form was previously known as Covesdem syndrome.

Signs and symptoms
Robinow noted the resemblance of affected patients faces to that of a fetus, using the term "fetal facies" to describe the appearance of a small face and widely spaced eyes. Clinical features also may include a short, upturned nose, a prominent forehead, and a flat nasal bridge. The upper lip may be "tented", exposing dental crowding, "tongue tie", or gum hypertrophy.
Though the eyes do not protrude, abnormalities in the lower eyelid may give that impression. Surgery may be necessary if the eyes cannot close fully. In addition, the ears may be set low on the head or have a deformed pinna.Patients suffer from dwarfism, short lower arms, small feet, and small hands. Fingers and toes may also be abnormally short and laterally or medially bent. The thumb may be displaced and some patients, notably in Turkey, experience ectrodactyly. All patients often suffer from vertebral segmentation abnormalities. Those with the dominant variant have, at most, a single butterfly vertebra. Those with the recessive form, however, may suffer from hemivertebrae, vertebral fusion, and rib anomalies. Some cases resemble Jarcho-Levin syndrome or spondylocostal dysostosis.Genital defects characteristically seen in males include a micropenis with a normally developed scrotum and testes. Sometimes, testicles may be undescended, or the patient may suffer from hypospadias. Female genital defects may include a reduced size clitoris and underdeveloped labia minora. Infrequently, the labia majora may also be underdeveloped. Some research has shown that females may experience vaginal atresia or haematocolpos.The autosomal recessive form of the disorder tends to be much more severe. Examples of differences are summarized in the following table:

Associated conditions
Medical conditions include frequent ear infection, hearing loss, hypotonia, developmental problems, respiratory problems, eating difficulties, light sensitivity, and esophageal reflux.Data on fertility and the development of secondary sex characteristics is relatively sparse. It has been reported that both male and female patients have had children. Males who have reproduced have all had the autosomal dominant form of the disorder; the fertility of those with the recessive variant is unknown.Researchers have also reported abnormalities in the renal tract of affected patients. Hydronephrosis is a relatively common condition, and researchers have theorized that this may lead to urinary tract infections. In addition, a number of patients have suffered from cystic dysplasia of the kidney.A number of other conditions are often associated with Robinow syndrome. About 15% of reported patients suffer from congenital heart defects. Though there is no clear pattern, the most common conditions include pulmonary stenosis and atresia. In addition, though intelligence is generally normal, around 15% of patients show developmental delays.

Genetics
Genetic studies have linked the autosomal recessive form of the disorder to the ROR2 gene on position 9 of the long arm of chromosome 9. The gene is responsible for aspects of bone and cartilage growth. This same gene is involved in causing autosomal dominant brachydactyly B.

The autosomal dominant form has been linked to three genes - WNT5A, Segment polarity protein dishevelled homolog DVL-1 (DVL1) and Segment polarity protein dishevelled homolog DVL-3 (DVL3). This form is often caused by new mutations and is generally less severe than the recessive form. Two further genes have been linked to this disorder - Frizzled-2 (FZD2) and Nucleoredoxin (NXN gene). All of these genes belong to the same metabolic pathway - the WNT system. This system is involved in secretion for various compounds both in the fetus and in the adult.
A fetal ultrasound can offer prenatal diagnosis 19 weeks into pregnancy. However, the characteristics of a fetus suffering from the milder dominant form may not always be easy to differentiate from a more serious recessive case. Genetic counseling is an option given the availability of a family history.

Diagnosis
Robinow syndrome is suspected by clinical findings and family history and confirmed by typical ROR-2 biallelic pathogenic variants identified by molecular genetic testing.

Treatment
Treatment of the various manifestations will usually be addressed by a multidisciplinary team.

History
The disorder was first described in 1969 by the German-American Human Geneticist Meinhard Robinow (1909–1997), along with physicians Frederic N </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 Metageria 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 Hashimotos encephalopathy and can you explain it in depth? [/INST] Hashimotos encephalopathy, also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a neurological condition characterized by encephalopathy, thyroid autoimmunity, and good clinical response to corticosteroids. It is associated with Hashimotos thyroiditis, and was first described in 1966. It is sometimes referred to as a neuroendocrine disorder, although the conditions relationship to the endocrine system is widely disputed.  It is recognized as a rare disease by the NIH Genetic and Rare Diseases Information Center.Up to 2005, almost 200 case reports of this disease were published. Between 1990 and 2000, 43 cases were published. Since that time, research has expanded and numerous cases are being reported by scientists around the world, suggesting that this rare condition is likely to have been significantly undiagnosed in the past. Over 100 scientific articles on Hashimotos encephalopathy were published between 2000 and 2013.

Signs and symptoms
The onset of symptoms tends to be fairly gradual and to occur over 1-12 years.Symptoms of Hashimotos encephalopathy may include:
Personality changes
Aggression
Delusional behavior
Concentration and memory problems
Coma
Disorientation
Headaches
Jerks in the muscles (myoclonus – 65% of cases)
Lack of coordination (ataxia – 65% of cases)
Partial paralysis on the right side
Psychosis
Seizures (60% of cases)
Sleep abnormalities (55% of cases)
Speech problems (transient aphasia – 80% of cases)
Status epilepticus (20% of  cases)
Tremors (80% of cases)

Pathogenesis
The mechanism of pathogenesis is not known, but is thought to be an autoimmune disorder, similar to Hashimotos thyroiditis, as its name suggests.Consistent with this hypothesis, autoantibodies to alpha-enolase have been found to be associated with Hashimotos encephalopathy. Since enolase is the penultimate step in glycolysis, if it were inhibited (for example by being bound by autoantibodies), one would expect decreased energy production by each cell, leading to resulting atrophy of the affected organ.This would occur most likely through each cell shrinking in size in response to the energy deficit (and/or in extreme situations from some cells dying via either apoptosis or necrosis, depending on location). This may occur as a result of enough ATP not being available to maintain cellular functions - notably, failure of the Na/K ATPase, resulting in a loss of the gradient to drive the Na/Ca antiporter, which normally keeps Ca+2 out of cells so it does not build to toxic levels that will rupture cell lysosomes leading to apoptosis. An additional feature of a low-energy state is failure to maintain axonal transport via dynein/kinesin ATPases, which in many diseases results in neuronal injury to both the brain and/or periphery.

Pathology
Very little is known about the pathology of Hashimotos encephalopathy. Post mortem studies of some individuals have shown lymphocytic vasculitis of venules and veins in the brain stem and a diffuse gliosis involving gray matter more than white matter.As mentioned above, autoantibodies to alpha-enolase associated with Hashimotos encephalopathy have thus far been the most hypothesized mechanism of injury.

Diagnosis
Laboratory and radiological findings
Increased liver enzyme levels (55% cases)
Increased thyroid-stimulating hormone (55% cases)
Increased erythrocyte sedimentation rate (25% cases)Cerebrospinal fluid findings:
Raised protein (25% cases)
Negative for 14–3–3 protein
May contain antithyroid antibodies
Magnetic resonance imaging abnormalities consistent with encephalopathy (26% f cases)
Single photon emission computed tomography shows focal and global hypoperfusion (75% of cases)
Cerebral angiography is normalThyroid hormone abnormalities are common (>80% of cases):
Subclinical hypothyroidism (35% of cases)
Overt hypothyroidism (20% of cases)
Hyperthyroidism (5% of cases)
Euthyroid on levothyroxine (10%  of cases)
Euthyroid not on levothyroxine (20% of cases)Thyroid antibodies – both antithyroid peroxidase antibodies (anti-TPO, antithyroid microsomal antibodies, anti-M) and antithyroglobulin antibodies (anti-Tg) – in the disease are elevated, but their levels do not correlate with the severity.Electroencephalogram studies, while almost always abnormal (98% of cases), are usually not diagnostic. The most common findings are diffuse or generalized slowing or frontal intermittent rhythmic delta activity. Prominent triphasic waves, focal slowing, epileptiform abnormalities, and photoparoxysmal and photomyogenic responses may be seen.A study from 2006 suggested the following diagnostic criteria:
Encephalopathy with cognitive impairment and at least one of the following features:
neuropsychiatric symptoms (e.g. hallucination, delusion or paranoia)
Myoclonus, generalised tonic-clonic or partial seizures
focal-neurological deficits
Elevated titres of thyroid tissue antibodies (TPO-ab or microsomal)
Euthyroidism (potentially achieved by treatment with L-T4 or L-T3) or mild hypothyroidism with TSH concentration below 20 mIU/L
No evidence for infectious, toxic, metabolic or neoplastic processes in blood, urine or CSF analyses
No serological evidence for neuronal antibodies (e.g. voltage-gated calcium channel, voltage-gated potassium channel, or other currently recognized paraneoplastic antibodies) to support another diagnosis
In imaging studies no evidence for vascular, neoplastic or structural lesions that might explain the symptoms
Complete or nearly complete remission after initiation of glucocorticoid therapy.

