<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 Asplenia and can you explain it in depth? [/INST] Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks. Hyposplenism is used to describe reduced (hypo-) splenic functioning, but not as severely affected as with asplenism.
Functional asplenia occurs when splenic tissue is present but does not work well (e.g. sickle-cell disease, polysplenia) -such patients are managed as if asplenic-, while in anatomic asplenia, the spleen itself is absent.

Causes
Congenital
Congenital asplenia is rare. There are two distinct types of genetic disorders: heterotaxy syndrome and isolated congenital asplenia.
polysplenia

Acquired
Acquired asplenia occurs for several reasons:

Following splenectomy due to splenic rupture from trauma or because of tumor
After splenectomy with the goal of interfering with splenic function, as a treatment for diseases (e.g. idiopathic thrombocytopenic purpura, thalassemia, spherocytosis), in which the spleens usual activity exacerbates the disease
After splenectomy with the goal of arresting the progression of cancers (Chronic lymphocytic leukemia, Hodgkins disease (starting in the 1970s), non-Hodgkin lymphoma)
Due to underlying diseases that destroy the spleen (autosplenectomy), e.g. sickle-cell disease.
Celiac disease: unknown physiopathology. In a 1970 study, it was the second most common cause of abnormalities of red blood cells linked to hyposplenism, after surgical splenectomy.

Functional asplenia
Functional asplenia can occur when patients with metabolic or haematological disorders have their splenic tissue organisation altered. This can lead to results similar to those seen in patients who have undergone a splenectomy e.g. becoming infected with encapsulated bacteria such as Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis. Patients who have some form of asplenia have an increased susceptibility to these encapsulated bacterial infections mainly because they lack IgM memory B cells and their non-adherence to polysaccharide vaccines. Furthermore, there is a deficiency of other splenic cells e.g. splenic macrophages. This combined with the lack of B cells can provide an environment favourable for the development of bacterial infections.

Partial splenectomy and preservation of splenic function
In an effort to preserve some of the spleens protective roles, attempts are now often made to preserve a small part of the spleen when performing either surgical subtotal (partial) splenectomy, or partial splenic embolization.
This may be particularly important in poorer countries where protective measures for patients with asplenia are not available.
However, it has been advised that preoperative vaccination is advisable until the remnant splenic tissue can reestablish its function.

Risks
Asplenia is a form of immunodeficiency, increasing the risk of sepsis from polysaccharide encapsulated bacteria, and can result in overwhelming post splenectomy infection (OPSI), often fatal within a few hours. In particular, patients are at risk from Streptococcus pneumoniae, Haemophilus influenzae, and meningococcus. The risk is elevated as much as 350–fold.The increased risk of infection is due to inability to clear opsonised bacteria from circulating blood.  There is also a deficiency of T-cell independent antibodies, such as those reactive to the polysaccharide capsule of Streptococcus pneumoniae.The risk to asplenic patients has been expressed as equivalent to an adult dying in a road traffic accident (in every 100 people without spleens, 1 to 5 would develop a severe infection per decade) (reference UK Splenectomy Trust Advice)—hence sensible precautions are advisable. Increased platelet counts can be seen in individuals without a functioning spleen.

Diagnosis
Diagnosis is confirmed by abdominal ultrasonography and detection of Howell-Jolly bodies in red blood cells.

Management
To minimise the risks associated with splenectomy, antibiotic and vaccination protocols have been established, but are often poorly adhered to by physicians and patients due to the complications resulting from antibiotic prophylaxis such as development of an overpopulation of Clostridium difficile in the intestinal tract.

Antibiotic prophylaxis
Because of the increased risk of infection, physicians administer oral antibiotics as prophylaxis after a surgical splenectomy, or starting at birth for congenital or functional asplenia.
Those with asplenia are also cautioned to start a full-dose course of antibiotics at the first onset of an upper or lower respiratory tract infection (for example, sore throat or cough), or at the onset of any fever. Even with a course of antibiotics and even with a history of relevant vaccination, persons without a functional spleen are at risk for Overwhelming post-splenectomy infection.In an emergency room or hospital setting, appropriate evaluation and treatment for an asplenic febrile patient should include a complete blood count with differential, blood culture with Gram stain, arterial blood gas analysis, chest x-ray, and consideration for lumbar puncture with CSF studies. None of these evaluations should delay the initiation of appropriate broad-spectrum intravenous antibiotics. The Surviving Sepsis Campaign guidelines state that antibiotics should be administered to a patient suspected of sepsis within 1 hour of presentation. Delay in starting antibiotics for any reason is associated with a poor outcome.

Vaccinations
It is suggested that splenectomized persons receive the following vaccinations, and ideally prior to planned splenectomy surgery:

Pneumococcal polysaccharide vaccine (not before 2 years of age).  Children may first need one or more boosters of  pneumococcal conjugate vaccine if they did not complete the full childhood series.
Haemophilus influenzae type b vaccine, especially if not received in childhood.  For adults who have not been previously vaccinated,  two doses given two months apart was advised in the new 2006 UK vaccination guidelines (in the UK may be given as a combined Hib/MenC vaccine).
Meningococcal conjugate vaccine, especially if not received in adolescence.  Previously vaccinated adults require a single booster and non-immunised adults advised, in UK since 2006, to have two doses given two months apart.  Children too young for the conjugate vaccine should receive meningococcal polysaccharide vaccine in the interim.
Influenza vaccine, every winter, to help prevent getting secondary bacterial infection.

Travel measures
In addition to the normal immunizations advised for the countries to be visited, Group A meningococcus should be included if visiting countries of particular risk (e.g </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 Acid–base homeostasis and can you explain it in depth? [/INST] Acid–base homeostasis is the homeostatic regulation of the pH of the bodys extracellular fluid (ECF). The proper balance between the acids and bases (i.e. the pH) in the ECF is crucial for the normal physiology of the body—and for cellular metabolism. The pH of the intracellular fluid and the extracellular fluid need to be maintained at a constant level.The three dimensional structures of many extracellular proteins, such as the plasma proteins and membrane proteins of the bodys cells, are very sensitive to the extracellular pH. Stringent mechanisms therefore exist to maintain the pH within very narrow limits. Outside the acceptable range of pH, proteins are denatured (i.e. their 3D structure is disrupted), causing enzymes and ion channels (among others) to malfunction.
An acid–base imbalance is known as acidemia when the pH is acidic, or alkalemia when the pH is alkaline.

Lines of defense
In humans and many other animals, acid–base homeostasis is maintained by multiple mechanisms involved in three lines of defense:
Chemical: The first lines of defense are immediate, consisting of the various chemical buffers which minimize pH changes that would otherwise occur in their absence. These buffers include the bicarbonate buffer system, the phosphate buffer system, and the protein buffer system.
Respiratory component: The second line of defense is rapid consisting of the control the carbonic acid (H2CO3) concentration in the ECF by changing the rate and depth of breathing by hyperventilation or hypoventilation. This blows off or retains carbon dioxide (and thus carbonic acid) in the blood plasma as required.
Metabolic component: The third line of defense is slow, best measured by the base excess, and mostly depends on the renal system which can add or remove bicarbonate ions (HCO−3) to or from the ECF. Bicarbonate ions are derived from metabolic carbon dioxide which is enzymatically converted to carbonic acid in the renal tubular cells. There, carbonic acid spontaneously dissociates into hydrogen ions and bicarbonate ions. When the pH in the ECF falls, hydrogen ions are excreted into urine, while bicarbonate ions are secreted into blood plasma, causing the plasma pH to rise. The converse happens if the pH in the ECF tends to rise: bicarbonate ions are then excreted into the urine and hydrogen ions into the blood plasma.The second and third lines of defense operate by making changes to the buffers, each of which consists of two components: a weak acid and its conjugate base. It is the ratio concentration of the weak acid to its conjugate base that determines the pH of the solution. Thus, by manipulating firstly the concentration of the weak acid, and secondly that of its conjugate base, the pH of the extracellular fluid (ECF) can be adjusted very accurately to the correct value. The bicarbonate buffer, consisting of a mixture of carbonic acid (H2CO3) and a bicarbonate (HCO−3) salt in solution, is the most abundant buffer in the extracellular fluid, and it is also the buffer whose acid-to-base ratio can be changed very easily and rapidly.

