<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Myelodysplastic syndrome and explain in detail? [/INST] A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include feeling tired, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.Risk factors include previous chemotherapy or radiation therapy, exposure to certain chemicals such as tobacco smoke, pesticides, and benzene, and exposure to heavy metals such as mercury or lead. Problems with blood cell formation result in some combination of low red blood cell, platelet, and white blood cell counts. Some types have an increase in immature blood cells, called blasts, in the bone marrow or blood. The types of MDS are based on specific changes in the blood cells and bone marrow.Treatments may include supportive care, drug therapy, and hematopoietic stem cell transplantation. Supportive care may include blood transfusions, medications to increase the making of red blood cells, and antibiotics. Drug therapy may include the medications lenalidomide, antithymocyte globulin, and azacitidine. Certain people can be cured with chemotherapy followed by a stem-cell transplant from a donor.About seven per 100,000 people are affected, with about four per 100,000 people newly acquiring the condition each year. The typical age of onset is 70 years. The outlook depends on the type of cells affected, the number of blasts in the bone marrow or blood, and the changes present in the chromosomes of the affected cells. The typical survival time following diagnosis is 2.5 years. The conditions were first recognized in the early 1900s. The current name came into use in 1976.

Signs and symptoms
Signs and symptoms are nonspecific and generally related to the blood cytopenias:

Anemia (low RBC count or reduced hemoglobin) – chronic tiredness, shortness of breath, chilled sensation, sometimes chest pain
Neutropenia (low neutrophil count) – increased susceptibility to infection
Thrombocytopenia (low platelet count) – increased susceptibility to bleeding and ecchymosis (bruising), as well as subcutaneous hemorrhaging resulting in purpura or petechiaeMany individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:
Neutropenia, anemia, and thrombocytopenia
Splenomegaly or rarely hepatomegaly
Abnormal granules in cells, abnormal nuclear shape and size
Chromosome abnormality, including chromosomal translocations and abnormal chromosome numberAlthough some risk exists for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. However, leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.  Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important factor in the persons medical history. Fever, weight loss and splenomegaly should point to a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) rather than pure myelodysplastic process.

Cause
Some people have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Xylene and benzene exposures have been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS. A link may exist between the development of MDS "in atomic-bomb survivors 40 to 60 years after radiation exposure" (in this case, referring to people who were in close proximity to the dropping of the atomic bombs in Hiroshima and Nagasaki during World War II). Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.

Pathophysiology
MDS most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of MDS can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary MDS can occur as a late toxicity of cancer therapy (therapy associated MDS, t-MDS). MDS after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7. MDS after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation. Other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into MDS.MDS is thought to arise from mutations in the multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB), then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occurs in an initially normal cell and transforms it into a cancer cell.Although recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML, but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion, MDS patients rarely experience injury from severe anemia.  The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells).  Long-term transfusion of packed red blood cells leads to iron overload.

Genetics
The recognition of epigenetic changes in DNA structure in MDS has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine) of three (the third is lenalidomide) commercially available medications approved by the U.S. Food and Drug Administration to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias.  The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of MDS to acute leukemia.Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients.  Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS.

5q- syndrome
Since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells.  By 2005, lenalidomide, a chemotherapy drug, was recognized to be effective in MDS patients with the 5q- syndrome, and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion.

Splicing factor mutations
Mutations in splicing factors have been found in 40–80% of cases with myelodysplastic syndrome, particularly in those with ringed sideroblasts.

IDH1 and IDH2 mutations
Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in 10–20% of patients with myelodysplastic syndrome, and confer a worsened prognosis in low-risk MDS. Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of MDS to a more malignant disease state.

GATA2 deficiency
GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations, in one of the two GATA2 genes. These autosomal dominant mutations cause a reduction in the cellular levels of the genes product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymph-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations is MDS that often progresses to acute myelocytic leukemia, or less commonly, chronic myelomonocytic leukemia.

Transient myeloproliferative disease
Transient myeloproliferative disease is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down syndrome or genetic changes similar to those in Down syndrome, develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia.

Diagnosis
The elimination of other causes of cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome, so differentiating MDS from anemia, thrombocytopenia, and leukopenia is important.A typical diagnostic investigation includes:

Full blood count and examination of blood film: The blood film morphology can provide clues about hemolytic anemia, clumping of the platelets leading to spurious thrombocytopenia, or leukemia.
Blood tests to eliminate other common causes of cytopenias such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, kidney failure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy: Age-appropriate cancer screening should be considered for all anemic patients.
Bone marrow examination by a hematopathologist: This is required to establish the diagnosis since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia.
Cytogenetics or chromosomal studies: This is ideally performed on the bone marrow aspirate. Conventional cytogenetics require a fresh specimen since live cells are induced to enter metaphase to allow chromosomes to be seen.
Interphase fluorescence in situ hybridization testing, usually ordered together with conventional cytogenetic testing, offers rapid detection of several chromosome abnormalities associated with MDS, including del 5q, −7, +8, and del 20q.
Virtual karyotyping can be done for MDS, which uses computational tools to construct the karyogram from disrupted DNA. Virtual karyotyping does not require cell culture and has a dramatically higher resolution than conventional cytogenetics, but cannot detect balanced translocations.
Flow cytometry is helpful to identify blasts, abnormal myeloid maturation, and establish the presence of any lymphoproliferative disorder in the marrow.
Testing for copper deficiency should not be overlooked, as it can morphologically resemble MDS in bone-marrow biopsies.The features generally used to define an MDS are blood cytopenias, ineffective hematopoiesis, dyserythropoiesis, dysgranulopoiesis, dysmegakaropoiesis, and increased myeloblasts.
Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains
(PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:

Granulocytic series:
Hypersegmented neutrophils (also seen in vit B12/folate deficiency)
Hyposegmented neutrophils (pseudo Pelger-Huet)
Hypogranular neutrophils or pseudo Chediak-Higashi (large azurophilic granules)
Auer rods – automatically RAEB II (if blast count < 5% in the peripheral blood and < 10% in the bone marrow aspirate); also note Auer rods may be seen in mature neutrophils in AML with translocation t(8;21)
Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
Erythroid series:
Binucleated erythroid precursors and karyorrhexis
Erythroid nuclear budding
Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
Loss of e-cadherin in normoblasts is a sign of aberrancy.
PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin-fixed bone-marrow biopsy). Note: one can see PAS vacuolar positivity in L1 and L2 blasts (FAB classification; the L1 and L2 nomenclature is not used in the WHO classification)
Ringed sideroblasts (10 or more iron granules encircling one-third or more of the nucleus) seen on Perls Prussian blue iron stain (>15% ringed sideroblasts when counted among red cell precursors for refractory anemia with ring sideroblasts)
Megakaryocytic series (can be the most subjective):
Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
Hypersegmented (osteoclastic appearing) megakaryocytes
Ballooning of the platelets (seen with interference contrast microscopy)Other stains can help in special cases (PAS and naphthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.
On the bone-marrow biopsy, high-grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors, which are islands of immature precursors cells (myeloblasts and promyelocytes) localized to the center of the intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles. This morphology can be difficult to differentiate from treated leukemia and recovering immature normal marrow elements. Also, topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.

Differential diagnosis
Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also, congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) have been recognized, Pearsons syndrome (sideroblastic anemia), Jordans anomaly – vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome, aminolevulinic acid enzyme deficiency and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines; however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity, and other poisons.All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes, and platelets or their progenitor cells, megakaryocytes).