Definition
A relapsing encephalopathy occurs in association with autoimmune (Hashimotos or Ords thyroiditis), with high titers of antithyroid antibodies. Clinically, the condition may present one or more symptoms.  Onset is often gradual and may go unnoticed by the patient and close associates to the patients. Symptoms sometimes resolve themselves within days to weeks, leaving a patient undiagnosed. For many other patients, the condition may result in ongoing problems with a variety of manifestations, often confusing clinicians due to the diffuse nature of symptoms.

Differential diagnosis
Alzheimers disease
Cerebrovascular accidents (stroke)
Creutzfeldt–Jakob disease
Epilepsy
Migraine (including basilar, hemiplegic, and retinal types)
Other forms of autoimmune encephalitis, including forms of limbic encephalitis such as anti-NMDA receptor encephalitis
Schizophrenia
Spontaneous cerebrospinal fluid leak
Viral encephalitis
Transient ischemic attack

Treatment
Because most patients respond to corticosteroids or immunosuppressant treatment, this condition is now also referred to as steroid-responsive encephalopathy.Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days. Thyroid hormone treatment is also included if required.Failure of some patients to respond to this first-line treatment has produced a variety of alternative treatments, including azathioprine, cyclophosphamide, chloroquine, methotrexate, periodic intravenous immunoglobulin, and plasma exchange. No controlled trials have been conducted, so the optimal treatment is not known.Seizures, if present, are controlled with typical antiepileptic agents.

Prognosis
Duration of treatment is usually between 2 and 25 years. Earlier reports suggested that 90% of cases stay in remission after discontinuation of treatment, but this is at odds with more recent studies, which suggest that relapse commonly occurs after initial high-dose steroid treatment. Left untreated, this condition can result in coma and death.

Epidemiology
The prevalence has been estimated to be 2.1/100,000 with a male-to-female ratio of 1:4. The mean age of onset is 44 with 20% of cases presenting before the age of 18 years. Most reported cases occur during the patients fifth decade of life.

History
The first case of HE was described by Brain et al. in 1966. The patient was a 48-year-old man with hypothyroidism, multiple episodes of encephalopathy, stroke-like symptoms, and Hashimotos thyroiditis confirmed by elevated antithyroid antibodies.

Alternative names
Steroid-responsive encephalopathy associated with autoimmune thyroiditis, SREAT
Nonvasculitic autoimmune meningoencephalitis, NAIM
Encephalopathy associated with autoimmune thyroid disease, EAATD

References
Further reading
Hashimotos Encephalopathy SREAT Alliance (2013). Understanding Hashimotos Encephalopathy: A Guide for Patients, Families, and Caregivers, Featuring Stories of HE Patients from Around the World. North Charleston, SC: CreateSpace Independent Publishing Platform. ISBN 9781484883099. OCLC 890816771.
Schiess N, Pardo CA (October 2008). "Hashimotos encephalopathy". Annals of the New York Academy of Sciences. 1142 (1): 254–65 </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 Aschers 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 Triparesis 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 Distal trisomy 10q and can you explain it in depth? [/INST] Distal trisomy 10 is a rare chromosomal disorder that causes several physical defects and intellectual disability.Humans, like all sexually reproducing species, have somatic cells that are in diploid [2N] state, meaning that N represent the number of chromosomes, and 2 the number of their copies. In humans, there are 23 chromosomes, but there are two sets of them, one from mother and one from father, totaling in 46, that are arranged according to their size, function and genes they carry. Each cell is supposed to have two of each, but sometimes due to mutations or malfunctions during cell division, mistakes are made that cause serious health problems. One such error is the cause of Distal trisomy 10q disorder.Each chromosome has two arms, labeled p (for petite, or short) and q (for long) </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 Ventricular dyssynchrony 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 Hemolytic jaundice and can you explain it in depth? [/INST] Hemolytic jaundice, also known as prehepatic jaundice, is a type of jaundice arising from hemolysis or excessive destruction of red blood cells, when the byproduct bilirubin is not excreted by the hepatic cells quickly enough. Unless the patient is concurrently affected by hepatic dysfunctions or is experiencing hepatocellular damage, the liver does not contribute to this type of jaundice.As one of the three categories of jaundice, the most obvious sign of hemolytic jaundice is the discolouration or yellowing of the sclera and the skin of the patient, but additional symptoms may be observed depending on the underlying causes of hemolysis. Hemolytic causes associated with bilirubin overproduction are diverse and include disorders such as sickle cell anemia, hereditary spherocytosis, thrombotic thrombocytopenic purpura, autoimmune hemolytic anemia, hemolysis secondary to drug toxicity, thalassemia minor, and congenital dyserythropoietic anemias. Pathophysiology of hemolytic jaundice directly involves the metabolism of bilirubin, where overproduction of bilirubin due to hemolysis exceeds the livers ability to conjugate bilirubin to glucuronic acid.Diagnosis of hemolytic jaundice is based mainly on visual assessment of the yellowing of the patients skin and sclera, while the cause of hemolysis must be determined using laboratory tests. Treatment of the condition is specific to the cause of hemolysis, but intense phototherapy and exchange transfusion can be used to help the patient excrete accumulated bilirubin. Complications related to hemolytic jaundice include hyperbilirubinemia and chronic bilirubin encephalopathy, which may be deadly without proper treatment.

Signs and symptoms
The signs and symptoms additional to the development of a yellowish colour in the sclera and skin are specific to the causes of hemolysis.
For example, if the patient has hemolytic jaundice resulting from sickle cell disease, vaso-occlusive phenomena like acute vaso-occlusive pain and acute chest syndrome may be observed in the acute phases, while in anemia, neurologic deficits and various pulmonary conditions may manifest in the chronic phase.Regardless of the causes, laboratory-confirmed elevation is predominantly seen in unconjugated bilirubin. Serum bilirubin concentration rarely exceeds 4 mg/dL, unless the patient has concurrent liver disease.

Causes
The underlying causes of hemolytic jaundice, as its name suggests, are disorders associated with hemolysis. Such disorders are manifold and the common causes include:

Sickle cell disease, in which a mutation in the globin gene causes the formation of sickle hemoglobin. This disease is marked by the manifestation of chronic compensated hemolytic anemia, with laboratory findings not limited to unconjugated hyperbilirubinemia but also elevated serum lactate dehydrogenase and low serum haptoglobin.
Thrombotic thrombocytopenic purpura, in which the reduced activity of the von Willebrand factor-cleaving protease ADAMTS13 causes a thrombotic microangiopathy. This disease, acquired or hereditary, is marked by very severe microangiopathic hemolytic anemia, with laboratory findings including extremely high serum lactate dehydrogenase and negative anti-RBC antibodies and Coombs test. Clinically, dark urine from hemoglobinuria may be observed because the hemolysis is intravascular (see Pathophysiology below).
Autoimmune hemolytic anemia (AIHA), in which autoantibodies react with self red blood cells and cause their destruction. This disease is marked by increased extravascular hemolysis, with laboratory findings including increased lactate dehydrogenase and decreased or absent haptoglobin in both warm and cold AIHA, and positive Coombs test. Clinically, jaundice or dark urine present in approximately one-third of the cases, and most of the symptoms are related to anemia.Other less commonly observed causes of hemolysis include:

Hemolysis secondary to drug toxicity
Thalassemia minor
Congenital dyserythropoietic anemiaThe above list is not exhaustive, and rare causes of hemolysis such as Bartonella infection, hemolysis due to transfusion reactions, and microangiopathic hemolytic anemia should be suspected when symptoms specific to those causes manifest.

Pathophysiology
Bilirubin overproduction
The mechanisms by which bilirubin is overproduced in hemolytic jaundice can be understood in relation to the two major sites of hemolysis: intravascular and extravascular.During intravascular hemolysis, red blood cells are broken down within the vasculature, allowing hemoglobin from the ruptured red blood cells to form haptoglobin-hemoglobin complexes with haptoglobin, which will be internalized and degraded by hepatocytes and the spleen. If the degree of hemolysis is abnormally high, the unbound hemoglobin is converted to methemoglobin from which the heme moiety is bound to hemopexin or to albumin, and both heme-hemopexin and heme-bound albumin are internalized by hepatocytes and subsequently degraded to bilirubin.
During extravascular hemolysis, red blood cells are destroyed by phagocytosis by macrophages in the reticuloendothelial system and digested by phagosomes. Hemoglobin within red blood cells are then degraded to release heme, which will be converted by microsomal heme oxygenase to iron, carbon monoxide and biliverdin, and are immediately reduced to unconjugated bilirubin by biliverdin reductase and released into the plasma.