Acid–base balance
The pH of the extracellular fluid, including the blood plasma, is normally tightly regulated between 7.32 and 7.42 by the chemical buffers, the respiratory system, and the renal system. The normal pH in the fetus differs from that in the adult. In the fetus, the pH in the umbilical vein pH is normally 7.25 to 7.45 and that in the umbilical artery is normally 7.18 to 7.38.Aqueous buffer solutions will react with strong acids or strong bases by absorbing excess H+ ions, or OH− ions, replacing the strong acids and bases with weak acids and weak bases. This has the effect of damping the effect of pH changes, or reducing the pH change that would otherwise have occurred. But buffers cannot correct abnormal pH levels in a solution, be that solution in a test tube or in the extracellular fluid. Buffers typically consist of a pair of compounds in solution, one of which is a weak acid and the other a weak base. The most abundant buffer in the ECF consists of a solution of carbonic acid (H2CO3), and the bicarbonate (HCO−3) salt of, usually, sodium (Na+). Thus, when there is an excess of OH− ions in the solution carbonic acid partially neutralizes them by forming H2O and bicarbonate (HCO−3) ions. Similarly an excess of H+ ions is partially neutralized by the bicarbonate component of the buffer solution to form carbonic acid (H2CO3), which, because it is a weak acid, remains largely in the undissociated form, releasing far fewer H+ ions into the solution than the original strong acid would have done.The pH of a buffer solution depends solely on the ratio of the molar concentrations of the weak acid to the weak base. The higher the concentration of the weak acid in the solution (compared to the weak base) the lower the resulting pH of the solution. Similarly, if the weak base predominates the higher the resulting pH.
This principle is exploited to regulate the pH of the extracellular fluids (rather than just buffering the pH). For the carbonic acid-bicarbonate buffer, a molar ratio of weak acid to weak base of 1:20 produces a pH of 7.4; and vice versa—when the pH of the extracellular fluids is 7.4 then the ratio of carbonic acid to bicarbonate ions in that fluid is 1:20.

Henderson–Hasselbalch equation
The Henderson–Hasselbalch equation, when applied to the carbonic acid-bicarbonate buffer system in the extracellular fluids, states that:

          p
          H

        =

          p

          K

              a

                H

                2

                C
                O

                3

        +

          log

            10

          (

                [

                    H
                    C
                    O

                    3

                    −

                ]

                [

                    H

                    2

                    C
                    O

                    3

                ]

          )

        ,

    {\displaystyle \mathrm {pH} =\mathrm {p} K_{\mathrm {a} ~\mathrm {H} _{2}\mathrm {CO} _{3}}+\log _{10}\left({\frac {[\mathrm {HCO} _{3}^{-}]}{[\mathrm {H} _{2}\mathrm {CO} _{3}]}}\right),}

where:

pH is the negative logarithm (or cologarithm) of molar concentration of hydrogen ions in the extracellular fluid.
pKa H2CO3 is the cologarithm of the acid dissociation constant of carbonic acid. It is equal to 6.1.
[HCO−3] is the molar concentration of bicarbonate in the blood plasma.
[H2CO3] is the molar concentration of carbonic acid in the extracellular fluid.However, since the carbonic acid concentration is directly proportional to the partial pressure of carbon dioxide (

          P

                  C
                  O

                2

    {\displaystyle P_{{\mathrm {CO} }_{2}}}
  ) in the extracellular fluid, the equation can be rewritten as follows:

          p
          H

        =
        6.1
        +

          log

            10

          (

                [

                    H
                    C
                    O

                    3

                    −

                ]

                0.0307
                ×

                  P

                        C
                        O

                        2

          )

        ,

    {\displaystyle \mathrm {pH} =6.1+\log _{10}\left({\frac {[\mathrm {HCO} _{3}^{-}]}{0.0307\times P_{\mathrm {CO} _{2}}}}\right),}

where:

pH is the negative logarithm of molar concentration of hydrogen ions in the extracellular fluid.
[HCO−3] is the molar concentration of bicarbonate in the plasma.
PCO2 is the partial pressure of carbon dioxide in the blood plasma.The pH of the extracellular fluids can thus be controlled by the regulation of

          P

                  C
                  O

                2

    {\displaystyle P_{{\mathrm {CO} }_{2}}}
   and the other metabolic acids.

Homeostatic mechanisms
Homeostatic control can change the PCO2 and hence the pH of the arterial plasma within a few seconds. The partial pressure of carbon dioxide in the arterial blood is monitored by the central chemoreceptors of the medulla oblongata. These chemoreceptors are sensitive to the levels of carbon dioxide and pH in the cerebrospinal fluid.The central chemoreceptors send their information to the respiratory centers in the medulla oblongata and pons of the brainstem. The respiratory centres then determine the average rate of ventilation of the alveoli of the lungs, to keep the PCO2 in the arterial blood constant. The respiratory center does so via motor neurons which activate the muscles of respiration (in particular, the diaphragm). A rise in the PCO2 in the arterial blood plasma above 5.3 kPa (40 mmHg) reflexly causes an increase in the rate and depth of breathing. Normal breathing is resumed when the partial pressure of carbon dioxide has returned to 5.3 kPa. The converse happens if the partial pressure of carbon dioxide falls below the normal range. Breathing may be temporally halted, or slowed down to allow carbon dioxide to accumulate once more in the lungs and arterial blood.
The sensor for the plasma HCO−3 concentration is not known for certain. It is very probable that the renal tubular cells of the distal convoluted tubules are themselves sensitive to the pH of the plasma. The metabolism of these cells produces CO2, which is rapidly converted to H+ and HCO−3 through the action of carbonic anhydrase. When the extracellular fluids tend towards acidity, the renal tubular cells secrete the H+ ions into the tubular fluid from where they exit the body via the urine. The HCO−3 ions are simultaneously secreted into the blood plasma, thus raising the bicarbonate ion concentration in the plasma, lowering the carbonic acid/bicarbonate ion ratio, and consequently raising the pH of the plasma. The converse happens when the plasma pH rises above normal: bicarbonate ions are excreted into the urine, and hydrogen ions into the plasma. These combine with the bicarbonate ions in the plasma to form carbonic acid (H+ + HCO−3

        ⇌

    {\displaystyle \rightleftharpoons }
   H2CO3), thus raising the carbonic acid:bicarbonate ratio in the extracellular fluids, and returning its pH to normal.In general, metabolism produces more waste acids than bases. Urine produced is generally acidic and is partially neutralized by the ammonia (NH3) that is excreted into the urine when glutamate and glutamine (carriers of excess, no longer needed, amino groups) are deaminated by the distal renal tubular epithelial cells. Thus some of the "acid content" of the urine resides in the resulting ammonium ion (NH4+) content of the urine, though this has no effect on pH homeostasis of the extracellular fluids.