Classification
World Health Organization
In the late 1990s, a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. In 2008, the WHO developed a new classification scheme that is based more on genetic findings, but morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy are still the screening tests used to decide which classification is best and which cytogenetic aberrations may be related.The list of dysplastic syndromes under the new WHO system includes:

Note : not all physicians concur with this reclassification, because the underlying pathology of this disease is not well understood.

Myelodysplastic syndrome unclassified
The WHO has proposed a criterion for diagnosis and classification of MDS that may apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features:
Rare cases with less than 5% blast will present with Auer rods. These cases usually have the features of RAMD.
Occasionally, cases of MDS present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to the single lineage. The terms refractory neutropenia and refractory thrombocytopenia have sometimes been used to describe these cases. A diagnosis of MDS in patients with neutropenia or thrombocytopenia without anemia should be made with caution.
Patients with RA or RAEB occasionally present with leukocytosis or thrombocytosis instead of the usual cytopenia.

Management
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to AML.
The IPSS scoring system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy.  Supportive care with blood products and hematopoietic growth factors (e.g. erythropoietin) is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National coverage determination. However, no comment on the use of hematopoietic growth factors for MDS was made in that document.Agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS:

5-azacytidine: 21-month median survival
Decitabine: Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with valproic acid.
Lenalidomide: Effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS
Decitabine/cedazuridine (Inqovi) is a fixed-dosed combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome. In the United States, treatment of MDS with lenalidomide costs about $9,200 per month. The chemotherapy may be supported by other drugs like all-trans retinoic acid (ATRA), however the evidence of benefit is not clear.HLA-matched allogeneic stem cell transplantation, particularly in younger (i.e. less than 40 years of age) and more severely affected patients, offers the potential for curative therapy. The success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tend to have a more favorable outcome with transplantation.

Iron levels
Iron overload can develop in MDS as a result of the RBC transfusions, which are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may alleviate the RBC transfusion need in some cases, many MDS patients may not respond to these treatments, thus may develop secondary hemochromatosis due to iron overload from repeated RBC transfusions.
Patients requiring relatively large numbers of RBC transfusions can experience the adverse effect of chronic iron overload on their liver, heart, and endocrine functions.
For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to < 1000 µg/L.Currently, two iron chelators are available in the US, deferoxamine for intravenous use and deferasirox for oral use. These options now provide potentially useful drugs for treating the iron overload problem. A third chelating agent is available in Europe, deferiprone, for oral use, but is not available in the US.Clinical trials in MDS patients are ongoing, with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy has been shown. Both the MDS Foundation and the National Comprehensive Cancer Network MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggests a potential value exists to iron chelation in patients who will undergo a stem-cell transplant. Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following postmarketing use of deferasirox, rare cases of acute kidney failure or liver failure occurred, some resulting in death. Due to this, patients should be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter.

Prognosis
The outlook in MDS is variable, with about 30% of patients progressing to refractory AML. The median survival time varies from years to months, depending on type. Stem-cell transplantation offers possible cure, with survival rates of 50% at 3 years, although older patients do poorly.Indicators of a good prognosis:
Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow (< 20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal or mixed karyotypes without complex chromosome abnormalities; and in vitro marrow culture with a nonleukemic growth pattern
Indicators of a poor prognosis:
Advanced age; severe neutropenia or thrombocytopenia; high blast count in the bone marrow (20–29%) or blasts in the blood;
Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section;
completely or mostly abnormal karyotypes, or complex marrow chromosome abnormalities and in vitro bone marrow culture with a leukemic growth pattern
Karyotype prognostic factors:

Good: normal, -Y, del(5q), del(20q)
Intermediate or variable: +8, other single or double anomalies
Poor: complex (>3 chromosomal aberrations); chromosome 7 anomaliesThe IPSS is the most commonly used tool in MDS to predict long-term outcome.Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or virtual karyotype.
The best prognosis is seen with RA and RARS, where some nontransplant patients live more than a decade (typical is on the order of 3–5 years, although long-term remission is possible if a bone-marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About one-quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated diseases. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997.  This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.

Genetic markers
Although not yet formally incorporated in the generally accepted classification systems, molecular profiling of myelodysplastic syndrome genomes has increased the understanding of prognostic molecular factors for this disease. For example, in low-risk MDS, IDH1 and IDH2 mutations are associated with significantly worsened survival.

Epidemiology
The exact number of people with MDS is not known because it can go undiagnosed and no tracking of the syndrome is mandated. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The number of new cases each year is probably increasing as the average age of the population increases, and some authors propose that the number of new cases in those over 70 may be as high as 15 per 100,000 per year.The typical age at diagnosis of MDS is between 60 and 75 years; a few people are younger than 50, and diagnoses are rare in children. Males are slightly more commonly affected than females.

History
Since the early 20th century, some people with acute myelogenous leukemia were begun to be recognized to have a preceding period of anemia and abnormal blood cell production </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Dolichocephaly and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hour and explain in detail? [/INST] An hour (symbol: h; also abbreviated hr) is a unit of time conventionally reckoned as 1⁄24 of a day and scientifically reckoned between 3,599 and 3,601 seconds, depending on the speed of Earths rotation. There are 60 minutes in an hour, and 24 hours in a day.
The hour was initially established in the ancient Near East as a variable measure of 1⁄12 of the night or daytime. Such seasonal, temporal, or unequal hours varied by season and latitude.
Equal or equinoctial hours were taken as 1⁄24 of the day as measured from noon to noon; the minor seasonal variations of this unit were eventually smoothed by making it 1⁄24 of the mean solar day. Since this unit was not constant due to long term variations in the Earths rotation, the hour was finally separated from the Earths rotation and defined in terms of the atomic or physical second.
In the modern metric system, hours are an accepted unit of time defined as 3,600 atomic seconds. However, on rare occasions an hour may incorporate a positive or negative leap second, making it last 3,599 or 3,601 seconds, in order to keep it within 0.9 seconds of UT1, which is based on measurements of the mean solar day.

Name
Hour is a development of the Anglo-Norman houre and Middle English ure, first attested in the 13th century.It displaced tide tīd, "time" and stound stund, span of time. The Anglo-Norman term was a borrowing of Old French ure, a variant of ore, which derived from Latin hōra and Greek hṓrā (ὥρα).
Like Old English tīd and stund, hṓrā was originally a vaguer word for any span of time, including seasons and years. Its Proto-Indo-European root has been reconstructed as *yeh₁- ("year, summer"), making hour distantly cognate with year.
The time of day is typically expressed in English in terms of hours. Whole hours on a 12-hour clock are expressed using the contracted phrase oclock, from the older of the clock. (10 am and 10 pm are both read as "ten oclock".)
Hours on a 24-hour clock ("military time") are expressed as "hundred" or "hundred hours". (1000 is read "ten hundred" or "ten hundred hours"; 10 pm would be "twenty-two hundred".)
Fifteen and thirty minutes past the hour is expressed as "a quarter past" or "after" and "half past", respectively, from their fraction of the hour. Fifteen minutes before the hour may be expressed as "a quarter to", "of", "till", or "before" the hour. (9:45 may be read "nine forty-five" or "a quarter till ten".)