Affinity of unconjugated bilirubin to albumin
In both settings of hemolysis mentioned above, only low levels of conjugated bilirubin may accumulate in the serum, with the amount falling within the normal limits of 4 percent of total bilirubin as conjugated bilirubin can be efficiently excreted in bile through being secreted across canalicular membrane. Increased levels of conjugated bilirubin will only be observed with coexisting hepatobiliary abnormalities. Only when the canalicular excretion capacity is exceeded, conjugated bilirubin will accumulate in the plasma. As unconjugated bilirubin has a high affinity to albumin, at high level it is not efficiently cleared through glomerular filtration and it binds to the elastic tissue of the skin and sclera, where high albumin content can be found. This explains the yellow discolouration observed in these tissues in hemolytic jaundice.

Diagnosis
Symptoms of jaundice can be observed superficially, thus visual methods are used to identify the condition. However, underlying causes of jaundice must be diagnosed through laboratory testing.

Visual assessment
In both newborns and adults, yellowing of the skin is a marker for jaundice. As most cases of jaundice are observed in newborns, healthcare workers use visual methods to identify the presence of this condition. A clinical jaundice scale, an adapted version of the Kramers scale, is used to quantify the severity of jaundice through the spread of skin discoloration from zone 1, the head, to zone 5, the palms and soles of the neonates body. Cephalocaudal progression of jaundice to zone 4 and 5 of the Kramers scale shows a significant positive correlation with serum bilirubin concentration of at least 11.0 mg per 100 ml, indicating the need for treatment.

Jaundice Eye Colour Index (JECI)
Conjunctival icterus can be quantified by the Jaundice Eye Colour Index (JECI) through digital photography of the sclera, where a JECI of 0 indicates a white colour, and a JECI of 0.1 indicates an intense yellow colour, which is a sign of hemolytic jaundice.

Screening laboratory tests
Multiple tests can be used to diagnose jaundice, but results of different parameters must be compared to determine its etiology.
When a patient shows signs of jaundice such as the yellowing of the skin and sclera, a urine test is performed to check the levels of urobilinogen present. The presence of urobilinogen and its increased levels indicate that there are more than normal amounts of bilirubin in the intestine, showing that jaundice observed is not due to the blockage of bile flow, and is of pre-hepatic or hepatic causes. Normal colour of the patients urine indicates the absence of unconjugated bilirubin.Results from the urine test should be confirmed by a complete blood count (CBC) and serum testing for total serum bilirubin and fractionated bilirubin. Increased reticulocytes and the presence of schistocytes in the blood smear of the patient observed during CBC indicates hemolysis. If the patient has hemolytic jaundice, serum testing will show that conjugated bilirubin will only account for less than 15% of the total serum bilirubin due to the increase of unconjugated bilirubin.Analysis of liver biopsies will show the levels of alkaline phosphatase, aspartate transaminase, and alanine transaminase in the patient, which has a negative correlation with liver function. Normal levels of these enzymes indicate that there is no significant hepatocellular damage.When an infant is suspected to have hemolytic jaundice, abnormal morphologies of erythrocytes can be analyzed to find out the causes of hemolysis. A Coombs test should be performed, and end-tidal carbon monoxide concentration should be monitored to understand the rate of hemolysis in the infants body </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Histoplasmosis and can you explain it in depth? [/INST] Histoplasmosis is a fungal infection caused by Histoplasma capsulatum. Symptoms of this infection vary greatly, but the disease affects primarily the lungs. Occasionally, other organs are affected; called disseminated histoplasmosis, it can be fatal if left untreated.
Histoplasmosis is common among AIDS patients because of their suppressed immunity. In immunocompetent individuals, past infection results in partial protection against ill effects if reinfected.
Histoplasma capsulatum is found in soil, often associated with decaying bat guano or bird droppings.  Disruption of soil from excavation or construction can release infectious elements that are inhaled and settle into the lung.
From 1938 to 2013 in the US, 105 outbreaks were reported in a total of 26 states plus Puerto Rico. In 1978 to 1979 during a large urban outbreak in which 100,000 people were exposed to the fungus in Indianapolis, victims had pericarditis, rheumatological syndromes, esophageal and vocal cord ulcers, parotitis, adrenal insufficiency, uveitis, fibrosing mediastinitis, interstitial nephritis, intestinal lymphangiectasia, and epididymitis. Histoplasmosis mimics colds, pneumonia, and the flu, and can be shed by bats in their feces.

Signs and symptoms
If symptoms of histoplasmosis infection occur, they start within 3 to 17 days after exposure; the typical time is 12–14 days. Most affected individuals have clinically silent manifestations and show no apparent ill effects. The acute phase of histoplasmosis is characterized by nonspecific respiratory symptoms, often cough or flu-like. Chest X-ray findings are normal in 40–70% of cases. Chronic histoplasmosis cases can  resemble tuberculosis; disseminated histoplasmosis affects multiple organ systems and is fatal unless treated.While histoplasmosis is the most common cause of mediastinitis, this remains a relatively rare disease. Severe infections can cause hepatosplenomegaly, lymphadenopathy, and adrenal enlargement. Lesions often left calcification nodules as they are healed.Presumed ocular histoplasmosis syndrome  causes chorioretinitis, where  the choroid and retina of the eyes are scarred, resulting in a loss of vision not unlike macular degeneration. Despite its name, the relationship to Histoplasma is controversial. Distinct from POHS, acute ocular histoplasmosis may rarely occur in immunodeficiency.

Complications
In absence of proper treatment and especially in immunocompromised individuals, complications can arise. These include recurrent pneumonia, respiratory failure, fibrosing mediastinitis, superior vena cava syndrome, pulmonary vessel obstruction, and progressive fibrosis of lymph nodes. Fibrosing mediastinitis is a serious complication and can be fatal. Smokers with structural lung disease have higher probability of developing chronic cavitary histoplasmosis.After healing of lesions, hard, calcified lymph nodes can erode the walls of the airway, causing hemoptysis.

Mechanisms
H. capsulatum grows in soil and material contaminated with bird or bat droppings (guano). The fungus has been found in poultry-house litter, caves, areas harboring bats, and bird roosts (particularly those of starlings). The fungus is thermally dimorphic; in the environment, it grows as a brownish mycelium, and at body temperature (37°C in humans), it morphs into a yeast. Histoplasmosis is not contagious but is contracted by inhalation of the spores from disturbed soil or guano. The inoculum is represented principally by microconidia. These are inhaled and reach the alveoli. In the alveoli, macrophages ingest these microconidia. They survive inside the phagosome. As the fungus is thermally dimorphic, these microconidia are transformed into yeast. They grow and multiply inside the phagosome. The macrophages travel in lymphatic circulation and can spread the disease to different organs.Within the phagosome, the fungus has an absolute requirement for thiamine. Cell-mediated immunity for histoplasmosis develops within 2 weeks. If the patient has strong cellular immunity, macrophages, epithelial cells, and lymphocytes surround the organisms and contain them, and eventually calcify. In immunocompromised individuals, the organisms disseminate to different organs such as bone, spleen, liver, adrenal glands, and mucocutaneous membranes, resulting in progressive disseminated histoplasmosis. Chronic lung disease can manifest.

Diagnosis
Clinically,  a wide spectrum of disease manifestations occurs, making diagnosis somewhat difficult. More severe forms include the chronic pulmonary form, often occurring in the presence of underlying pulmonary disease, and a disseminated form, which is characterized by the progressive spread of infection to extrapulmonary sites. Oral manifestations have been reported as the main complaint of the disseminated forms, leading the patient to seek treatment, whereas pulmonary symptoms in disseminated disease may be mild or even misinterpreted as flu. Histoplasmosis can be diagnosed by samples containing the fungus taken from sputum (via bronchoalveolar lavage), blood, or infected organs.  It can also be diagnosed by detection of antigens in blood or urine samples by ELISA or polymerase chain reaction. Antigens can cross-react with antigens of African histoplasmosis (caused by Histoplasma duboisii), blastomycosis, coccidioidomycosis, paracoccidioidomycosis, and talaromycosis infection. Histoplasmosis can also be diagnosed by a test for antibodies against Histoplasma in the blood.  Histoplasma skin tests indicate whether persons have been exposed, but do not indicate whether they have the disease. Formal histoplasmosis diagnoses are often confirmed only by culturing the fungus directly. Sabouraud agar is one agar growth medium on which the fungus can be cultured. Cutaneous manifestations of disseminated disease are diverse and often present as a nondescript rash with systemic complaints. Diagnosis is best established by urine antigen testing, as blood cultures may take up to 6 weeks for diagnostic growth to occur and serum antigen testing often comes back with a false negative before 4 weeks of disseminated infection.