Imbalance
Acid–base imbalance occurs when a significant insult causes the blood pH to shift out of the normal range (7.32 to 7.42). An abnormally low pH in the extracellular fluid is called an acidemia and an abnormally high pH is called an alkalemia.
Acidemia and alkalemia unambiguously refer to the actual change in the pH of the extracellular fluid (ECF) </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 Treacher Collins syndrome and can you explain it in depth? [/INST] Treacher Collins syndrome (TCS) is a genetic disorder characterized by deformities of the ears, eyes, cheekbones, and chin. The degree to which a person is affected, however, may vary from mild to severe. Complications may include breathing problems, problems seeing, cleft palate, and hearing loss. Those affected generally have normal intelligence.TCS is usually autosomal dominant. More than half the time it occurs as a result of a new mutation rather than being inherited from a persons parents. The involved genes may include TCOF1, POLR1C, or POLR1D. Diagnosis is generally suspected based on symptoms and X-rays, and potentially confirmation by genetic testing.Treacher Collins syndrome is not curable. Symptoms may be managed with reconstructive surgery, hearing aids, speech therapy, and other assistive devices. Life expectancy is generally normal. TCS occurs in about one in 50,000 people. The syndrome is named after Edward Treacher Collins, an English surgeon and ophthalmologist, who described its essential traits in 1900.

Signs and symptoms
Symptoms in people with Treacher Collins syndrome vary. Some individuals are so mildly affected that they remain undiagnosed, while others have moderate to severe facial involvement and life-threatening airway compromise. Most of the features of TCS are symmetrical and are already recognizable at birth.The most common symptom of Treacher Collins syndrome is underdevelopment of the lower jaw and underdevelopment of the zygomatic bone. This can be accompanied by the tongue being retracted. The small mandible can result in a poor occlusion of the teeth or in more severe cases, trouble breathing or swallowing. The respiratory system of a child with Treacher Collins syndrome is the primary concern at birth, with other issues only addressed once respiratory function has been stabilized. Underdevelopment of the zygomatic bone gives the cheeks a sunken appearance.The external ear is sometimes small, rotated, malformed, or absent entirely in people with TCS. Symmetric, bilateral narrowing or absence of the external ear canal, is also described. In most cases, the bones of the middle ear and the middle ear cavity are misshapen. Inner ear malformations are rarely described. As a result of these abnormalities, a majority of the individuals with TCS have conductive hearing loss.Most affected people also experience eye problems, including coloboma (notches) in the lower eyelids, partial or complete absence of eyelashes on the lower lid, downward angled eyelids, drooping of upper and lower eyelids, and narrowing of the tear ducts. Vision loss can occur and is associated with strabismus, refractive errors, and anisometropia. It can also be caused by severely dry eyes, a consequence of lower eyelid abnormalities and frequent eye infections.Although an abnormally shaped skull is not distinctive for Treacher Collins syndrome, brachycephaly with bitemporal narrowing is sometimes observed. Cleft palate is also common.Dental anomalies are seen in 60% of affected people, including tooth agenesis (33%), discoloration (enamel opacities) (20%), malplacement of the maxillary first molars (13%), and wide spacing of the teeth. In some cases, dental anomalies in combination with mandible hypoplasia result in a malocclusion. This can lead to problems with food intake and the ability to close the mouth.Less common features of TCS may add to an affected persons breathing problems, including sleep apnea. Choanal atresia or stenosis is a narrowing or absence of the choanae, the internal opening of the nasal passages, which may also be observed. Underdevelopment of the pharynx can also narrow the airway.Features related to TCS that are seen less frequently include nasal deformities, high-arched palate, macrostomia, preauricular hair displacement, cleft palate, hypertelorism, notched upper eyelid, and congenital heart defects.Although facial deformity is often associated with developmental delay and intellectual disability, more than 95% of people affected with TCS have normal intelligence. The psychological and social problems associated with facial deformity can affect quality of life in individuals with TCS.

Genetics
Mutations in TCOF1, POLR1C, or POLR1D genes can cause Treacher Collins syndrome. TCOF1 gene mutations are the most common cause of the disorder, with POLR1C and POLR1D gene mutations causing an additional 2% of cases. In individuals without an identified mutation in one of these genes, the genetic cause of the condition is unknown. The TCOF1, POLR1C, and POLR1D genes code for proteins which play important roles in the early development of bones and other tissues of the face. Mutations in these genes  reduce the production of rRNA, which may trigger the self-destruction (apoptosis) of certain cells involved in the development of facial bones and tissues. It is unclear why the effects of a reduction in rRNA are limited to facial development. Mutations in TCOF1 and POLR1D cause the autosomal dominant form of Treacher Collins, and mutations in POLR1C cause the autosomal recessive form.

TCOF1
TCOF1 is the primary gene associated with TCS, a mutation in this gene being found in 90–95% of the individuals with TCS. However, in some individuals with typical symptoms of TCS, mutations in TCOF1 have not been found. Investigation of the DNA has resulted in the identification of the kind of mutations found in TCOF1. The majority of mutations are small deletions or insertions, though splice site and missense mutations also have been identified.Mutation analysis has unveiled more than 100 disease-causing mutations in TCOF1, which are mostly family-specific mutations. The only recurrent mutation accounts for about 17% of the cases.TCOF1 is found on the 5th chromosome in the 5q32 region. It codes for a relatively simple nucleolar protein called treacle, that is thought to be involved in ribosome assembly. Mutations in TCOF1 lead to haploinsufficiency of the treacle protein. Haploinsufficiency occurs when a diploid organism has only one functional copy of a gene, because the other copy is inactivated by a mutation. The one normal copy of the gene does not produce enough protein, causing disease. Haploinsufficiency of the treacle protein leads to a depletion of the neural crest cell precursor, which leads to a reduced number of crest cells migrating to the first and second pharyngeal arches. These cells play an important role in the development of the craniofacial appearance, and loss of one copy of treacle affects the cells ability to form the bones and tissues of the face.

Other mutations
POLR1C and POLR1D mutations are responsible for a minority of cases of Treacher Collins. POLR1C is found on chromosome 6 at position 6q21.2 and POLR1D is found on chromosome 13 at position 13q12.2. Those genes code for a protein subunits shared between RNA polymerase I and III. Both of these polymerases are important for ribosome biogenesis.

Diagnosis
Genetic counseling
TCS is inherited in an autosomal dominant manner and the penetrance of the affected gene is almost complete. Some recent investigations, though, described some rare cases in which the penetrance in TCS was not complete. Causes may be a variable expressivity, an incomplete penetrance or germline mosaicism. Only 40% of the mutations are inherited. The remaining 60% are a result of a de novo mutation, where a child has a new mutation in the responsible gene and did not inherit it from either parent. In the outcome of the disease, inter- and intrafamilial variability occurs. This suggests that when an affected child is born, it is important to investigate the parents to determine whether the affected gene is present, because the parent could have a mild form of the disease that has not been diagnosed. In this case, the risk of having another affected child is 50%. If the parents do not have the affected gene, the recurrence risk appears to be low. In following generations, the severity of the clinical symptoms increases.

Prenatal diagnosis
Mutations in the main genes responsible for TCS can be detected with chorionic villus sampling or amniocentesis. Rare mutations may not be detected by these methods. Ultrasonography can be used to detect craniofacial abnormalities later in pregnancy, but may not detect milder cases.