History
Antiquity
The ancient Greeks kept time differently from the way we do today. Instead of dividing the time between one midnight and the next into 24 equal hours, they divided the time from sunrise to sunset into 12 "seasonal hours" (their actual duration depending on season), and the time from sunset to the next sunrise again in 12 "seasonal hours". Initially, only the day was divided into 12 seasonal hours and the night into 3 or 4 night watches.By the Hellenistic period the night was also divided into 12 hours. The day-and-night (νυχθήμερον) was probably first divided into twenty-four hours by Hipparchus of Nicaea. The Greek astronomer Andronicus of Cyrrhus oversaw the construction of a horologion called the Tower of the Winds in Athens during the first century BCE. This structure tracked a 24-hour day using both sundials and mechanical hour indicators.The canonical hours were introduced to early Christianity  from Second Temple Judaism.
By AD 60, the Didache recommends disciples to pray the Lords Prayer three times a day; this practice found its way into the canonical hours as well. By the second and third centuries, such Church Fathers as Clement of Alexandria, Origen, and Tertullian wrote of the practice of Morning and Evening Prayer, and of the prayers at the third, sixth and ninth hours.
In the early church, during the night before every feast, a vigil was kept. The word "Vigils", at first applied to the Night Office, comes from a Latin source, namely the Vigiliae or nocturnal watches or guards of the soldiers. The night from six oclock in the evening to six oclock in the morning was divided into four watches or vigils of three hours each, the first, the second, the third, and the fourth vigil.The Horae were originally personifications of seasonal aspects of nature, not of the time of day.
The list of twelve Horae representing the twelve hours of the day is recorded only in Late Antiquity, by Nonnus. The first and twelfth of the Horae were added to the original set of ten:

Auge (first light)
Anatole (sunrise)]
Mousike (morning hour of music and study)
Gymnastike (morning hour of exercise)
Nymphe (morning hour of ablutions)
Mesembria (noon)
Sponde (libations poured after lunch)
Elete (prayer)
Akte (eating and pleasure)
Hesperis (start of evening)
Dysis (sunset)
Arktos (night sky)

Middle Ages
Medieval astronomers such as al-Biruni and Sacrobosco,   divided the hour into 60 minutes, each of 60 seconds; this derives from Babylonian astronomy, where the corresponding terms denoted the time required for the Suns apparent motion through the ecliptic to describe one minute or second of arc, respectively.
In present terms, the Babylonian degree of time was thus four minutes long, the "minute" of time was thus four seconds long and the "second" 1/15 of a second.)
In medieval Europe, the Roman hours continued to be marked on sundials but the more important units of time were the canonical hours of the Orthodox and Catholic Church. During daylight, these followed the pattern set by the three-hour bells of the Roman markets, which were succeeded by the bells of local churches. They rang prime at about 6 am, terce at about 9 am, sext at noon, nones at about 3 pm, and vespers at either 6 pm or sunset. Matins and lauds precede these irregularly in the morning hours; compline follows them irregularly before sleep; and the midnight office follows that. Vatican II ordered their reformation for the Catholic Church in 1963, though they continue to be observed in the Orthodox churches.
When mechanical clocks began to be used to show hours of daylight or nighttime, their period needed to be changed every morning and evening (for example, by changing the length of their pendula). The use of 24 hours for the entire day meant hours varied much less and the clocks needed to be adjusted only a few times a month.

Modernity
The minor irregularities of the apparent solar day were smoothed by measuring time using the mean solar day, using the Suns movement along the celestial equator rather than along the ecliptic. The irregularities of this time system were so minor that most clocks reckoning such hours did not need adjustment. However, scientific measurements eventually became precise enough to note the effect of tidal deceleration of the Earth by the Moon, which gradually lengthens the Earths days.
During the French Revolution, a general decimalisation of measures was enacted, including decimal time between 1793 and 1795. Under its provisions, the French hour (French: heure) was 1⁄10 of the day and divided formally into 100 decimal minutes (minute décimale) and informally into 10 tenths (décime). This hour was only briefly in official use, being repealed by the same 1795 legislation that first established the metric system.
The metric system bases its measurements of time upon the second, defined since 1952 in terms of the Earths rotation in AD 1900. Its hours are a secondary unit computed as precisely 3,600 seconds. However, an hour of Coordinated Universal Time (UTC), used as the basis of most civil time, has lasted 3,601 seconds 27 times since 1972 in order to keep it within 0.9 seconds of universal time, which is based on measurements of the mean solar day at 0° longitude. The addition of these seconds accommodates the very gradual slowing of the rotation of the Earth.
In modern life, the ubiquity of clocks and other timekeeping devices means that segmentation of days according to their hours is commonplace. Most forms of employment, whether wage or salaried labour, involve compensation based upon measured or expected hours worked. The fight for an eight-hour day was a part of labour movements around the world. Informal rush hours and happy hours cover the times of day when commuting slows down due to congestion or alcoholic drinks being available at discounted prices. The hour record for the greatest distance travelled by a cyclist within the span of an hour is one of cyclings greatest honours.

Counting hours
Many different ways of counting the hours have been used. Because sunrise, sunset, and, to a lesser extent, noon, are the conspicuous points in the day, starting to count at these times was, for most people in most early societies, much easier than starting at midnight. However, with accurate clocks and modern astronomical equipment (and the telegraph or similar means to transfer a time signal in a split-second), this issue is much less relevant.
Astrolabes, sundials, and astronomical clocks sometimes show the hour length and count using some of these older definitions and counting methods.

Counting from dawn
In ancient and medieval cultures, the counting of hours generally started with sunrise. Before the widespread use of artificial light, societies were more concerned with the division between night and day, and daily routines often began when light was sufficient."Babylonian hours" divide the day and night into 24 equal hours, reckoned from the time of sunrise.  They are so named from the false belief of ancient authors that the Babylonians divided the day into 24 parts, beginning at sunrise.  In fact, they divided the day into 12 parts (called kaspu or "double hours") or into 60 equal parts.

Unequal hours
Sunrise marked the beginning of the first hour, the middle of the day was at the end of the sixth hour and sunset at the end of the twelfth hour. This meant that the duration of hours varied with the season. In the Northern hemisphere, particularly in the more northerly latitudes, summer daytime hours were longer than winter daytime hours, each being one twelfth of the time between sunrise and sunset. These variable-length hours were variously known as temporal, unequal, or seasonal hours and were in use until the appearance of the mechanical clock, which furthered the adoption of equal length hours.This is also the system used in Jewish law and frequently called "Talmudic hour" (Shaa Zemanit) in a variety of texts. The Talmudic hour is one twelfth of time elapsed from sunrise to sunset, day hours therefore being longer than night hours in the summer; in winter they reverse.
The Indic day began at sunrise. The term hora was used to indicate an hour. The time was measured based on the length of the shadow at day time. A hora translated to 2.5 pe. There are 60 pe per day, 60 minutes per pe and 60 kshana (snap of a finger or instant) per minute. Pe was measured with a bowl with a hole placed in still water. Time taken for this graduated bowl was one pe. Kings usually had an officer in charge of this clock.

Counting from sunset
In so-called "Italian time", "Italian hours", or "old Czech time", the first hour started with the sunset Angelus bell (or at the end of dusk, i.e., half an hour after sunset, depending on local custom and geographical latitude). The hours were numbered from 1 to 24. For example, in Lugano, the sun rose in December during the 14th hour and noon was during the 19th hour; in June the sun rose during the 7th hour and noon was in the 15th hour. Sunset was always at the end of the 24th hour. The clocks in church towers struck only from 1 to 12, thus only during night or early morning hours.
This manner of counting hours had the advantage that everyone could easily know how much time they had to finish their days work without artificial light. It was already widely used in Italy by the 14th century and lasted until the mid-18th century; it was officially abolished in 1755, or in some regions customary until the mid-19th century.The system of Italian hours can be seen on a number of clocks in Europe, where the dial is numbered from 1 to 24 in either Roman or Arabic numerals. The St Marks Clock in Venice, and the Orloj in Prague are famous examples. It was also used in Poland and Bohemia until the 17th century.
The Islamic day begins at sunset. The first prayer of the day (maghrib) is to be performed between just after sunset and the end of twilight. Until 1968 Saudi Arabia used the system of counting 24 equal hours with the first hour starting at sunset.