Types
Histoplasmosis may be divided into these types:: 316–317
Primary pulmonary histoplasmosis
Progressive disseminated histoplasmosis
Primary cutaneous histoplasmosis
African histoplasmosis

Prevention
Testing or decontaminating most sites that may be contaminated with H. capsulatum is impractical, but the sources below list environments where histoplasmosis is common, and precautions to reduce a persons risk of exposure, in the three parts of the world where the disease is prevalent. Precautions common to all geographical locations would be to avoid accumulations of bird or bat droppings.The US National Institute for Occupational Safety and Health  provides information on work practices and personal protective equipment that may reduce the risk of infection.A review paper includes information on locations in which Histoplasma has been found in Africa (in chicken runs, on bats, in the caves bats inhabit, and in soil), and a thorough reference list including English, French, and Spanish language references.

Treatment
In the majority of immunocompetent individuals, histoplasmosis resolves without any treatment. Antifungal medications are used to treat severe cases of acute histoplasmosis and all cases of chronic and disseminated disease. Typical treatment of severe disease first involves treatment with amphotericin B, followed by oral itraconazole.Liposomal preparations of amphotericin B are more effective than deoxycholate preparations. The liposomal preparation is preferred in patients who might be at risk of nephrotoxicity, although all preparations of amphotericin B have risk of nephrotoxicity. Individuals taking amphotericin B are monitored for renal function. Liposomal amphotericin B is better at treating people with progressive disseminated Histoplasmosis and underlying HIV when compared to deoxycholate amphotericin B. Meanwhile, fluconazole performs poorly when compared to other azoles.Treatment with itraconazole must continue for at least a year in severe cases, while in acute pulmonary Histoplasmosis, 6 to 12 weeks treatment is sufficient. Alternatives to itraconazole are posaconazole, voriconazole, and fluconazole. Individuals taking itraconazole are monitored for hepatic function.

Prognosis
About 90% of patients with normal immune systems regain health without any intervention. Less than 5% need serious treatments.

Epidemiology
H. capsulatum is found throughout the world. It is endemic in certain areas of the United States, particularly in states bordering the Ohio River valley and the lower Mississippi River. The humidity and acidity patterns of soil are associated with endemicity. Bird and bat droppings in soil promote the growth of Histoplasma. Contact with such soil aerosolizes the microconidia, which can infect humans. It is also common in caves in Southern and East Africa. Positive Histoplasmin skin tests occur in as many as 90% of the people living in areas where H </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 Hip fracture and can you explain it in depth? [/INST] A hip fracture is a break that occurs in the upper part of the femur (thigh bone). Symptoms may include pain around the hip, particularly with movement, and shortening of the leg. Usually the person cannot walk.They most often occur as a result of a fall. (Femoral head fractures are a rare kind of hip fracture that may also be the result of a fall but are more commonly caused by more violent incidents such as traffic accidents.) Risk factors include osteoporosis, taking many medications, alcohol use, and metastatic cancer. Diagnosis is generally by X-rays. Magnetic resonance imaging, a CT scan, or a bone scan may occasionally be required to make the diagnosis.Pain management may involve opioids or a nerve block. If the persons health allows, surgery is generally recommended within two days. Options for surgery may include a total hip replacement or stabilizing the fracture with screws. Treatment to prevent blood clots following surgery is recommended.About 15% of women break their hip at some point in life; women are more often affected than men. Hip fractures become more common with age. The risk of death in the year following a fracture is about 20% in older people.

Signs and symptoms
The classic clinical presentation of a hip fracture is an elderly patient who sustained a low-energy fall and now has groin pain and is unable to bear weight. Pain may be referred to the supracondylar knee. On examination, the affected extremity is often shortened and externally rotated compared to the unaffected leg.

Complications
Nonunion, failure of the fracture to heal, is common in fractures of the neck of the femur, but much more rare with other types of hip fracture. Avascular necrosis of the femoral head occurs frequently (20%) in intracapsular hip fractures, because the blood supply is interrupted.Malunion, healing of the fracture in a distorted position, is very common.  The thigh muscles tend to pull on the bone fragments, causing them to overlap and reunite incorrectly. Shortening, varus deformity, valgus deformity, and rotational malunion all occur often because the fracture may be unstable and collapse before it heals.  This may not be as much of a concern in patients with limited independence and mobility.Hip fractures rarely result in neurological or vascular injury.

Medical
Many people are unwell before breaking a hip; it is common for the break to have been caused by a fall due to some illness, especially in the elderly.  Nevertheless, the stress of the injury, and a likely surgery, increases the risk of medical illness including heart attack, stroke, and chest infection.Hip fracture patients are at considerable risk for thromboemoblism, blood clots that dislodge and travel in the bloodstream. Deep venous thrombosis (DVT) is when the blood in the leg veins clots and causes pain and swelling. This is very common after hip fracture as the circulation is stagnant and the blood is hypercoagulable as a response to injury. DVT can occur without causing symptoms.  A pulmonary embolism (PE) occurs when clotted blood from a DVT comes loose from the leg veins and passes up to the lungs. Circulation to parts of the lungs is cut off which can be very dangerous. Fatal PE may have an incidence of 2% after hip fracture and may contribute to illness and mortality in other cases.Mental confusion is extremely common following a hip fracture. It usually clears completely, but the disorienting experience of pain, immobility, loss of independence, moving to a strange place, surgery, and drugs combine to cause delirium or accentuate pre-existing dementia.
Urinary tract infection (UTI) can occur. Patients are immobilized and in bed for many days; they are frequently catheterised, commonly causing infection.
Prolonged immobilization and difficulty moving make it hard to avoid pressure sores on the sacrum and heels of patients with hip fractures. Whenever possible, early mobilization is advocated; otherwise, alternating pressure mattresses should be used.

Risk factors
Hip fracture following a fall is likely to be a pathological fracture. The most common causes of weakness in bone are:
Osteoporosis.
Other metabolic bone diseases such as Pagets disease, osteomalacia, osteopetrosis and osteogenesis imperfecta. Stress fractures may occur in the hip region with metabolic bone disease.
Elevated levels of homocysteine, a toxic natural amino acid.
Benign or malignant primary bone tumors are rare causes of hip fractures.
Metastatic cancer deposits in the proximal femur may weaken the bone and cause a pathological hip fracture.
Infection in the bone is a rare cause of hip fracture.
Tobacco smoking (associated with osteoporosis).

Mechanism
Functional anatomy
The hip joint is a ball-and-socket joint. The femur connects at the acetabulum of the pelvis and projects laterally before angling medially and inferiorly to form the knee. Although this joint has three degrees of freedom, it is still stable due to the interaction of ligaments and cartilage. The labrum lines the circumference of the acetabulum to provide stability and shock absorption. Articular cartilage covers the concave area of acetabulum, providing more stability and shock absorption.  Surrounding the entire joint itself is a capsule secured by the tendon of the psoas muscle and three ligaments. The iliofemoral, or Y, ligament is located anteriorly and serves to prevent hip hyperextension. The pubofemoral ligament is located anteriorly just underneath the iliofemoral ligament and serves primarily to resist abduction, extension, and some external rotation. Finally the ischiofemoral ligament on the posterior side of the capsule resists extension, adduction, and internal rotation. When considering the biomechanics of hip fractures, it is important to examine the mechanical loads the hip experiences during low energy falls.

Biomechanics
The hip joint is unique in that it experiences combined mechanical loads. An axial load along the shaft of the femur results in compressive stress. Bending load at the neck of the femur causes tensile stress along the upper part of the neck and compressive stress along the lower part of the neck. While osteoarthritis and osteoporosis are associated with bone fracture as we age, these diseases are not the cause of the fracture alone. Low energy falls from standing are responsible for the majority of fractures in the elderly, but fall direction is also a key factor. Elderly tend to fall to the side as instead of forward, and the lateral hip and strikes the ground first. During a sideways fall, the chances of hip fracture see a 15-fold and 12-fold increase in elderly males and females, respectively.

Neurological factors
Elderly individuals are also predisposed to hip fractures due to many factors that can compromise proprioception and balance, including medications, vertigo, stroke, and peripheral neuropathy.

Diagnosis
Physical examination
Displaced fractures of the trochanter or femoral neck will classically cause external rotation and shortening of the leg when the patient is laying supine.