Clinical findings
TCS is often first suspected with characteristic symptoms observed during a physical exam. However, the clinical presentation of TCS can resemble other diseases, making diagnosis difficult. The OMENS classification was developed as a comprehensive and stage-based approach to differentiate the diseases. This acronym describes five distinct dysmorphic manifestations, namely orbital asymmetry, mandibular hypoplasia, auricular deformity, nerve development, and soft-tissue disease.Orbital symmetry

O0: normal orbital size, position
O1: abnormal orbital size
O2: abnormal orbital position
O3: abnormal orbital size and positionMandible

M0: normal mandible
M1: small mandible and glenoid fossa with short ramus
M2: ramus short and abnormally shaped2A: glenoid fossa in anatomical acceptable position
2B: Temperomandibular joint inferiorly (TMJ), medially, anteriorly displaced, with severely hypoplastic condyleM3: Complete absence of ramus, glenoid fossa, and TMJEar

E0: normal ear
E1: Minor hypoplasia and cupping with all structures present
E2: Absence of external auditory canal with variable hypoplasia of the auricle
E3: Malposition of the lobule with absent auricle, lobular remnant usually inferior anteriorly displacedFacial nerve

N0: No facial nerve involvement
N1: Upper facial nerve involvement (temporal or zygomatic branches)
N2: Lower facial nerve involvement (buccal, mandibular or cervical)
N3: All branches affectedSoft tissue

S0: No soft tissue or muscle deficiency
S1: Minimal tissue or muscle deficiency
S2: Moderate tissue or muscle deficiency
S3: Severe tissue or muscle deficiency

Radiographs
A few techniques are used to confirm the diagnosis in TCS.An orthopantomogram (OPG) is a panoramic dental X-ray of the upper and lower jaw. It shows a two-dimensional image from ear to ear. Particularly, OPG facilitates an accurate postoperative follow-up and monitoring of bone growth under a mono- or double-distractor treatment. Thereby, some TCS features could be seen on OPG, but better techniques are used to include the whole spectrum of TCS abnormalities instead of showing only the jaw abnormalities.Another method of radiographic evaluation is taking an X-ray image of the whole head. The lateral cephalometric radiograph in TCS shows hypoplasia of the facial bones, like the malar bone, mandible, and the mastoid.Finally, occipitomental radiographs are used to detect hypoplasia or discontinuity of the zygomatic arch.

CT scan
A temporal-bone CT using thin slices makes it possible to diagnose the degree of stenosis and atresia of the external auditory canal, the status of the middle ear cavity, the absent or dysplastic and rudimentary ossicles, or inner ear abnormalities such as a deficient cochlea. Two- and three-dimensional CT reconstructions with VRT and bone and skin-surfacing are helpful for more accurate staging and the three-dimensional  planning of mandibular and external ear reconstructive surgery.

Differential diagnosis
Other diseases have similar characteristics to Treacher Collins syndrome. In the differential diagnosis, one should consider the acrofacial dysostoses. The facial appearance resembles that of Treacher Collins syndrome, but additional limb abnormalities occur in those persons. Examples of these diseases are Nager syndrome and  Miller syndrome.The oculoauriculovertebral spectrum should also be considered in the differential diagnosis. An example is hemifacial microsomia, which primarily affects development of the ear, mouth, and mandible. This anomaly may occur bilaterally. Another disease which belongs to this spectrum is Goldenhar syndrome, which includes vertebral abnormalities, epibulbar dermoids and facial deformities.

Treatment
The treatment of individuals with TCS may involve the intervention of professionals from multiple disciplines. The primary concerns are breathing and feeding, as a consequence of the hypoplasia of the mandibula and the obstruction of the hypopharynx by the tongue. Sometimes, they may require a tracheostomy to maintain an adequate airway, and a gastrostomy to assure an adequate caloric intake while protecting the airway. Corrective surgery of the face is performed at defined ages, depending on the developmental state.An overview of the present guidelines:

If a cleft palate is present, the repair normally takes place at 9–12 months old. Before surgery,  a polysomnography with a palatal plate in place is needed. This may predict the postoperative situation and gives insight on the chance of the presence of sleep apnea (OSAS) after the operation.
Hearing loss is treated by bone conduction amplification, speech therapy, and educational intervention to avoid language/speech problems. The bone-anchored hearing aid is an alternative for individuals with ear anomalies.
Zygomatic and orbital reconstruction is performed when the cranio-orbitozygomatic bone is completely developed, usually at the age of 5–7 years. In children, an autologous bone graft is mostly used. In combination with this transplantation, lipofilling can be used in the periorbital area to get an optimal result of the reconstruction. Reconstruction of the lower eyelid coloboma includes the use of a myocutaneous flap, which is elevated and in this manner closes the eyelid defect.
External ear reconstruction is usually done when the individual is at least eight years old. Sometimes, the external auditory canal or middle ear can also be treated.
The optimal age for the maxillomandibular reconstruction is controversial; as of 2004, this classification has been used:Type I (mild) and Type IIa (moderate)           13–16 years
Type IIb (moderate to severe malformation)     at skeletal maturity
Type III (severe)                              6–10 years
When the teeth are cutting, the teeth should be under supervision of an orthodontist to make sure no abnormalities occur. If abnormalities like dislocation or an overgrowth of teeth are seen, appropriate action can be undertaken as soon as possible.
Orthognatic treatments usually take place after the age of 16 years; at this point, all teeth are in place and the jaw and dentures are mature. Whenever OSAS is detected, the level of obstruction is determined through endoscopy of the upper airways. Mandibular advancement can be an effective way to improve both breathing and æsthetics, while a chinplasty only restores the profile.
If a nose reconstruction is necessary, it is usually performed after the orthognatic surgery and after the age of 18 years.
The contour of the facial soft tissues generally requires correction at a later age, because of the facial skeletal maturity. The use of microsurgical methods, like the free flap transfer, has improved the correction of facial soft tissue contours. Another technique to improve the facial soft tissue contours is lipofilling. For instance, lipofilling is used to reconstruct the eyelids.

Hearing loss
Hearing loss in Treacher Collins syndrome is caused by deformed structures in the outer and middle ear. The hearing loss is generally bilateral with a conductive loss of about 50–70 dB. Even in cases with normal auricles and open external auditory canals, the ossicular chain is often malformed.Attempts to surgically reconstruct the external auditory canal and improve hearing in children with TCS have not yielded positive results.Auditory rehabilitation with bone-anchored hearing aids (BAHAs) or a conventional bone conduction aid has proven preferable to surgical reconstruction.

Psychiatric
The disorder can be associated with a number of psychological symptoms, including anxiety, depression, social phobia, and distress about body image. People who have this disorder may also experience discrimination, bullying, and name calling, especially when young </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 Ototoxicity and can you explain it in depth? [/INST] Ototoxicity is the property of being toxic to the ear (oto-), specifically the cochlea or auditory nerve and sometimes the vestibular system, for example, as a side effect of a drug. The effects of ototoxicity can be reversible and temporary, or irreversible and permanent.
It has been recognized since the 19th century.
There are many well-known ototoxic drugs used in clinical situations, and they are prescribed, despite the risk of hearing disorders, for very serious health conditions.
Ototoxic drugs include antibiotics (such as gentamicin, streptomycin, tobramycin), loop diuretics (such as furosemide), and platinum-based chemotherapy agents (such as cisplatin and carboplatin). A number of nonsteroidal anti-inflammatory drugs (NSAIDS) have also been shown to be ototoxic. This can result in sensorineural hearing loss, dysequilibrium, or both. Some environmental and occupational chemicals have also been shown to affect the auditory system and interact with noise.