Counting from noon
For many centuries, up to 1925, astronomers counted the hours and days from noon, because it was the easiest solar event to measure accurately. An advantage of this method (used in the Julian Date system, in which a new Julian Day begins at noon) is that the date doesnt change during a single nights observing.

Counting from midnight
In the modern 12-hour clock, counting the hours starts at midnight and restarts at noon. Hours are numbered 12, 1, 2, ..., 11. Solar noon is always close to 12 noon (ignoring artificial adjustments due to time zones and daylight saving time), differing according to the equation of time by as much as fifteen minutes either way. At the equinoxes sunrise is around 6 a.m. (Latin: ante meridiem, before noon), and sunset around 6 p.m. (Latin: post meridiem, after noon).
In the modern 24-hour clock, counting the hours starts at midnight, and hours are numbered from 0 to 23. Solar noon is always close to 12:00, again differing according to the equation of time. At the equinoxes sunrise is around 06:00, and sunset around 18:00.

History of timekeeping in other cultures
Egypt
The ancient Egyptians began dividing the night into wnwt at some time before the compilation of the Dynasty V Pyramid Texts in the 24th century BC. By 2150 BC (Dynasty IX), diagrams of stars inside Egyptian coffin lids—variously known as "diagonal calendars" or "star clocks"—attest that there were exactly 12 of these. Clagett writes that it is "certain" this duodecimal division of the night followed the adoption of the Egyptian civil calendar, usually placed c. 2800 BC on the basis of analyses of the Sothic cycle, but a lunar calendar presumably long predated this and also would have had twelve months in each of its years. The coffin diagrams show that the Egyptians took note of the heliacal risings of 36 stars or constellations (now known as "decans"), one for each of the ten-day "weeks" of their civil calendar.  (12 sets of alternate "triangle decans" were used for the 5 epagomenal days between years.) Each night, the rising of eleven of these decans were noted, separating the night into twelve divisions whose middle terms would have lasted about 40 minutes each. (Another seven stars were noted by the Egyptians during the twilight and predawn periods, although they were not important for the hour divisions.) The original decans used by the Egyptians would have fallen noticeably out of their proper places over a span of several centuries. By the time of Amenhotep III (c. 1350 BC), the priests at Karnak were using water clocks to determine the hours. These were filled to the brim at sunset and the hour determined by comparing the water level against one of its twelve gauges, one for each month of the year. During the New Kingdom, another system of decans was used, made up of 24 stars over the course of the year and 12 within any one night.
The later division of the day into 12 hours was accomplished by sundials marked with ten equal divisions. The morning and evening periods when the sundials failed to note time were observed as the first and last hours.The Egyptian hours were closely connected both with the priesthood of the gods and with their divine services. By the New Kingdom, each hour was conceived as a specific region of the sky or underworld through which Ras solar barge travelled. Protective deities were assigned to each and were used as the names of the hours. As the protectors and resurrectors of the sun, the goddesses of the night hours were considered to hold power over all lifespans and thus became part of Egyptian funerary rituals. Two fire-spitting cobras were said to guard the gates of each hour of the underworld, and Wadjet and the rearing cobra (uraeus) were also sometimes referenced as wnwt from their role protecting the dead through these gates. The Egyptian word for astronomer, used as a synonym for priest, was wnwty, "one of the wnwt", as it were "one of the hours". The earliest forms of wnwt include one or three stars, with the later solar hours including the determinative hieroglyph for "sun".

East Asia
Ancient China divided its day into 100 "marks" (Chinese: 刻, oc *kʰək, p kè) running from midnight to midnight. The system is said to have been used since remote antiquity, credited to the legendary Yellow Emperor, but is first attested in Han-era water clocks and in the 2nd-century history of that dynasty. It was measured with sundials and water clocks. Into the Eastern Han, the Chinese measured their day schematically, adding the 20-ke difference between the solstices evenly throughout the year, one every nine days. During the night, time was more commonly reckoned during the night by the "watches" (Chinese: 更, oc *kæŋ, p gēng) of the guard, which were reckoned as a fifth of the time from sunset to sunrise.Imperial China continued to use ke and geng but also began to divide the day into 12 "double hours" (t 時, s 时, oc *də, p shí, lit. "time[s]") named after the earthly branches and sometimes also known by the name of the corresponding animal of the Chinese zodiac. The first shi originally ran from 11 pm to 1 am but was reckoned as starting at midnight by the time of the History of Song, compiled during the early Yuan. These apparently began to be used during the Eastern Han that preceded the Three Kingdoms era, but the sections that would have covered them are missing from their official histories; they first appear in official use in the Tang-era Book of Sui. Variations of all these units were subsequently adopted by Japan and the other countries of the Sinosphere.
The 12 shi supposedly began to be divided into 24 hours under the Tang, although they are first attested in the Ming-era Book of Yuan. In that work, the hours were known by the same earthly branches as the shi, with the first half noted as its "starting" and the second as "completed" or "proper" shi. In modern China, these are instead simply numbered and described as "little shi". The modern ke is now used to count quarter-hours, rather than a separate unit.
As with the Egyptian night and daytime hours, the division of the day into twelve shi has been credited to the example set by the rough number of lunar cycles in a solar year, although the 12-year Jovian orbital cycle was more important to traditional Chinese and Babylonian reckoning of the zodiac.

Southeast Asia
In Thailand, Laos, and Cambodia, the traditional system of noting hours is the six-hour clock. This reckons each of a days 24 hours apart from noon as part of a fourth of the day. 7 am was the first hour of the first half of daytime; 1 pm the first hour of the latter half of daytime; 7 pm the first hour of the first half of nighttime; and 1 am the first hour of the latter half of nighttime. This system existed in the Ayutthaya Kingdom, deriving its current phrasing from the practice of publicly announcing the daytime hours with a gong and the nighttime hours with a drum </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Shortness of breath and explain in detail? [/INST] Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity", and recommends evaluating dyspnea by assessing the intensity of its distinct sensations, the degree of distress and discomfort involved, and its burden or impact on the patients activities of daily living. Distinct sensations include effort/work to breathe, chest tightness or pain, and "air hunger" (the feeling of not enough oxygen). The tripod position is often assumed to be a sign.
Dyspnea is a normal symptom of heavy physical exertion but becomes pathological if it occurs in unexpected situations, when resting or during light exertion. In 85% of cases it is due to asthma, pneumonia, cardiac ischemia, interstitial lung disease, congestive heart failure, chronic obstructive pulmonary disease, or psychogenic causes, such as panic disorder and anxiety.  The best treatment to relieve or even remove shortness of breath typically depends on the underlying cause.

Definition
Dyspnea, in medical terms, is "shortness of breath".
The American Thoracic Society defines dyspnea as: "A subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity." Other definitions also describe it as "difficulty in breathing", "disordered or inadequate breathing",  "uncomfortable awareness of breathing", and as the experience of "breathlessness" (which may be either acute or chronic).