Imaging
Typically, radiographs are taken of the hip from the front (AP view), and side (lateral view). Frog leg views are to be avoided, as they may cause severe pain and further displace the fracture. In situations where a hip fracture is suspected but not obvious on x-ray, an MRI is the next test of choice. If an MRI is not available or the patient can not be placed into the scanner a CT may be used as a substitute. MRI sensitivity for radiographically occult fracture is greater than CT. Bone scan is another useful alternative however substantial drawbacks include decreased sensitivity, early false negative results and decreased conspicuity of findings due to age-related metabolic changes in the elderly.A case demonstrating a possible order of imaging in initially subtle findings:

As the patients most often require an operation, full pre-operative general investigation is required. This would normally include blood tests, ECG and chest x-ray.

Types
X-rays of the affected hip usually make the diagnosis obvious; AP (anteroposterior) and lateral views should be obtained.
Trochanteric fractures are subdivided into either intertrochanteric (between the greater and lesser trochanter) or pertrochanteric (through the trochanters) by the Müller AO Classification of fractures. Practically, the difference between these types is minor. The terms are often used synonymously. An isolated trochanteric fracture involves one of the trochanters without going through the anatomical axis of the femur, and may occur in young individuals due to forceful muscle contraction. Yet, an isolated trochanteric fracture may not be regarded as a true hip fracture because it is not cross-sectional.

Prevention
The majority of hip fractures are the result of a fall, particularly in the elderly.  Therefore, identifying why the fall occurred, and implementing treatments or changes, is key to reducing the occurrence of hip fractures.  Multiple contributing factors are often identified. These can include environmental factors and medical factors (such as postural hypotension or co-existing disabilities from disease such as Stroke or Parkinsons disease which cause visual and/or balance impairments).  A recent study has identified a high incidence of undiagnosed cervical spondylotic myelopathy (CSM) amongst patients with a hip fracture. This is relatively unrecognised consequent of CSM.Additionally, there is some evidence to systems designed to offer protection in the case of a fall. Hip protectors, for example appear to decrease the number of hip fractures among the elderly, but they are often not used.

Management
Most hip fractures are treated surgically by implanting a prosthesis. Surgical treatment outweighs the risks of nonsurgical treatment which requires extensive bedrest. Prolonged immobilization increases risk of thromboembolism, pneumonia, deconditioning, and decubitus ulcers. Regardless, the surgery is a major stress, particularly in the elderly. Pain is also significant, and can also result in immobilization, so patients are encouraged to become mobile as soon as possible, often with the assistance of physical therapy. Skeletal traction pending surgery is not supported by the evidence. Regional nerve blocks are useful for pain management in hip fractures. Peripheral nerve blocks may reduce pain on movement and acute confusional state, may improve time to first mobilisation, and may reduce the risk of postoperative lower respiratory tract infection. Surgery can be performed under general anaesthesia or with neuraxial techniques – choice is based on surgical and patient factors, as outcomes such as mortality and post-procedure complications including pneumonia, MI, stroke or confusion, are not affected by anaesthetic technique.Red blood cell transfusion is common for people undergoing hip fracture surgery due to the blood loss sustained during surgery and from the injury. The benefits of giving blood when the hemoglobin is less than 10 g/dL versus less than 8 g/dL are not clear. Waiting until the hemoglobin was less than 8 g/dL or the person had symptoms may increase the risk of heart problems.If operative treatment is refused or the risks of surgery are considered to be too high the main emphasis of treatment is on pain relief. Skeletal traction may be considered for long-term treatment. Aggressive chest physiotherapy is needed to reduce the risk of pneumonia and skilled rehabilitation and nursing to avoid pressure sores and DVT/pulmonary embolism Most people will be bedbound for several months. Non-operative treatment is now limited to only the most medically unstable or demented patients or those who are nonambulatory at baseline with minimal pain during transfers.Surgery on the same day or day following the break is estimated to reduce postoperative mortality in people who are medically stable.

Intracapsular fractures
For low-grade fractures (Garden types 1 and 2), standard treatment is fixation of the fracture in situ with screws or a sliding screw/plate device. This treatment can also be offered for displaced fractures after the fracture has been reduced.Fractures managed by closed reduction can possibly be treated by percutaneously inserted screws.In elderly patients with displaced or intracapsular fractures many surgeons prefer to undertake a hemiarthroplasty, replacing the broken part of the bone with a metal implant. However, in elderly people who are medically well and still active, a total hip replacement may be indicated. Independently mobile older adults with hip fractures may benefit from a total hip replacement instead of hemiarthroplasty.Traction is contraindicated in femoral neck fractures due to it affecting blood flow to the head of the femur.The latest evidence suggests that there may be little or no difference between screws and fixed angle plates as internal fixation implants for intracapsular hip fractures in older adults. The findings are based on low quality evidence that cant firmly conclude major difference in hip function, quality of life, and additional surgery.

Trochanteric fracture
A trochanteric fracture, below the neck of the femur, has a good chance of healing.
Closed reduction may not be satisfactory and open reduction then becomes necessary. The use of open reduction has been reported as 8-13% among pertrochanteric fractures, and 52% among intertrochanteric fractures. Both intertrochanteric and pertrochanteric fractures may be treated by a dynamic hip screw and plate, or an intramedullary rod.The fracture typically takes 3–6 months to heal. As it is only common in elderly, removal of the dynamic hip screw is usually not recommended to avoid unnecessary risk of second operation and the increased risk of re-fracture after implant removal. The most common cause for hip fractures in the elderly is osteoporosis; if this is the case, treatment of the osteoporosis can well reduce the risk of further fracture. Only young patients tend to consider having it removed; the implant may function as a stress riser, increasing the risk of a break if another accident occurs.

Subtrochanteric fractures
Subtrochanteric fractures may be treated with an intramedullary nail or a screw-plate construction and may require traction pre-operatively, though this practice is uncommon. It is unclear if any specific type of nail results in different outcomes than any other type of nail.A lateral incision over the trochanter is made and a cerclage wire is placed around the fracture for reduction. Once reduction has been achieved a guide canal for the nail is made through the proximal cortex and medullary. The nail is inserted through the canal and is fixated proximally and distally with screws. X-rays are obtained to ensure proper reduction and placement of the nail and screws are achieved.

Rehabilitation
Rehabilitation has been proven to increase daily functional status. Forty percent of individuals with hip fractures are also diagnosed with dementia or mild cognitive impairment which often results in poorer post-surgical outcomes.  In such cases enhanced rehabilitation and care models have been shown to have limited positive effects in reducing delirium and hospital length of stay.   It is unclear if the use of anabolic steroids effects recovery.There is not enough evidence to ascertain what are the best strategies to promote walking after hip fracture surgery. On the other hand, there is moderate-certaintly evidence that rehabilitation after hip fracture surgery, when delivered by a multidisciplinary team and supervised by an appropriate medical specialist, results in fewer cases of poor outcome, like death and deterioration in residential status.

Nutrition supplementation
Oral supplements with non-protein energy, protein, vitamins and minerals started before or early after surgery may prevent complications during the first year after hip fracture in aged adults; without seemingly effects on mortality.

Surgical complications
Deep or superficial wound infection has an approximate incidence of 2%. It is a serious problem as superficial infection may lead to deep infection. This may cause infection of the healing bone and contamination of the implants. It is difficult to eliminate infection in the presence of metal foreign bodies such as implants. Bacteria inside the implants are inaccessible to the bodys defence system and to antibiotics. The management is to attempt to suppress the infection with drainage and antibiotics until the bone is healed. Then the implant should be removed, following which the infection may clear up.
Implant failure may occur; the metal screws and plate can break, back out, or cut out superiorly and enter the joint. This occurs either through inaccurate implant placement or if the fixation does not hold in weak and brittle bone. In the event of failure, the surgery may be redone or changed to a total hip replacement. Mal-positioning: The fracture can be fixed and subsequently heal in an incorrect position; especially rotation. This may not be a severe problem or may require subsequent osteotomy surgery for correction.

Prognosis
Hip fractures are very dangerous episodes, especially for elderly and frail patients. The risk of dying from the stress of the surgery and the injury in the first thirty days is about 10%. At one year after fracture, this may reach 30%. If the condition is untreated the pain and immobility imposed on the patient increase that risk. Problems such as pressure sores and chest infections are all increased by immobility. The prognosis of untreated hip fractures is very poor.

Post operation
Among those affected over the age of 65, 40% are transferred directly to long-term care facilities, long-term rehabilitation facilities, or nursing homes; most of those affected require some sort of living assistance from family or home-care providers.  50% permanently require walkers, canes, or crutches for mobility; all require some sort of mobility assistance throughout the healing process. Most of the recovery of walking ability and activities of daily living occurs within 6 months of the fracture. After the fracture about half of older people recover their pre-fracture level of mobility and ability to perform instrumental activities of daily living, while 40–70% regain their level of independence for basic activities of daily living.Among those affected over the age of 50, approximately 25% die within the next year due to complications such as blood clots (deep venous thrombosis, pulmonary embolism), infections, and pneumonia.Patients with hip fractures are at high risk for future fractures including hip, wrist, shoulder, and spine. After treatment of the acute fracture, the risk of future fractures should be addressed. Currently, only 1 in 4 patients after a hip fracture receives treatment and work up for osteoporosis, the underlying cause of most of the fractures. Current treatment standards include the starting of a bisphosphonate to reduce future fracture risk by up to 50%.