Signs and symptoms
Symptoms of ototoxicity include partial or profound hearing loss, vertigo, and tinnitus.The cochlea is primarily a hearing structure situated in the inner ear. It is the snail-shaped shell containing several nerve endings that makes hearing possible.
Ototoxicity typically results when the inner ear is poisoned by medication that damages the cochlea, vestibule, semi-circular canals, or the auditory/ vestibulocochlear nerve. The damaged structure then produces the symptoms the patient presents with. Ototoxicity in the cochlea may cause hearing loss of the high-frequency pitch ranges or complete deafness, or losses at points between.  It may present with bilaterally symmetrical symptoms, or asymmetrically, with one ear developing the condition after the other or not at all. The time frames for progress of the disease vary greatly and symptoms of hearing loss may be temporary or permanent.The vestibule and semi-circular canal are inner-ear components that comprise the vestibular system. Together they detect all directions of head movement. Two types of otolith organs are housed in the vestibule: the saccule, which points vertically and detects vertical acceleration, and the utricle, which points horizontally and detects horizontal acceleration. The otolith organs together sense the heads position with respect to gravity when the body is static; then the heads movement when it tilts; and pitch changes during any linear motion of the head. The saccule and utricle detect different motions, which information the brain receives and integrates to determine where the head is and how and where it is moving.
The semi-circular canals are three bony structures filled with fluid. As with the vestibule, the primary purpose of the canals is to detect movement. Each canal is oriented at right angles to the others, enabling detection of movement in any plane. The posterior canal detects rolling motion, or motion about the X axis; the anterior canal detects pitch, or motion about the Y axis; the horizontal canal detects yaw motion, or motion about the Z axis.
When a medication is toxic in the vestibule or the semi-circular canals, the patient senses loss of balance or orientation rather than losses in hearing. Symptoms in these organs present as vertigo, difficulties walking in low light and darkness, disequilibrium, oscillopsia among others. Each of these problems is related to balance and the mind is confused with the direction of motion or lack of motion. Both the vestibule and semi-circular canals transmit information to the brain about movement; when these are poisoned, they are unable to function properly which results in miscommunication with the brain.
When the vestibule and/or semi-circular canals are affected by ototoxicity, the eye can also be affected. Nystagmus and oscillopsia are two conditions that overlap the vestibular and ocular systems. These symptoms cause the patient to have difficulties with seeing and processing images. The body subconsciously tries to compensate for the imbalance signals being sent to the brain by trying to obtain visual cues to support the information it is receiving. This results in that dizziness and "woozy" feeling patients use to describe conditions such as oscillopsia and vertigo.Cranial nerve VIII is the least affected component of the ear when ototoxicity arises, but if the nerve is affected, the damage is most often permanent. Symptoms present similar to those resulting from vestibular and cochlear damage, including tinnitus, ringing of the ears, difficulty walking, deafness, and balance and orientation issues.

Ototoxic agents
Antibiotics
Antibiotics in the aminoglycoside class, such as gentamicin and tobramycin, may produce cochleotoxicity through a poorly understood mechanism. It may result from antibiotic binding to NMDA receptors in the cochlea and damaging neurons through excitotoxicity. Aminoglycoside-induced production of reactive oxygen species may also injure cells of the cochlea. Once-daily dosing and co-administration of N-acetylcysteine may protect against aminoglycoside-induced ototoxicity. The anti-bacterial activity of aminoglycoside compounds is due to inhibition of ribosome function and these compounds similarly inhibit protein synthesis by mitochondrial ribosomes because mitochondria evolved from a bacterial ancestor. Consequently, aminoglycoside effects on production of reactive oxygen species as well as dysregulation of cellular calcium ion homeostasis may result from disruption of mitochondrial function. Ototoxicity of gentamicin can be exploited to treat some individuals with Ménières disease by destroying the inner ear,  which stops the vertigo attacks but causes permanent deafness.
Due to the effects on mitochondria, certain inherited mitochondrial disorders result in increased sensitivity to the toxic effects of aminoglycosides.
Macrolide antibiotics, including erythromycin, are associated with reversible ototoxic effects. The underlying mechanism of ototoxicity may be impairment of ion transport in the stria vascularis. Predisposing factors include renal impairment, hepatic impairment, and recent organ transplantation.

Loop diuretics
Certain types of diuretics are associated with varying levels of risk for ototoxicity. Loop and thiazide diuretics carry this side effect. The loop diuretic furosemide is associated with ototoxicity, particularly when doses exceed 240 mg per hour. The related compound ethacrynic acid has a higher association with ototoxicity, and is therefore used only in patients with sulfa allergies. Diuretics are thought to alter the ionic gradient within the stria vascularis. Bumetanide confers a decreased risk of ototoxicity compared to furosemide.

Chemotherapeutic agents
Platinum-containing chemotherapeutic agents, including cisplatin and carboplatin, are associated with cochleotoxicity characterized by progressive, high-frequency hearing loss with or without tinnitus (ringing in the ears). Ototoxicity is less frequently seen with the related compound oxaliplatin. The severity of cisplatin-induced ototoxicity is dependent upon the cumulative dose administered and the age of the patient, with young children being most susceptible. The exact mechanism of cisplatin ototoxicity is not known. The drug is understood to damage multiple regions of the cochlea, causing the death of outer hair cells, as well as damage to the spiral ganglion neurons and cells of the stria vascularis. Long-term retention of cisplatin in the cochlea may contribute to the drugs cochleotoxic potential. Once inside the cochlea, cisplatin has been proposed to cause cellular toxicity through a number of different mechanisms, including through the production of reactive oxygen species. The decreased incidence of oxaliplatin ototoxicity has been attributed to decreased uptake of the drug by cells of the cochlea. Administration of amifostine has been used in attempts to prevent cisplatin-induced ototoxicity, but the American Society of Clinical Oncology recommends against its routine use.The vinca alkaloids, including vincristine, are also associated with reversible ototoxicity.

Antiseptics and disinfectants
Topical skin preparations such as chlorhexidine and ethyl alcohol have the potential to be ototoxic should they enter the inner ear through the round window membrane. This potential was first noted after a small percentage of patients undergoing early myringoplasty operations experienced severe sensorineural hearing loss. It was found that in all operations involving this complication the preoperative sterilization was done with chlorhexidine. The ototoxicity of chlorhexidine was further confirmed by studies with animal models.Several other skin preparations have been shown to be potentially ototoxic in the animal model. These preparations include acetic acid, propylene glycol, quaternary ammonium compounds, and any alcohol-based preparations. However, it is difficult to extrapolate these results to human ototoxicity because the human round window membrane is much thicker than in any animal model.

Other medicinal ototoxic drugs
At high doses, quinine, aspirin and other salicylates may also cause high-pitch tinnitus and hearing loss in both ears, typically reversible upon discontinuation of the drug. Erectile dysfunction medications may have the potential to cause hearing loss. However the link between erectile dysfunction medications and hearing loss remains uncertain.Previous noise exposure has not been found to potentiate ototoxic hearing loss. The American Academy of Audiology includes in their position statement that exposure to noise at the same time as aminoglycosides may exacerbate ototoxicity. The American Academy of Audiology recommends people being treated with ototoxic chemotherapeutics avoid excessive noise levels during treatment and for several months following cessation of treatment. Opiates in combination with excessive noise levels may also have an additive effect on ototoxic hearing loss.