Differential diagnosis
While shortness of breath is generally caused by disorders of the cardiac or respiratory system, others such as the neurological, musculoskeletal, endocrine, hematologic, and psychiatric systems may be the cause. DiagnosisPro, an online medical expert system, listed 497 distinct causes in October 2010. The most common cardiovascular causes are acute myocardial infarction and congestive heart failure while common pulmonary causes include chronic obstructive pulmonary disease, asthma, pneumothorax, pulmonary edema and pneumonia. On a pathophysiological basis the causes can be divided into: (1) an increased awareness of normal breathing such as during an anxiety attack, (2) an increase in the work of breathing and (3) an abnormality in the ventilatory or respiratory system.The tempo of onset and the duration of dyspnea are useful in knowing the etiology of dyspnea. Acute shortness of breath is usually connected with sudden physiological changes, such as laryngeal edema, bronchospasm, myocardial infarction, pulmonary embolism, or pneumothorax. Patients with COPD and idiopathic pulmonary fibrosis (IPF) have a mild onset and gradual progression of dyspnea on exertion, punctuated by acute exacerbations of shortness of breath. In contrast, most asthmatics do not have daily symptoms, but have intermittent episodes of dyspnea, cough, and chest tightness that are usually associated with specific triggers, such as an upper respiratory tract infection or exposure to allergens.

Acute coronary syndrome
Acute coronary syndrome frequently presents with retrosternal chest discomfort and difficulty catching the breath. It however may atypically present with shortness of breath alone. Risk factors include old age, smoking, hypertension, hyperlipidemia, and diabetes. An electrocardiogram and cardiac enzymes are important both for diagnosis and directing treatment. Treatment involves measures to decrease the oxygen requirement of the heart and efforts to increase blood flow.

COVID-19
People that have been infected by COVID-19 may have symptoms such as a fever, dry cough, loss of smell and taste, and in moderate to severe cases, shortness of breath.

Congestive heart failure
Congestive heart failure frequently presents with shortness of breath with exertion, orthopnea, and paroxysmal nocturnal dyspnea.  It affects between 1–2% of the general United States population and occurs in 10% of those over 65 years old. Risk factors for acute decompensation include high dietary salt intake, medication noncompliance, cardiac ischemia, abnormal heart rhythms, kidney failure, pulmonary emboli, hypertension, and infections. Treatment efforts are directed towards decreasing lung congestion.

Chronic obstructive pulmonary disease
People with chronic obstructive pulmonary disease (COPD), most commonly emphysema or chronic bronchitis, frequently have chronic shortness of breath and a chronic productive cough. An acute exacerbation presents with increased shortness of breath and sputum production. COPD is a risk factor for pneumonia; thus this condition should be ruled out. In an acute exacerbation treatment is with a combination of anticholinergics, beta2-adrenoceptor agonists, steroids and possibly positive pressure ventilation.

Asthma
Asthma is the most common reason for presenting to the emergency room with shortness of breath. It is the most common lung disease in both developing and developed countries affecting about 5% of the population. Other symptoms include wheezing, tightness in the chest, and a non productive cough.
Inhaled corticosteroids are the preferred treatment for children, however these drugs can reduce the growth rate. Acute symptoms are treated with short-acting bronchodilators.

Pneumothorax
Pneumothorax presents typically with pleuritic chest pain of acute onset and shortness of breath not improved with oxygen. Physical findings may include absent breath sounds on one side of the chest, jugular venous distension, and tracheal deviation.

Pneumonia
The symptoms of pneumonia are fever, productive cough, shortness of breath, and pleuritic chest pain. Inspiratory crackles may be heard on exam. A chest x-ray can be useful to differentiate pneumonia from congestive heart failure. As the cause is usually a bacterial infection, antibiotics are typically used for treatment.

Pulmonary embolism
Pulmonary embolism classically presents with an acute onset of shortness of breath. Other presenting symptoms include pleuritic chest pain, cough, hemoptysis, and fever. Risk factors include deep vein thrombosis, recent surgery, cancer, and previous thromboembolism. It must always be considered in those with acute onset of shortness of breath owing to its high risk of mortality. Diagnosis, however, may be difficult and Wells Score is often used to assess the clinical probability.  Treatment, depending on severity of symptoms, typically starts with anticoagulants; the presence of ominous signs (low blood pressure) may warrant the use of thrombolytic drugs.

Anemia
Anemia that develops gradually usually presents with exertional dyspnea, fatigue, weakness, and tachycardia. It may lead to heart failure. Anaemia is often a cause of dyspnea.  Menstruation, particularly if excessive, can contribute to anaemia and to consequential dyspnea in women. Headaches are also a symptom of dyspnea in patients with anaemia. Some patients report a numb sensation in their head, and others have reported blurred vision caused by hypotension behind the eye due to a lack of oxygen and pressure; these patients have also reported severe head pains, many of which lead to permanent brain damage. Symptoms can include loss of concentration, focus, fatigue, language faculty impairment and memory loss.

Cancer
Shortness of breath is common in people with cancer and may be caused by numerous different factors. In people with advanced cancer, acute shortness of periods of time with severe shortness of breath may occur, along with a more continuous feeling of breathlessness.

Other
Other important or common causes of shortness of breath include cardiac tamponade, anaphylaxis, interstitial lung disease, panic attacks, and pulmonary hypertension. Also, around 2/3 of women experience shortness of breath as a part of a normal pregnancy.Cardiac tamponade presents with dyspnea, tachycardia, elevated jugular venous pressure, and pulsus paradoxus. The gold standard for diagnosis is ultrasound.Anaphylaxis typically begins over a few minutes in a person with a previous history of the same. Other symptoms include urticaria, throat swelling, and gastrointestinal upset. The primary treatment is epinephrine.Interstitial lung disease presents with gradual onset of shortness of breath typically with a history of a predisposing environmental exposure. Shortness of breath is often the only symptom in those with tachydysrhythmias.Panic attacks typically present with hyperventilation, sweating, and numbness. They are however a diagnosis of exclusion.Neurological conditions such as spinal cord injury, phrenic nerve injuries, Guillain–Barré syndrome, amyotrophic lateral sclerosis, multiple sclerosis and muscular dystrophy can all cause an individual to experience shortness of breath. Shortness of breath can also occur as a result of vocal cord dysfunction (VCD).Sarcoidosis is an inflammatory disease of unknown etiology that generally presents with dry cough, fatigue, and shortness of breath, although multiple organ systems may be affected, with involvement of sites such as the eyes, the skin and the joints.

Pathophysiology
Different physiological pathways may lead to shortness of breath including via ASIC chemoreceptors, mechanoreceptors, and lung receptors.It is thought that three main components contribute to dyspnea: afferent signals, efferent signals, and central information processing. It is believed the central processing in the brain compares the afferent and efferent signals; and dyspnea results when a "mismatch" occurs between the two: such as when the need for ventilation (afferent signaling) is not being met by physical breathing (efferent signaling).Afferent signals are sensory neuronal signals that ascend to the brain. Afferent neurons significant in dyspnea arise from a large number of sources including the carotid bodies, medulla, lungs, and chest wall. Chemoreceptors in the carotid bodies and medulla supply information regarding the blood gas levels of O2, CO2  and H+. In the lungs, juxtacapillary (J) receptors are sensitive to pulmonary interstitial edema, while stretch receptors signal bronchoconstriction. Muscle spindles in the chest wall signal the stretch and tension of the respiratory muscles. Thus, poor ventilation leading to hypercapnia, left heart failure leading to interstitial edema (impairing gas exchange), asthma causing bronchoconstriction (limiting airflow) and muscle fatigue leading to ineffective respiratory muscle action could all contribute to a feeling of dyspnea.Efferent signals are the motor neuronal signals descending to the respiratory muscles. The most important respiratory muscle is the diaphragm. Other respiratory muscles include the external and internal intercostal muscles, the abdominal muscles and the accessory breathing muscles.As the brain receives its plentiful supply of afferent information relating to ventilation, it is able to compare it to the current level of respiration as determined by the efferent signals. If the level of respiration is inappropriate for the bodys status then dyspnea might occur. There is also a psychological component to dyspnea, as some people may become aware of their breathing in such circumstances but not experience the typical distress of dyspnea.