Epidemiology
Hip fractures are seen globally and are a serious concern at the individual and population level. By 2050, it is estimated that there will be six million cases of hip fractures worldwide. One study published in 2001 found that in the US alone, 310,000 individuals were hospitalized due to hip fractures, which can account for 30% of Americans who were hospitalized that year. Another study found that in 2011, femur neck fractures were among the most expensive conditions seen in US hospitals, with an aggregated cost of nearly $4.9 billion for 316,000 inpatient hospitalizations. Rates of hip fractures are declining in the United States, possibly due to increased use of bisphosphonates and risk management. Falling, poor vision, weight, and height are all seen as risk factors. Falling is one of the most common risk factors for hip fractures. Approximately 90% of hip fractures are attributed to falls from standing height.Given the high morbidity and mortality associated with hip fractures and the cost to the health system, in England and Wales, the National Hip Fracture Database is a mandatory nationwide audit of care and treatment of all hip fractures.

Population
All populations experience hip fractures but numbers vary with race, gender, and age. Women have three times as many hip fractures as men. In a lifetime, men have an estimated 6% risk whereas postmenopausal women have an estimated 14% risk of having a hip fracture </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 cutaneous lupus erythematosus 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 Primary myelofibrosis and can you explain it in depth? [/INST] Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL gene markers. In PMF, the healthy marrow is replaced by scar tissue (fibrosis), resulting in a lack of production of normal blood cells. Symptoms include anemia, increased infection and an enlarged spleen (splenomegaly).
In 2016, prefibrotic primary myelofibrosis was formally classified as a distinct condition that progresses to overt PMF in many patients, the primary diagnostic difference being the grade of fibrosis.

Signs and symptoms
The primary feature of primary myelofibrosis is bone marrow fibrosis, but it is often accompanied by:

Abdominal fullness related to an enlarged spleen (splenomegaly).
Bone pain
Bruising and easy bleeding due to inadequate numbers of platelets
Cachexia (loss of appetite, weight loss, and fatigue)
Enlargement of both the liver and spleen
Fatigue
Gout and high uric acid levels
Increased susceptibility to infection, such as pneumonia
Pallor and shortness of breath due to anemia
In rarer cases, a raised red blood cell volume
Cutaneous myelofibrosis is a rare skin condition characterized by dermal and subcutaneous nodules.: 746

Causes
The underlying cause of PMF is unknown (idiopathic disease). There is an association between mutations to the JAK2, CALR, or MPL gene and myelofibrosis. Approximately 90% of those with myelofibrosis have one of these mutations and 10% carry none of these mutations. These mutations are not specific to myelofibrosis, and are linked to other myeloproliferative neoplasms, specifically polycythemia vera and essential thrombocythemia.The V617F mutation to the JAK2 protein is found in approximately half of individuals with primary myelofibrosis. The V617F mutation is a change of valine to phenylalanine at the 617 position. Janus kinases (JAKs) are non-receptor tyrosine kinases essential for the activation of signaling that is mediated by cytokine receptors lacking catalytic activity. These include receptors for erythropoietin, thrombopoietin, most interleukins and interferon. JAK2 mutations are significant because JAK2 plays a role in controlling production of blood cells from hematopoietic stem cells. The V617F mutation appears to make hematopoietic cells more sensitive to growth factors that need JAK2 for signal transduction, which include erythropoietin and thrombopoietin.The MPL gene codes for a protein that acts as a receptor for thrombopoietin. A mutation in that gene, known as a W515 mutation, leads to the production of an abnormal thrombopoietin receptor protein, which results in the overproduction of abnormal megakaryocytes. The abnormal megakaryocytes stimulate other cells, the fibroblasts, to produce collagen in the bone marrow, by secreting PDGF and TGF-β1.

Mechanism
Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of blood cellular components. It is one of the myeloproliferative disorders, diseases of the bone marrow in which excess cells are produced at some stage. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes) leads to replacement of the hematopoietic tissue of the bone marrow by connective tissue via collagen fibrosis. The decrease in hematopoietic tissue impairs the patients ability to generate new blood cells, resulting in progressive pancytopenia, a shortage of all blood cell types. However, the proliferation of fibroblasts and deposition of collagen is a secondary phenomenon, and the fibroblasts themselves are not part of the abnormal cell clone.In primary myelofibrosis, progressive scarring, or fibrosis, of the bone marrow occurs, for the reasons outlined above. The result is extramedullary hematopoiesis, i.e. blood cell formation occurring in sites other than the bone marrow, as the hemopoietic cells are forced to migrate to other areas, particularly the liver and spleen. This causes an enlargement of these organs. In the liver, the abnormal size is called hepatomegaly. Enlargement of the spleen is called splenomegaly, which also contributes to causing pancytopenia, particularly thrombocytopenia and anemia. Another complication of extramedullary hematopoiesis is poikilocytosis, or the presence of abnormally shaped red blood cells.Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly, essential thrombocythemia. In these cases, myelofibrosis occurs as a result of somatic evolution of the abnormal hematopoietic stem cell clone that caused the original disorder. In some cases, the development of myelofibrosis following these disorders may be accelerated by the oral chemotherapy drug hydroxyurea.

Sites of hematopoiesis
The principal site of extramedullary hematopoiesis in myelofibrosis is the spleen, which is usually markedly enlarged, sometimes weighing as much as 4000 g. As a result of massive enlargement of the spleen, multiple subcapsular infarcts often occur in the spleen, meaning that due to interrupted oxygen supply to the spleen partial or complete tissue death happens. On the cellular level, the spleen contains red blood cell precursors, granulocyte precursors and megakaryocytes, with the megakaryocytes prominent in their number and in their bizarre shapes. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition, as discussed under "Mechanism" above. Sometimes unusual activity of the red blood cells, white blood cells, or platelets is seen. The liver is often moderately enlarged, with foci of extramedullary hematopoiesis. Microscopically, lymph nodes also contain foci of hematopoiesis, but these are insufficient to cause enlargement.There are also reports of hematopoiesis taking place in the lungs. These cases are associated with hypertension in the pulmonary arteries.The bone marrow in a typical case is hypercellular and diffusely fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually dysplastic.

Diagnosis
Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50.Diagnosis is made on the basis of bone marrow biopsy. Fibrosis grade 2 or 3 defines overt PMF whereas grade 0 or 1 defines prefibrotic primary myelofibrosis.A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both.Blood tests are also used in diagnosis. Primary myelofibrosis can begin with a blood picture similar to that found in polycythemia vera or chronic myeloid leukemia. Most people with myelofibrosis have moderate to severe anemia. Eventually thrombocytopenia, a decrease of blood platelets develops. When viewed through a microscope, a blood smear will appear markedly abnormal, with presentation of pancytopenia, which is a reduction in the number of all blood cell types: red blood cells, white blood cells, and platelets. Red blood cells may show abnormalities including bizarre shapes, such as teardrop-shaped cells, and nucleated red blood cell precursors may appear in the blood smear (leukoerythroblastic reaction). Normally, mature red blood cells in adults do not have a cell nucleus, and the presence of nucleated red blood cells suggests that immature cells are being released into the bloodstream in response to a very high demand for the bone marrow to produce new red blood cells. Immature white cells and platelets (large megakaryocytes) are also seen in blood samples, and basophil counts are increased. When late in the disease progression an attempt is made to take a sample of bone marrow by aspiration, it may result in a dry tap, meaning that where the needle can normally suck out a sample of semi-liquid bone marrow, it produces no sample because the marrow has been replaced with collagen fibers </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 Craniodiaphyseal 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 X-linked endothelial corneal dystrophy 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 Sinusoidal hemangioma 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 Sick building syndrome and can you explain it in depth? [/INST] Sick building syndrome (SBS) is a condition in which people in a building develop symptoms of illness or become infected with chronic disease from the building in which they work or reside. The outbreaks may or may not be a direct result of inadequate cleaning or inappropriate cleaning methods. SBS has also been used to describe staff concerns in post-war buildings with misplanned building aerodynamics, defects in the construction materials or assembly process and-or inadequate maintenance. Certain symptoms tend to increase in severity with the time people spend in the building; often improving over time or even disappearing when people are away from the building. SBS is also used interchangeably with "building-related symptoms", which orients the name of the condition around patients symptoms rather than a "sick" building. A 1984 World Health Organization (WHO) report suggested up to 30% of new and remodeled buildings worldwide may be subject of complaints related to poor indoor air quality.
Other causes have been attributed to contaminants produced by outgassing of some types of building materials, volatile organic compounds (VOC), improper exhaust ventilation of ozone (byproduct of some office machinery), light industrial chemicals used within, or lack of adequate fresh-air intake/air filtration (see minimum efficiency reporting value).The main identifying observation is an increased incidence of complaints of symptoms such as headache, eye, nose, and throat irritation, fatigue, and dizziness and nausea. In fact the 1989 Oxford English Dictionary defines SBS in that way. The World Health Organization created a 484-page tome on indoor air quality back in 1984 when SBS was attributed only to non-organic causes, and suggested that the book might form a basis for legislation or litigation.Case studies can contribute to a better understanding and management of sick building syndrome. Sick building causes are frequently pinned down to flaws in the heating, ventilation, and air conditioning (HVAC) systems. However, there have been inconsistent findings on whether air conditioning systems result in SBS or not.More recently, sick building was confirmed as a vector for the transmission of SARS in 2003. Norovirus has also been linked with buildings because of "the small inoculum required to produce infection (<100 viral particles), prolonged viral shedding, and its ability to survive in the environment." Many norovirus outbreaks have been traced back to cruise ships with food service in unsanitary conditions, or filthy personal hygiene around the toilet.