Ototoxicants in the environment and workplace
Ototoxic effects are also seen with quinine, pesticides, solvents, asphyxiants, and heavy metals such as mercury and lead. When combining multiple ototoxicants, the risk of hearing loss becomes greater. As these exposures are common, this hearing impairment can affect many occupations and industries.  Examples of activities that often have exposures to both noise and solvents include:
Printing
Painting
Construction
Fueling vehicles and aircraft
Firefighting
Weapons firing
Pesticide sprayingOtotoxic chemicals in the environment (from contaminated air or water) or in the workplace interact with mechanical stresses on the hair cells of the cochlea in different ways. For mixtures containing organic solvents such as toluene, styrene or xylene, the combined exposure with noise increases the risk of occupational hearing loss in a synergistic manner. The risk is greatest when the co-exposure is with impulse noise. Carbon monoxide has been shown to increase the severity of the hearing loss from noise. Given the potential for enhanced risk of hearing loss, exposures and contact with products such as fuels, paint thinners, degreasers, white spirits, exhaust, should be kept to a minimum. Noise exposures should be kept below 85 decibels, and the chemical exposures should be below the recommended exposure limits given by regulatory agencies.
Drug exposures mixed with noise potentially lead to increased risk of ototoxic hearing loss. Noise exposure combined with the chemotherapeutic cisplatin puts individuals at increased risk of ototoxic hearing loss. Noise at 85 dB SPL or above added to the amount of hair cell death in the high frequency region of the cochlea in chinchillas.The hearing loss caused by chemicals can be very similar to a hearing loss caused by excessive noise.  A 2018 informational bulletin by the US Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH) introduces the issue, provides examples of ototoxic chemicals, lists the industries and occupations at risk and provides prevention information.

Treatment
No specific treatment may be available, but withdrawal of the ototoxic drug may be warranted when the consequences of doing so are less severe than those of the ototoxicity. Co-administration of anti-oxidants may limit the ototoxic effects.Ototoxic monitoring during exposure is recommended by the American Academy of Audiology to allow for proper detection and possible prevention or rehabilitation of the hearing loss through a cochlear implant or hearing aid. Monitoring can be completed through performing otoacoustic emissions testing or high frequency audiometry. Successful monitoring includes a baseline test before, or soon after, exposure to the ototoxicant. Follow-up testing is completed in increments after the first exposure, throughout the cessation of treatment. Shifts in hearing status are monitored and relayed to the prescribing physician to make treatment decisions.It is difficult to distinguish between nerve damage and structural damage due to similarity of the symptoms.  Diagnosis of ototoxicity typically results from ruling out all other possible sources of hearing loss and is often the catchall explanation for the symptoms. Treatment options vary depending on the patient and the diagnosis </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 Syphilitic aortitis and can you explain it in depth? [/INST] Syphilitic aortitis  is inflammation of the aorta associated with the tertiary stage of syphilis infection. SA begins as inflammation of the outermost layer of the blood vessel, including the blood vessels that supply the aorta itself with blood, the vasa vasorum. As SA worsens, the vasa vasorum undergo hyperplastic thickening of their walls thereby restricting blood flow and causing ischemia of the outer two-thirds of the aortic wall </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 Tuberculosis verrucosa cutis and can you explain it in depth? [/INST] Tuberculosis verrucosa cutis is a rash of small, red papular nodules in the skin that may appear 2–4 weeks after inoculation by Mycobacterium tuberculosis in a previously infected and immunocompetent individual.
It is also known as "prosectors wart" because it was a common occupational disease of prosectors, the preparers of dissections and autopsies </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 Dialysis disequilibrium syndrome and can you explain it in depth? [/INST] Dialysis disequilibrium syndrome (DDS) is the collection of neurological signs and symptoms, attributed to cerebral edema, during or following shortly after intermittent hemodialysis or CRRT.Classically, DDS arises in individuals starting hemodialysis due to end-stage chronic kidney disease and is associated, in particular, with "aggressive" (high solute removal) dialysis.   However, it may also arise in fast onset, i.e. acute kidney failure in certain conditions.

Symptoms and signs
Diagnosis of mild DDS is often complicated by other dialysis complications such as malignant hypertension, uremia, encephalopathy, subdural hemorrhage, hyper- and hypoglycaemia, or electrolyte imbalances. Presentation of moderate and severe DDS requires immediate identification and treatment as the condition can result in severe neurological issues and death.1. Headache
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<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 Ectopic pregnancy and can you explain it in depth? [/INST] Ectopic pregnancy is a complication of pregnancy in which the embryo attaches outside the uterus. Signs and symptoms classically include abdominal pain and vaginal bleeding, but fewer than 50 percent of affected women have both of these symptoms. The pain may be described as sharp, dull, or crampy. Pain may also spread to the shoulder if bleeding into the abdomen has occurred. Severe bleeding may result in a fast heart rate, fainting, or shock. With very rare exceptions the fetus is unable to survive.Risk factors for ectopic pregnancy include pelvic inflammatory disease, often due to chlamydia infection; tobacco smoking; prior tubal surgery; a history of infertility; and the use of assisted reproductive technology. Those who have previously had an ectopic pregnancy are at much higher risk of having another one. Most ectopic pregnancies (90%) occur in the fallopian tube, which are known as tubal pregnancies, but implantation can also occur on the cervix, ovaries, caesarean scar, or within the abdomen. Detection of ectopic pregnancy is typically by blood tests for human chorionic gonadotropin (hCG) and ultrasound. This may require testing on more than one occasion. Ultrasound works best when performed from within the vagina. Other causes of similar symptoms include: miscarriage, ovarian torsion, and acute appendicitis.Prevention is by decreasing risk factors such as chlamydia infections through screening and treatment. While some ectopic pregnancies will miscarry without treatment, the standard treatment for ectopic pregnancy is an abortion. The use of the medication methotrexate works as well as surgery in some cases. Specifically it works well when the beta-HCG is low and the size of the ectopic is small. Surgery such as a salpingectomy is still typically recommended if the tube has ruptured, there is a fetal heartbeat, or the womans vital signs are unstable. The surgery may be laparoscopic or through a larger incision, known as a laparotomy. Maternal morbidity and mortality are reduced with treatment.The rate of ectopic pregnancy is about 11 to 20 per 1,000 live births in developed countries, though it may be as high as 4% among those using assisted reproductive technology. It is the most common cause of death among women during the first trimester at approximately 6-13% of the total. In the developed world outcomes have improved while in the developing world they often remain poor. The risk of death among those in the developed world is between 0.1 and 0.3 percent while in the developing world it is between one and three percent. The first known description of an ectopic pregnancy is by Al-Zahrawi in the 11th century. The word "ectopic" means "out of place".

Signs and symptoms
Up to 10% of women with ectopic pregnancy have no symptoms, and one-third have no medical signs. In many cases the symptoms have low specificity, and can be similar to those of other genitourinary and gastrointestinal disorders, such as appendicitis, salpingitis, rupture of a corpus luteum cyst, miscarriage, ovarian torsion or urinary tract infection. Clinical presentation of ectopic pregnancy occurs at a mean of 7.2 weeks after the last normal menstrual period, with a range of four to eight weeks. Later presentations are more common in communities deprived of modern diagnostic ability.
Signs and symptoms of ectopic pregnancy include increased hCG, vaginal bleeding (in varying amounts), sudden lower abdominal pain, pelvic pain, a tender cervix, an adnexal mass, or adnexal tenderness. In the absence of ultrasound or hCG assessment, heavy vaginal bleeding may lead to a misdiagnosis of miscarriage. Nausea, vomiting and diarrhea are more rare symptoms of ectopic pregnancy.Rupture of an ectopic pregnancy can lead to symptoms such as abdominal distension, tenderness, peritonism and hypovolemic shock. A woman with ectopic pregnancy may be excessively mobile with upright posturing, in order to decrease intrapelvic blood flow, which can lead to swelling of the abdominal cavity and cause additional pain.