Diagnosis
The initial approach to evaluation begins by assessment of the airway, breathing, and circulation followed by a medical history and physical examination. Signs and symptoms that represent significant severity include hypotension, hypoxemia, tracheal deviation, altered mental status, unstable dysrhythmia, stridor, intercostal indrawing, cyanosis, tripod positioning, pronounced use of accessory muscles (sternocleidomastoid, scalenes) and absent breath sounds.A number of scales may be used to quantify the degree of shortness of breath. It may be subjectively rated on a scale from 1 to 10 with descriptors associated with the number (The Modified Borg Scale). The MRC breathlessness scale suggests five grades of dyspnea based on the circumstances and severity in which it arises.

Blood tests
A number of labs may be helpful in determining the cause of shortness of breath. D-dimer, while useful to rule out a pulmonary embolism in those who are at low risk, is not of much value if it is positive, as it may be positive in a number of conditions that lead to shortness of breath. A low level of brain natriuretic peptide is useful in ruling out congestive heart failure; however, a high level, while supportive of the diagnosis, could also be due to advanced age, kidney failure, acute coronary syndrome, or a large pulmonary embolism.

Imaging
A chest x-ray is useful to confirm or rule out a pneumothorax, pulmonary edema, or pneumonia. Spiral computed tomography with intravenous radiocontrast is the imaging study of choice to evaluate for pulmonary embolism.

Treatment
The primary treatment of shortness of breath is directed at its underlying cause. Extra supplemental oxygen is effective in those with hypoxia; however, this has no effect in those with normal blood oxygen saturations.

Physiotherapy
Individuals can benefit from a variety of physical therapy interventions. Persons with neurological/neuromuscular abnormalities may have breathing difficulties due to weak or paralyzed intercostal, abdominal and/or other muscles needed for ventilation. Some physical therapy interventions for this population include active assisted cough techniques, volume augmentation such as breath stacking, education about body position and ventilation patterns and movement strategies to facilitate breathing.  Pulmonary rehabilitation may alleviate symptoms in some people, such as those with COPD, but will not cure the underlying disease. Fan therapy to the face has been shown to relieve shortness of breath in patients with a variety of advanced illnesses including cancer. The mechanism of action is thought to be stimulation of the trigeminal nerve.

Palliative medicine
Systemic immediate release opioids are beneficial in emergently reducing the symptom severity of shortness of breath due to both cancer and non cancer causes; long-acting/sustained-release opioids are also used to prevent/continue treatment of dyspnea in palliative setting. There is a lack of evidence to recommend midazolam, nebulised opioids, the use of gas mixtures, or cognitive-behavioral therapy yet.

Non-pharmacological techniques
Non-pharmacological interventions provide key tools for the management of breathlessness. Potentially beneficial approaches include active management of psychosocial issues (anxiety, depression, etc.), and implementation of self-management strategies, such as physical and mental relaxation techniques, pacing techniques, energy conservation techniques, learning exercises to control breathing, and education. The use of a fan may possibly be beneficial. Cognitive behavioural therapy may also be helpful.

Pharmacological treatment
For people with severe, chronic, or uncontrollable breathlessness, non-pharmacological approaches to treating breathlessness may be combined with medication. For people who have cancer that is causing the breathlessness, medications that have been suggested include opioids, benzodiazepines, oxygen, and steroids </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rheumatoid nodule and explain in detail? [/INST] A rheumatoid nodule is a lump of tissue, or an area of swelling, that appear on the exterior of the skin usually around the olecranon (tip of the elbow) or the interphalangeal joints (finger knuckles), but can appear in other areas. There are four different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules, and central nervous systems nodules. These nodules occur almost exclusively in association with rheumatoid arthritis. Very rarely do rheumatoid nodules occur as rheumatoid nodulosis (multiple nodules on the hands or other areas) in the absence of rheumatoid arthritis. Rheumatoid nodules can also appear in other areas of the body other than the skin. Less commonly they occur in the lining of the lung or other internal organs. The occurrence of nodules in the lung of miners exposed to silica dust was known as Caplan’s syndrome. Rarely, the nodules occur at diverse sites on body (e.g. upper eyelid, distal region of the soles of the feet, vulva and internally in the gallbladder, lung, heart valves, larynx, and spine).Rheumatoid nodules can vary in size from 2 mm to 5 cm and are usually rather firm to the touch. Quite often they are associated with synovial pockets or bursae. About 5% of people with rheumatoid arthritis have such nodules within two years of disease onset, and the cumulative prevalence is about 20 to 30%. Risk factors of developing rheumatoid nodules include as smoking and trauma to small vessels.In the majority of the time, nodules are not painful or disabling in any way. They are usually more of an unsightly nuisance. However, rheumatoid nodules can become painful when infection or ulcers occur on the skin of the nodule. Some nodules can actually disappear over time, but other times, they can grow larger making prediction of nodular size difficult to predict.Treatment also can be quite difficult, but surgical removal and injection of corticosteroids have both shown good results towards the treatment for rheumatoid nodules.

Pathophysiology
Although the exact process is unknown, there are a few hypotheses for the generation of rheumatoid nodules. It has been observed that rheumatoid nodules frequently form over extensor sites and areas vulnerable to trauma. The trauma causes inflammatory particles to build up and leads to a secondary inflammatory response which ultimately causes fibrin release and necrosis. Another hypothesis suggests that the inflammation of blood vessels activates complement components, which leads to the deposit of rheumatoid factors and fibrin.The rheumatoid nodule is the most common cutaneous manifestation of rheumatoid arthritis (RA). Rheumatoid arthritis involves chronic inflammation of synovial membranes, which leads to degradation of articular cartilage and the juxta-articular bone. Inflammation is caused by T cells, B cells and monocytes when endothelial cells are activated. Neovascularization, or the growth of new blood vessels, serves as an additional marker for rheumatoid arthritis. A hyperplastic synovial lining layer can be caused by the expansion of synovial fibroblast and macrophage cells. This expansion of the synovial membrane, sometimes referred to as "pannus," can lead to bony erosions and cartilage degradation at the site of the cartilage-bone junction in the periarticular bone.It is important to note that the cause of rheumatoid arthritis is unknown. It is speculated that genetic and environmental factors can both contribute to the development of rheumatoid arthritis. Gene loci and antigens, such as HLA class II antigens, have been seen as closely associated with rheumatoid arthritis. Environmental risk factors include smoking, periodontitis, viral infections and gut, mouth and lung microbiomes. Researchers have noted that Prevotella species, which are expanded in the gastrointestinal tract in early RA, and Porphyromonas gingivalis, which is associated with periodontitis, may have a role in pathogenesis.