Signs and symptoms
Human exposure to aerosols has been documented to give rise to a variety of adverse health effects. Building occupants complain of symptoms such as sensory irritation of the eyes, nose, or throat; neurotoxic or general health problems; skin irritation; nonspecific hypersensitivity reactions; infectious diseases; and odor and taste sensations. Exposure to poor lighting conditions has led to general malaise.Extrinsic allergic alveolitis has been associated with the presence of fungi and bacteria in the moist air of residential houses and commercial offices. A study in 2017 correlated several inflammatory diseases of the respiration tract with objective evidence of damp-caused damage in homes.The WHO has classified the reported symptoms into broad categories, including: mucous membrane irritation (eye, nose, and throat irritation), neurotoxic effects (headaches, fatigue, and irritability), asthma and asthma-like symptoms (chest tightness and wheezing), skin dryness and irritation, gastrointestinal complaints and more.Several sick occupants may report individual symptoms which do not appear to be connected. The key to discovery is the increased incidence of illnesses in general with onset or exacerbation within a fairly close time frame – usually within a period of weeks. In most cases, SBS symptoms will be relieved soon after the occupants leave the particular room or zone. However, there can be lingering effects of various neurotoxins, which may not clear up when the occupant leaves the building. In some cases – particularly in sensitive individuals – there can be long-term health effects.

Cause
ASHRAE has recognized that polluted urban air, designated within the United States Environmental Protection Agency (EPA)s air quality ratings as unacceptable, requires the installation of treatment such as filtration for which the HVAC practitioners generally apply carbon-impregnated filters and their likes. Different toxins will aggravate the human body in different ways. Some people are more allergic to mold, while others are highly sensitive to dust. Inadequate ventilation will exaggerate small problems (such as deteriorating fiberglass insulation or cooking fumes) into a much more serious indoor air quality problem. Common products such as paint, insulation, rigid foam, Particle Board, plywood, duct liners, exhaust fumes and other chemical contaminants from indoor or outdoor sources, and biological contaminants can be trapped inside by the HVAC AC system. As this air is recycled using fan coils the overall oxygenation ratio drops and becomes harmful. When combined with other stress factors such as traffic noise, poor lighting, inhabitants of buildings located in a polluted urban area can quickly become ill as their immune system is overwhelmed. Certain VOCs, considered toxic chemical contaminants to humans, are used as adhesives in all common building construction products. These aromatic carbon rings / VOCs can cause acute and chronic health effects on the occupants of a building, including cancer, paralysis, lung failure, and others. Bacterial spores, fungal spores, mold spores, pollen, and viruses are types of biological contaminants and can all cause allergic reactions or illness described as SBS. In addition, pollution from outdoors, such as motor vehicle exhaust, can infiltrate into poorly designed buildings and contribute to poor indoor air quality, high ppm of CO and CO2. Adult SBS symptoms were associated with a history of allergic rhinitis, eczema and asthma.A 2015 study concerning the association of SBS and indoor air pollutants in office buildings in Iran found that, as carbon dioxide levels increase in a building, symptoms like nausea, headaches, nasal irritation, dyspnea, and throat dryness have also been shown to increase. Certain work conditions have been found to be correlated with specific symptoms. For example, higher light intensity was significantly related to skin dryness, eye pain, and malaise. Higher temperature has also been found to correlate with symptoms such as sneezing, skin redness, itchy eyes and headache, while lower relative humidity has been associated with sneezing, skin redness, and pain of the eyes.In 1973, in response to the oil crisis and conservation concerns, ASHRAE Standards 62-73 and 62-81 reduced required ventilation from 10 cubic feet per minute (4.7 L/s) per person to 5 cubic feet per minute (2.4 L/s) per person, but this was found to be a contributing factor to sick building syndrome. As of the 2016 revision, ASHRAE ventilation standards call for 5 to 10 cubic feet per minute of ventilation per occupant (depending on the occupancy type) in addition to ventilation based on the zone floor area delivered to the breathing zone.

Psychological factors
One study looked at commercial buildings and their employees, comparing some environmental factors suspected of inducing SBS to a self-reported survey of the occupants, finding that the measured psycho-social circumstances appeared more influential than the tested environmental factors. The authors of that study pointed to the self-reported nature of the observations as a limitation of the research.Research has shown that SBS shares several symptoms common in other conditions thought to be at least partially caused by psychosomatic tendencies. The umbrella term "autoimmune/inflammatory syndrome induced by adjuvants" has been suggested. Other members of the suggested group include silicosis, macrophagic myofascitis, Gulf War syndrome, and post-vaccination phenomena.

Workplace
Greater effects were found with features of the psycho-social work environment including high job demands and low support. The report concluded that the physical environment of office buildings appears to be less important than features of the psycho-social work environment in explaining differences in the prevalence of symptoms. However, there is still a relationship between sick building syndrome and symptoms of workers regardless of workplace stress.Excessive work stress or dissatisfaction, poor interpersonal relationships and poor communication are often seen to be associated with SBS, recent studies show that a combination of environmental sensitivity and stress can greatly contribute to sick building syndrome.Specific work-related stressors are related with specific SBS symptoms. Workload and work conflict are significantly associated with general symptoms (headache, abnormal tiredness, sensation of cold or nausea). While crowded workspaces and low work satisfaction are associated with upper respiratory symptoms. Work productivity has been associated with ventilation rates, a contributing factor to SBS, and theres a significant increase in production as ventilation rates increase, by 1.7% for every two-fold increase of ventilation rate. Printer effluent, released into the office air as ultra-fine particles (UFPs) as toner is burned during the printing process, may lead to certain SBS symptoms. Printer effluent may contain a variety of toxins to which a subset of office workers are sensitive, triggering SBS symptoms.Specific careers are also associated with specific SBS symptoms. Transport, communication, healthcare, and social workers have highest prevalence of general symptoms. Skin symptoms such as eczema, itching, and rashes on hands and face are associated with technical work. Forestry, agriculture, and sales workers have the lowest rates of sick building syndrome symptoms.From the assessment done by Fisk and Mudarri, 21% of asthma cases in the United States were caused by wet environments with mold that exist in all indoor environments, such as schools, office buildings, houses and apartments. Also found the exposure to the mold increases the chances of respiratory issues by 30 to 50 percent. Additionally, studies showing that health effects with dampness and mold in indoor environments found that increased risk of adverse health effects occurs with dampness or visible mold environments.Milton et al. determined the cost of sick leave specific for one business was an estimated $480 per employee, and about five days of sick leave per year could be attributed to low ventilation rates. When comparing low ventilation rate areas of the building to higher ventilation rate areas, the relative risk of short-term sick leave was 1.53 times greater in the low ventilation areas.

Home
Sick building syndrome can also occur due to factors of the home. Laminate flooring can cause more exposure to chemicals and more resulting SBS symptoms compared to stone, tile, and cement flooring. Recent redecorating and new furnishings within the last year were also found to be associated with increased symptoms, along with dampness and related factors, having pets, and the presence of cockroaches. The presence of mosquitoes was also a factor related to more symptoms, though it is unclear whether it was due to the presence of mosquitoes or the use of repellents.

Mold
Some studies have found that Sick building syndrome may be associated with indoor mould or mycotoxin contamination. However, the attribution of sick building syndrome to mould is controversial and supported by little evidence.
 Reducing the dampness in all indoor environment will prevent all the respiratory issues caused by dampness and mold in indoor environment.