Complications
The most common complication is rupture with internal bleeding which may lead to hypovolemic shock. Damage to the fallopian tubes can lead to difficulty becoming pregnant in the future. The womans other fallopian tube may function sufficiently for pregnancy. After the removal of one damaged fallopian tube, pregnancy remains possible in the future. If both are removed, in-vitro fertilization remains an option for women hoping to become pregnant.

Causes
There are a number of risk factors for ectopic pregnancies. However, in as many as one-third to one-half no risk factors can be identified. Risk factors include: pelvic inflammatory disease, infertility, use of an intrauterine device (IUD), previous exposure to diethylstilbestrol (DES), tubal surgery, intrauterine surgery (e.g. D&C), smoking, previous ectopic pregnancy, endometriosis, and tubal ligation. A previous induced abortion does not appear to increase the risk. The IUD does not increase the risk of ectopic pregnancy, but with an IUD if pregnancy occurs it is more likely to be ectopic than intrauterine. The risk of ectopic pregnancy after chlamydia infection is low. The exact mechanism through which chlamydia increases the risk of ectopic pregnancy is uncertain, though some research suggests that the infection can affect the structure of fallopian tubes.

Tube damage
Tubal pregnancy is when the egg is implanted in the fallopian tubes. Hair-like cilia located on the internal surface of the fallopian tubes carry the fertilized egg to the uterus. Fallopian cilia are sometimes seen in reduced numbers subsequent to an ectopic pregnancy, leading to a hypothesis that cilia damage in the fallopian tubes is likely to lead to an ectopic pregnancy. Women who smoke have a higher chance of an ectopic pregnancy in the fallopian tubes. Smoking leads to risk factors of damaging and destroying cilia. As cilia degenerate, the amount of time it takes for the fertilized egg to reach the uterus will increase. The fertilized egg, if it does not reach the uterus in time, will hatch from the non-adhesive zona pellucida and implant itself inside the fallopian tube, thus causing the ectopic pregnancy.
Women with pelvic inflammatory disease (PID) have a high occurrence of ectopic pregnancy. This results from the build-up of scar tissue in the fallopian tubes, causing damage to cilia. However, if both tubes were completely blocked, so that sperm and egg were physically unable to meet, then fertilization of the egg would naturally be impossible, and neither normal pregnancy nor ectopic pregnancy could occur. Intrauterine adhesions (IUA) present in Ashermans syndrome can cause ectopic cervical pregnancy or, if adhesions partially block access to the tubes via the ostia, ectopic tubal pregnancy. Ashermans syndrome usually occurs from intrauterine surgery, most commonly after D&C.  Endometrial/pelvic/genital tuberculosis, another cause of Ashermans syndrome, can also lead to ectopic pregnancy as infection may lead to tubal adhesions in addition to intrauterine adhesions.Tubal ligation can predispose to ectopic pregnancy. Reversal of tubal sterilization (tubal reversal) carries a risk for ectopic pregnancy. This is higher if more destructive methods of tubal ligation (tubal cautery, partial removal of the tubes) have been used than less destructive methods (tubal clipping). A history of a tubal pregnancy increases the risk of future occurrences to about 10%. This risk is not reduced by removing the affected tube, even if the other tube appears normal. The best method for diagnosing this is to do an early ultrasound.

Other
Although some investigations have shown that patients may be at higher risk for ectopic pregnancy with advancing age, it is believed that age is a variable which could act as a surrogate for other risk factors. Vaginal douching is thought by some to increase ectopic pregnancies. Women exposed to DES in utero (also known as "DES daughters") also have an elevated risk of ectopic pregnancy. However, DES has not been used since 1971 in the United States. It has also been suggested that pathologic generation of nitric oxide through increased iNOS production may decrease tubal ciliary beats and smooth muscle contractions and thus affect embryo transport, which may consequently result in ectopic pregnancy. The low socioeconomic status may be risk factors for ectopic pregnancy.

Diagnosis
An ectopic pregnancy should be considered as the cause of abdominal pain or vaginal bleeding in every woman who has a positive pregnancy test. The primary goal of diagnostic procedures in possible ectopic pregnancy is to triage according to risk rather than establishing pregnancy location.

Transvaginal ultrasonography
An ultrasound showing a gestational sac with fetal heart in the fallopian tube has a very high specificity of ectopic pregnancy. It involves a long, thin transducer, covered with the conducting gel and a plastic/latex sheath and inserted into the vagina. Transvaginal ultrasonography has a sensitivity of at least 90% for ectopic pregnancy. The diagnostic ultrasonographic finding in ectopic pregnancy is an adnexal mass that moves separately from the ovary. In around 60% of cases, it is an inhomogeneous or a noncystic adnexal mass sometimes known as the "blob sign". It is generally spherical, but a more tubular appearance may be seen in case of hematosalpinx. This sign has been estimated to have a sensitivity of 84% and specificity of 99% in diagnosing ectopic pregnancy. In the study estimating these values, the blob sign had a positive predictive value of 96% and a negative predictive value of 95%. The visualization of an empty extrauterine gestational sac is sometimes known as the "bagel sign", and is present in around 20% of cases. In another 20% of cases, there is visualization of a gestational sac containing a yolk sac or an embryo. Ectopic pregnancies where there is visualization of cardiac activity are sometimes termed "viable ectopic".

The combination of a positive pregnancy test and the presence of what appears to be a normal intrauterine pregnancy does not exclude an ectopic pregnancy, since there may be either a heterotopic pregnancy or a "pseudosac", which is a collection of within the endometrial cavity that may be seen in up to 20% of women.A small amount of anechogenic-free fluid in the recto-uterine pouch is commonly found in both intrauterine and ectopic pregnancies. The presence of echogenic fluid is estimated at between 28 and 56% of women with an ectopic pregnancy, and strongly indicates the presence of hemoperitoneum. However, it does not necessarily result from tubal rupture but is commonly a result from leakage from the distal tubal opening. As a rule of thumb, the finding of free fluid is significant if it reaches the fundus or is present in the vesico-uterine pouch. A further marker of serious intra-abdominal bleeding is the presence of fluid in the hepatorenal recess of the subhepatic space.Currently, Doppler ultrasonography is not considered to significantly contribute to the diagnosis of ectopic pregnancy.A common misdiagnosis is of a normal intrauterine pregnancy is where the pregnancy is implanted laterally in an arcuate uterus, potentially being misdiagnosed as an interstitial pregnancy.

Ultrasonography and β-hCG
Where no intrauterine pregnancy (IUP) is seen on ultrasound, measuring β-human chorionic gonadotropin (β-hCG) levels may aid in the diagnosis. The rationale is that a low β-hCG level may indicate that the pregnancy is intrauterine but yet too small to be visible on ultrasonography. While some physicians consider that the threshold where an intrauterine pregnancy should be visible on transvaginal ultrasound is around 1500 mIU/mL of β-hCG, a review in the JAMA Rational Clinical Examination Series showed that there is no single threshold for the β-human chorionic gonadotropin that confirms an ectopic pregnancy.  Instead, the best test in a pregnant woman is a high resolution transvaginal ultrasound. The presence of an adnexal mass in the absence of an intrauterine pregnancy on transvaginal sonography increases the likelihood of an ectopic pregnancy 100-fold (LR+ 111).  When there are no adnexal abnormalities on transvaginal sonography, the likelihood of an ectopic pregnancy decreases (LR- 0.12). An empty uterus with levels higher than 1500 mIU/mL may be evidence of an ectopic pregnancy, but may also be consistent with an intrauterine pregnancy which is simply too small to be seen on ultrasound. If the diagnosis is uncertain, it may be necessary to wait a few days and repeat the blood work. This can be done by measuring the β-hCG level approximately 48 hours later and repeating the ultrasound. The serum hCG ratios and logistic regression models appear to be better than absolute single serum hCG level. If the β-hCG falls on repeat examination, this strongly suggests a spontaneous abortion or rupture. The fall in serum hCG over 48 hours may be measured as the hCG ratio, which is calculated as:

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    {\displaystyle hCG~ratio={\frac {hCG~at~48h}{hCG~at~0h}}}

An hCG ratio of 0.87, that is, a decrease in hCG of 13% over 48 hours, has a sensitivity of 93% and specificity of 97% for predicting a failing pregnancy of unknown location (PUL). The majority of cases of ectopic pregnancy will have serial serum hCG levels that increase more slowly than would be expected with an IUP (that is, a suboptimal rise), or decrease more slowly than would be expected with a failing PUL. However, up to 20% of cases of ectopic pregnancy have serum hCG doubling times similar to that of an IUP, and around 10% of EP cases have hCG patterns similar to a failing PUL.