Pathology
Histological examination of nodules shows that they consist of a shell of fibrous tissue surrounding a center of fibrinoid necrosis. Pea-sized nodules have one centre. Larger nodules tend to be multilocular, with many separate shells or with connections between the necrotic centers. Individual necrotic centers may contain a cleft or several centers of necrosis may all open on to a large bursal pocket containing synovial fluid.
The boundary between the necrotic center and the outer fibrous shell is made up of the characteristic feature of the nodule, which is known as a cellular palisade. The palisade is a densely packed layer of macrophages and fibroblasts which tend to be arranged radially, like the seeds of a kiwifruit or fig. Further out into the fibrous shell there is a zone that contains T cells and plasma cells in association with blood vessels. The histology of pulmonary nodules are similar to that of subcutaneous nodules, with central necrosis surrounded by palisading macrophages and inflammatory infiltrate.

Risk Factors
Rheumatoid nodules develop if a person currently has rheumatoid arthritis. However, not all people with rheumatoid arthritis develop rheumatoid nodules. Some risk factors for rheumatoid nodules for people with rheumatoid arthritis may include:
Smoking (strong association)
Elevated levels of serum rheumatoid factors
HLA-DRB1 gene (weak association)
Trauma to small vessels
Having severe rheumatoid arthritis
Taking Methotrexate over other arthritis drugs

Diagnosis
Differential diagnosis of rheumatoid nodules can be classified from localization, depth pathology, age of onset, persistence, rheumatoid factor, concomitant joint disease, and bone erosions. Diagnosis is typically determined clinically by a rheumatologist. Rheumatoid arthritis associated rheumatoid nodules are typically subcutaneous and occur at extensor sites. The onset typically starts in adulthood and presents with rheumatoid factors and bone erosions, and concomitant joint diseases. The pathology is characterized by central necrosis, palisading mononuclear cells, and perivascular lymphocytic infiltrations.Rheumatoid nodulosis is characterized by multiple subcutaneous nodules presenting with rheumatoid factors but an absence of joint complaints. The nodules are typically small and concentrated on the extensor sites of the hands and feet, sometimes accompanied by bone erosions. The onset typically starts in adulthood with a pathology similar to rheumatoid arthritis associated rheumatoid nodules.Benign rheumatoid nodules are often not associated with rheumatoid factors or concomitant joint diseases. They are typically found on the feet, scalp, and pretibial regions.  Frequently seen in children before the age of 18, the pathology is similar to that of rheumatoid arthritis associated rheumatoid nodules. The nodules are non-tender and undergo rapid growth, but also resolve spontaneously. A similar presentation occurring more intracutaneously (superficial) is known as granuloma annulare.Rheumatic fever nodules are typically associated with acute rheumatic fever in children. They are not accompanied by rheumatoid factors or bone erosions, but are associated with concomitant joint diseases. No larger than the size of peas, they are typically found at extensor sites and processus spinosi of the vertebrae. The pathology is characterized by central necrosis and little histiocytic/lymphocytic infiltration.

Prevalence
There are 4 different types of rheumatoid nodules: subcutaneous rheumatoid nodules, cardiac nodules, pulmonary nodules and central nervous system nodules.
Subcutaneous rheumatoid nodules
According to a study done by the BARFOT study group, 7% of individuals diagnosed with rheumatoid arthritis reported the presence of subcutaneous rheumatoid nodules upon initial diagnosis. And about 30-40% of all those diagnosed with rheumatoid arthritis reported developing these nodules throughout the course of the disease. Subcutaneous rheumatoid nodules is correlated with the increased risk of cardiovascular and respiratory disease, and those with detected subcutaneous rheumatoid nodules should be assessed for cardiovascular and respiratory risk factors.Cardiac nodules
Rheumatoid nodules may also form in the heart. Specifically, it could develop in the myocardium, pericardium, and other valvular structures, and these nodules can be discovered through echocardiograms. There are little studies with minimal data on  the development of cardiac nodules in association with rheumatoid arthritis, but the general consensus is that such occurrences is relatively rare.
Pulmonary Nodules
The reported prevalence of pulmonary nodules has varying depending on the method of detection. In a 1984 study done on lung biopsies in rheumatoid arthritis, the reported prevalence was about 32% in a sample size of 40 individuals. However, another clinical study utilizing a different method of detection; plain film radiographs of the chest; showed that only 2 out of 516 people (~0.4%) diagnosed with rheumatoid arthritis developed pulmonary nodules. Additionally, other clinical studies have reported increased pulmonary nodule growth following treatments with methotrexate, leflunomide, and etanercept.Central nervous system nodules
Like cardiac nodules, nodules developing in the central nervous system is also relatively rare. Most reports of nodule growth on the central nervous system also presented with severe stages of erosive joint diseases </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tularemia and explain in detail? [/INST] Tularemia, also known as rabbit fever, is an infectious disease caused by the bacterium Francisella tularensis. Symptoms may include fever, skin ulcers, and enlarged lymph nodes. Occasionally, a form that results in pneumonia or a throat infection may occur.The bacterium is typically spread by ticks, deer flies, or contact with infected animals. It may also be spread by drinking contaminated water or breathing in contaminated dust. It does not spread directly between people. Diagnosis is by blood tests or cultures of the infected site.Prevention is by using insect repellent, wearing long pants, rapidly removing ticks, and not disturbing dead animals. Treatment is typically with the antibiotic streptomycin. Gentamicin, doxycycline, or ciprofloxacin may also be used.Between the 1970s and 2015, around 200 cases were reported in the United States a year. Males are affected more often than females. It occurs most frequently in the young and the middle aged. In the United States, most cases occur in the summer. The disease is named after Tulare County, California, where the disease was discovered in 1911. A number of other animals, such as rabbits, may also be infected.

Signs and symptoms
Depending on the site of infection, tularemia has six characteristic clinical variants: ulceroglandular (the most common type representing 75% of all forms), glandular, oropharyngeal, pneumonic, oculoglandular, and typhoidal.The incubation period for tularemia is one to 14 days; most human infections become apparent after three to five days. In most susceptible mammals, the clinical signs include fever, lethargy, loss of appetite, signs of sepsis, and possibly death. Nonhuman mammals rarely develop the skin lesions seen in people. Subclinical infections are common, and animals often develop specific antibodies to the organism. Fever is moderate or very high, and tularemia bacilli can be isolated from blood cultures at this stage. The face and eyes redden and become inflamed. Inflammation spreads to the lymph nodes, which enlarge and may suppurate (mimicking bubonic plague). Lymph node involvement is accompanied by a high fever.

Cause
Tularemia is caused by the bacteria Francisella tularensis which is typically spread by ticks, deer flies, and contact with infected animals.

Bacteria
The bacteria can penetrate into the body through damaged skin, mucous membranes, and inhalation. Humans are most often infected by tick/deer fly bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. Hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. It has been contracted from inhaling particles from an infected rabbit ground up in a lawnmower (see below). Tularemia is not spread directly from person to person. Humans can also be infected through bioterrorism attempts.Francisella tularensis can live both within and outside the cells of the animal it infects, meaning it is a facultative intracellular bacterium. It primarily infects macrophages, a type of white blood cell, and thus is able to evade the immune system. The course of disease involves the spread of the organism to multiple organ systems, including the lungs, liver, spleen, and lymphatic system. The course of disease is different depending on the route of exposure. Mortality in untreated (before the antibiotic era) patients has been as high as 50% in the pneumoniac and typhoidal forms of the disease, which however account for less than 10% of cases.