Indoor temperature
Indoor temperature under 18 °C (64 °F) has been shown to be associated with increased respiratory and cardiovascular diseases, increased blood levels, and increased hospitalization.

Diagnosis
While sick building syndrome (SBS) encompasses a multitude of non-specific symptoms, building-related illness (BRI) comprises specific, diagnosable symptoms caused by certain agents (chemicals, bacteria, fungi, etc.). These can typically be identified, measured, and quantified. There are usually 4 causal agents in BRI; 1.) Immunologic, 2.) Infectious, 3.) toxic, and 4.) irritant. For instance, Legionnaires disease, usually caused by Legionella pneumophila, involves a specific organism which could be ascertained through clinical findings as the source of contamination within a building.

Prevention
Regular inspections to indicate for presence of mold or other toxins
Adequate maintenance of all building mechanical systems
Toxin-absorbing plants, such as sansevieria
Roof shingle non-pressure cleaning for removal of algae, mold, and Gloeocapsa magma
Using ozone to eliminate the many sources, such as VOCs, molds, mildews, bacteria, viruses, and even odors. However, numerous studies identify high-ozone shock treatment as ineffective despite commercial popularity and popular belief.
Replacement of water-stained ceiling tiles and carpeting
Only using paints, adhesives, solvents, and pesticides in well-ventilated areas or only using these pollutant sources during periods of non-occupancy
Increasing the number of air exchanges; the American Society of Heating, Refrigeration and Air-Conditioning Engineers recommend a minimum of 8.4 air exchanges per 24-hour period
Increased ventilation rates that are above the minimum guidelines
Proper and frequent maintenance of HVAC systems
UV-C light in the HVAC plenum
Installation of HVAC air cleaning systems or devices to remove VOCs and bioeffluents (people odors)
Central vacuums that completely remove all particles from the house including the ultrafine particles (UFPs) which are less than 0.1 μm
Regular vacuuming with a HEPA filter vacuum cleaner to collect and retain 99.97% of particles down to and including 0.3 micrometers
Placing bedding in sunshine, which is related to a study done in a high-humidity area where damp bedding was common and associated with SBS
Lighting in the workplace should be designed to give individuals control, and be natural when possible
Relocating office printers outside the air conditioning boundary, perhaps to another building
Replacing current office printers with lower emission rate printers
Identification and removal of products containing harmful ingredients

Management
SBS, as a non specific blanket term, does not have any specific cause or cure. Any known cure would be associated with the specific eventual disease that was cause by exposure to known contaminants. In all cases, alleviation consists of removing the affected person from the building associated. BRI, on the other hand, utilizes treatment appropriate for the contaminant identified within the building (e.g., antibiotics for Legionnaires disease).In most cases, simply improving the indoor air quality (IAQ) of a particular building will attenuate, or even eliminate, the continued exposure to toxins. For the individual, the recovery may be a process involved with targeting the acute symptoms of a specific illness, as in the case of mold toxins. Treating various building-related illnesses is vital to the overall understanding of SBS. Careful analysis by certified building professionals and Medical Doctors can help to identify the exact cause of the BRI, and help to illustrate a causal path to infection. With this knowledge one can, theoretically, remediate a building of contaminants and rebuild the structure with new materials. Office BRI may more likely than not be explained by three events: "Wide range in the threshold of response in any population (susceptibility), a spectrum of response to any given agent, or variability in exposure within large office buildings." Isolating any one of the three aspects of office BRI can be a great challenge, which is why those who find themselves with BRI should take three steps, history, examinations, and interventions. History describes the action of continually monitoring and recording the health of workers experiencing BRI, as well as obtaining records of previous building alterations or related activity. Examinations go hand in hand with monitoring employee health. This step is done by physically examining the entire workspace and evaluating possible threats to health status among employees. Interventions follow accordingly based on the results of the Examination and History report.

Epidemiology
Some studies have found that women have higher reports of SBS symptoms than men. It is not entirely clear, however, if this is due to biological, social, or occupational factors.
A 2001 study published in the Journal Indoor Air, gathered 1464 office-working participants to increase the scientific understanding of gender differences under the Sick Building Syndrome phenomenon. Using questionnaires, ergonomic investigations, building evaluations, as well as physical, biological, and chemical variables, the investigators obtained results that compare with past studies of SBS and gender. The study team found that across most test variables, prevalence rates were different in most areas, but there was also a deep stratification of working conditions between genders as well. For example, mens workplaces tend to be significantly larger and have all-around better job characteristics. Secondly, there was a noticeable difference in reporting rates, specifically that women have higher rates of reporting roughly 20% higher than men. This information was similar to that found in previous studies, thus indicating a potential difference in willingness to report.There might be a gender difference in reporting rates of sick building syndrome, because women tend to report more symptoms than men do. Along with this, some studies have found that women have a more responsive immune system and are more prone to mucosal dryness and facial erythema. Also, women are alleged by some to be more exposed to indoor environmental factors because they have a greater tendency to have clerical jobs, wherein they are exposed to unique office equipment and materials (example: blueprint machines, toner-based printers), whereas men often have jobs based outside of offices.

History
In the late 1970s, it was noted that nonspecific symptoms were reported by tenants in newly constructed homes, offices, and nurseries. In media it was called "office illness". The term "sick building syndrome" was coined by the WHO in 1986, when they also estimated that 10–30% of newly built office buildings in the West had indoor air problems. Early Danish and British studies reported symptoms.
Poor indoor environments attracted attention. The Swedish allergy study (SOU 1989:76) designated "sick building" as a cause of the allergy epidemic as was feared. In the 1990s, therefore, extensive research into "sick building" was carried out. Various physical and chemical factors in the buildings were examined on a broad front.
The problem was highlighted increasingly in media and was described as a "ticking time bomb". Many studies were performed in individual buildings.
In the 1990s "sick buildings" were contrasted against "healthy buildings". The chemical contents of building materials were highlighted. Many building material manufacturers were actively working to gain control of the chemical content and to replace criticized additives. The ventilation industry advocated above all more well-functioning ventilation. Others perceived ecological construction, natural materials, and simple techniques as a solution.
At the end of the 1990s came an increased distrust of the concept of "sick building". A dissertation at the Karolinska Institutet in Stockholm 1999 questioned the methodology of previous research, and a Danish study from 2005 showed these flaws experimentally. It was suggested that sick building syndrome was not really a coherent syndrome and was not a disease to be individually diagnosed, but a collection of as many as to dozen semi related diseases. In 2006 the Swedish National Board of Health and Welfare recommended in the medical journal Läkartidningen that "sick building syndrome" should not be used as a clinical diagnosis. Thereafter, it has become increasingly less common to use terms such as "sick buildings" and "sick building syndrome" in research. However, the concept remains alive in popular culture and is used to designate the set of symptoms related to poor home or work environment engineering. "Sick building" is therefore an expression used especially in the context of workplace health.
Sick building syndrome made a rapid journey from media to courtroom where professional engineers and architects became named defendants and were represented by their respective professional practice insurers. Proceedings invariably relied on expert witnesses, medical and technical experts along with building managers, contractors and manufacturers of finishes and furnishings, testifying as to cause and effect. Most of these actions resulted in sealed settlement agreements, none of these being dramatic. The insurers needed a defense based upon Standards of Professional Practice to meet a court decision that declared that in a modern, essentially sealed building, the HVAC systems must produce breathing air for suitable human consumption. ASHRAE (American Society of Heating, Refrigeration and Air Conditioning Engineers, currently with over 50,000 international members) undertook the task of codifying its indoor air quality (IAQ) standard.
ASHRAE empirical research determined that "acceptability" was a function of outdoor (fresh air) ventilation rate and used carbon dioxide as an accurate measurement of occupant presence and activity. Building odors and contaminants would be suitably controlled by this dilution methodology. ASHRAE codified a level of 1,000 ppm of carbon dioxide and specified the use of widely available sense-and-control equipment to assure compliance. The 1989 issue of ASHRAE 62.1-1989 published the whys and wherefores and overrode the 1981 requirements that were aimed at a ventilation level of 5,000 ppm of carbon dioxide, (the OAHA workplace limit), federally set to minimize HVAC system energy consumption. This apparently ended the SBS epidemic.
Over time, building materials changed with respect to emissions potential. Smoking vanished and dramatic improvements in ambient air quality, coupled with code compliant ventilation and maintenance, per ASHRAE standards have all contributed to the acceptability of the indoor air environment.

See also
Aerotoxic syndrome
Havana syndrome
Healthy building
Multiple chemical sensitivity
NASA Clean Air Study
Nosocomial infection
Somatization disorder
Fan death

References
Further reading
Martín-Gil J., Yanguas M. C., San José J </s>