Spread
The most common way the disease is spread is via arthropod vectors. Ticks involved include Amblyomma, Dermacentor, Haemaphysalis, and Ixodes. Rodents, rabbits, and hares often serve as reservoir hosts, but waterborne infection accounts for 5 to 10% of all tularemia in the United States. Tularemia can also be transmitted by biting flies, particularly the deer fly Chrysops discalis. Individual flies can remain infectious for 14 days and ticks for over two years. Tularemia may also be spread by direct contact with contaminated animals or material, by ingestion of poorly cooked flesh of infected animals or contaminated water, or by inhalation of contaminated dust.

Diagnosis
Pathology
In lymph node biopsies, the typical histopathologic pattern is characterized by geographic areas of necrosis with neutrophils and necrotizing granulomas. The pattern is non specific and similar to other infectious lymphadenopathies.The laboratorial isolation of F. tularensis requires special media such as buffered charcoal yeast extract agar. It cannot be isolated in the routine culture media because of the need for sulfhydryl group donors (such as cysteine). The microbiologist must be informed when tularemia is suspected not only to include the special media for appropriate isolation, but also to ensure that safety precautions are taken to avoid contamination of laboratory personnel. Serological tests (detection of antibodies in the serum of the patients) are available and widely used. Cross reactivity with Brucella can confuse interpretation of the results, so diagnosis should not rely only on serology. Molecular methods such as PCR are available in reference laboratories.

Prevention
There are no safe, available, approved vaccines against tularemia. However, vaccination research and development continues, with live attenuated vaccines being the most thoroughly researched and most likely candidate for approval. Sub-unit vaccine candidates, such as killed-whole cell vaccines, are also under investigation, however research has not reached a state of public use.Optimal preventative practices include limiting direct exposure when handling potentially infected animals by wearing gloves and face masks (importantly when skinning deceased animals).

Treatment
If infection occurs or is suspected, treatment is generally with the antibiotics streptomycin or Gentamicin. Doxycycline was previously used. Gentamicin may be easier to obtain than streptomycin. There is also tentative evidence to support the use of quinolone antibiotics.

Prognosis
Since the invention of antibiotics, the rate of death associated with tularemia has decreased from 60% to less than 4%.

Epidemiology
Tularemia is most common in the Northern Hemisphere, including North America and parts of Europe and Asia. It occurs between 30º and 71º north latitude.In the United States, although records show that tularemia was never particularly common, incidence rates continued to drop over the course of the 20th century. Between 1990 and 2000, the rate dropped to less than 1 per one million, meaning the disease is extremely rare in the United States today.In Europe, tularemia is generally rare, though outbreaks with hundreds of cases occur every few years in neighboring Finland and Sweden. In Sweden over a period from 1984 to 2012 a total of 4,830 cases of tularemia occurred (most of the infections were acquired within the country). About 1.86 cases per 100,000 persons occur each year with higher rates in those between 55 and 70.

Outbreaks
From May to October 2000, an outbreak of tularemia in Marthas Vineyard, Massachusetts, resulted in one fatality, and brought the interest of the United States Centers for Disease Control and Prevention (CDC) as a potential investigative ground for aerosolised Francisella tularensis. For a time, Marthas Vineyard was identified as the only place in the world where documented cases of tularemia resulted from lawn mowing. However, in May 2015 a resident of Lafayette, Colorado, died from aerosolised F. tularensis, which was also connected to lawn mowing, highlighting this new vector of risk.
An outbreak of tularemia occurred in Kosovo in 1999–2000.In 2004, three researchers at Boston Medical Center, in Massachusetts, were accidentally infected with F. tularensis, after apparently failing to follow safety procedures.In 2005, small amounts of F. tularensis were detected in the National Mall area of Washington, D.C., the morning after an antiwar demonstration on September 24, 2005. Biohazard sensors were triggered at six locations surrounding the Mall. While thousands of people were potentially exposed, no infections were reported. The detected bacteria likely originated from a natural source, not from a bioterror attempt.In 2005, an outbreak occurred in Germany amongst participants in a hare hunt. About 27 people came into contact with contaminated blood and meat after the hunt. Ten of the exposed, aged 11 to 73, developed tularemia. One of these died due to complications caused by chronic heart disease.Tularemia is endemic in the Gori region of the Eurasian country of Georgia. The last outbreak was in 2006. The disease is also endemic on the uninhabited Pakri Islands off the northern coast of Estonia. Used for bombing practice by Soviet forces, chemical and bacteriological weapons may have been dropped on these islands.In July 2007, an outbreak was reported in the Spanish autonomous region of Castile and León and traced to the plague of voles infesting the region. Another outbreak had taken place ten years before in the same area.In January 2011, researchers searching for brucellosis among feral pig populations in Texas discovered widespread tularemia infection or evidence of past infection in feral hog populations of at least two Texas counties, even though tularemia is not normally associated with pigs at all. Precautions were recommended for those who hunt, dress, or prepare feral hogs. Since feral hogs roam over large distances, concern exists that tularemia may spread or already be present in feral hogs over a wide geographic area.In November 2011, it was found in Tasmania. Reports claimed it to be the first in the Southern Hemisphere. However, the causative organism was documented to have been isolated from a foot wound in the Northern Territory in 2003.In 2014, at least five cases of tularemia were reported in Colorado and at least three more cases in early 2015, including one death as a result of lawn mowing, as noted above. In the summer of 2015, a popular hiking area just north of Boulder was identified as a site of animal infection and signs were posted to warn hikers.

History
The tularemia bacterium was first isolated by G.W. McCoy of the United States Public Health Service plague lab and reported in 1912. Scientists determined tularemia could be dangerous to humans; a human being may catch the infection after contacting an infected animal. The ailment soon became associated with hunters, cooks and agricultural workers.

Biological weapon
The Centers for Disease Control and Prevention (CDC) regard F. tularensis as a viable biological warfare agent, and it has been included in the biological warfare programs of the United States, Soviet Union and Japan at various times. A former Soviet biological weapons scientist, Ken Alibek, has alleged that an outbreak of tularemia among German soldiers shortly before the Battle of Stalingrad was due to the release of F. tularensis by Soviet forces. Others who have studied the pathogen "propose that an outbreak resulting from natural causes is more likely". In the United States, practical research into using rabbit fever as a biological warfare agent took place in 1954 at Pine Bluff Arsenal, Arkansas, an extension of the Fort Detrick program </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Exfoliation and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Endocrine disease and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Micromastia and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tanapox and explain in detail? [/INST] Tanapox (a virus from the genus Yatapoxvirus) was first seen among individuals in the flood plain of the Tana River in Kenya during two epidemics (1957 and 1962) of acute febrile illness accompanied by localized skin lesions.

Signs and symptoms
The incubation period in human cases remains unknown, but in a person who underwent voluntary inoculation, erythema and central thickening appear by the fourth day. Most patients present a mild pre-eruptive fever that lasts 3–4 days, severe headaches and backaches, and often itching at the site where the skin lesion develops.There is initially a small nodule, without any central abrasion. This small nodule soon becomes papular and gradually enlarges to reach a maximum diameter of about 15 mm by the end of the second week of infection. The draining lymph nodes are also enlarged and tender from about the fifth day following the appearance of the skin lesion. The lesion remains mostly nodular but, ulcerates during the third week and then gradually heals within five to six weeks, leaving a scar.
In Kenya, the lesions were almost always solitary and were found on the upper arm, face, neck, and truck. Conversely, in Zaire, 22% of patients had multiple lesions, usually two or three </s>