Other methods
Direct examination
A laparoscopy or laparotomy can also be performed to visually confirm an ectopic pregnancy. This is generally reserved for women presenting with signs of an acute abdomen and hypovolemic shock. Often if a tubal abortion or tubal rupture has occurred, it is difficult to find the pregnancy tissue. A laparoscopy in very early ectopic pregnancy rarely shows a normal-looking fallopian tube.

Culdocentesis
Culdocentesis, in which fluid is retrieved from the space separating the vagina and rectum, is a less commonly performed test that may be used to look for internal bleeding. In this test, a needle is inserted into the space at the very top of the vagina, behind the uterus and in front of the rectum. Any blood or fluid found may have been derived from a ruptured ectopic pregnancy.

Progesterone levels
Progesterone levels of less than 20 nmol/L have a high predictive value for failing pregnancies, whilst levels over 25 nmol/L are likely to predict viable pregnancies, and levels over 60 nmol/L are strongly so. This may help in identifying failing PUL that are at low risk and thereby needing less follow-up. Inhibin A may also be useful for predicting spontaneous resolution of PUL, but is not as good as progesterone for this purpose.

Mathematical models
There are various mathematical models, such as logistic regression models and Bayesian networks, for the prediction of PUL outcome based on multiple parameters. Mathematical models also aim to identify PULs that are low risk, that is, failing PULs and IUPs.

Dilation and curettage
Dilation and curettage (D&C) is sometimes used to diagnose pregnancy location with the aim of differentiating between an EP and a non-viable IUP in situations where a viable IUP can be ruled out. Specific indications for this procedure include either of the following:
No visible IUP on transvaginal ultrasonography with a serum hCG of more than 2000 mIU/mL.
An abnormal rise in hCG level.  A rise of 35% over 48 hours is proposed as the minimal rise consistent with a viable intrauterine pregnancy.
An abnormal fall in hCG level, such as defined as one of less than 20% in two days.

Classification
Tubal pregnancy
The vast majority of ectopic pregnancies implant in the fallopian tube. Pregnancies can grow in the fimbrial end (5% of all ectopic pregnancies), the ampullary section (80%), the isthmus (12%), and the cornual and interstitial part of the tube (2%). Mortality of a tubal pregnancy at the isthmus or within the uterus (interstitial pregnancy) is higher as there is increased vascularity that may result more likely in sudden major internal bleeding. A review published in 2010 supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur.

Nontubal ectopic pregnancy
Two percent of ectopic pregnancies occur in the ovary, cervix, or are intra-abdominal. Transvaginal ultrasound examination is usually able to detect a cervical pregnancy. An ovarian pregnancy is differentiated from a tubal pregnancy by the Spiegelberg criteria.While a fetus of ectopic pregnancy is typically not viable, very rarely, a live baby has been delivered from an abdominal pregnancy. In such a situation the placenta sits on the intra-abdominal organs or the peritoneum and has found sufficient blood supply. This is generally bowel or mesentery, but other sites, such as the renal (kidney), liver or hepatic (liver) artery or even aorta have been described. Support to near viability has occasionally been described, but even in Third World countries, the diagnosis is most commonly made at 16 to 20 weeks gestation. Such a fetus would have to be delivered by laparotomy. Maternal morbidity and mortality from extrauterine pregnancy are high as attempts to remove the placenta from the organs to which it is attached usually lead to uncontrollable bleeding from the attachment site. If the organ to which the placenta is attached is removable, such as a section of bowel, then the placenta should be removed together with that organ. This is such a rare occurrence that true data is unavailable and reliance must be made on anecdotal reports. However, the vast majority of abdominal pregnancies require intervention well before fetal viability because of the risk of bleeding.
With the increase in Cesarean sections performed worldwide, Cesarean section ectopic pregnancies (CSP) are rare, but becoming more common. The incidence of CSP is not well known, however there have been estimates based on different populations of 1:1800–1:2216. CSP are characterized by abnormal implantation into the scar from a previous cesarean section, and allowed to continue can cause serious complications such as uterine rupture and hemorrhage. Patients with CSP generally present without symptoms, however symptoms can include vaginal bleeding that may or may not be associated with pain. The diagnosis of CSP is made by ultrasound and four characteristics are noted: (1) Empty uterine cavity with bright hyperechoic endometrial stripe (2) Empty cervical canal (3) Intrauterine mass in the anterior part of the uterine isthmus, and (4) Absence of the anterior uterine muscle layer, and/or absence or thinning between the bladder and gestational sac, measuring less than 5 mm. Given the rarity of the diagnosis, treatment options tend to be described in case reports and series, ranging from medical with methotrexate or KCl to surgical with dilation and curettage, uterine wedge resection, or hysterectomy. A double-balloon catheter technique has also been described, allowing for uterine preservation. Recurrence risk for CSP is unknown, and early ultrasound in the next pregnancy is recommended.

Heterotopic pregnancy
In rare cases of ectopic pregnancy, there may be two fertilized eggs, one outside the uterus and the other inside. This is called a heterotopic pregnancy. Often the intrauterine pregnancy is discovered later than the ectopic, mainly because of the painful emergency nature of ectopic pregnancies. Since ectopic pregnancies are normally discovered and removed very early in the pregnancy, an ultrasound may not find the additional pregnancy inside the uterus. When hCG levels continue to rise after the removal of the ectopic pregnancy, there is the chance that a pregnancy inside the uterus is still viable. This is normally discovered through an ultrasound.
Although rare, heterotopic pregnancies are becoming more common, likely due to increased use of IVF. The survival rate of the uterine fetus of a heterotopic pregnancy is around 70%.

Persistent ectopic pregnancy
A persistent ectopic pregnancy refers to the continuation of trophoblastic growth after a surgical intervention to remove an ectopic pregnancy. After a conservative procedure that attempts to preserve the affected fallopian tube such as a salpingotomy, in about 15–20% the major portion of the ectopic growth may have been removed, but some trophoblastic tissue, perhaps deeply embedded, has escaped removal and continues to grow, generating a new rise in hCG levels. After weeks this may lead to new clinical symptoms including bleeding. For this reason hCG levels may have to be monitored after removal of an ectopic pregnancy to assure their decline, also methotrexate can be given at the time of surgery prophylactically.

Pregnancy of unknown location
Pregnancy of unknown location (PUL) is the term used for a pregnancy where there is a positive pregnancy test but no pregnancy has been visualized using transvaginal ultrasonography. Specialized early pregnancy departments have estimated that between 8% and 10% of women attending for an ultrasound assessment in early pregnancy will be classified as having a PUL. The true nature of the pregnancy can be an ongoing viable intrauterine pregnancy, a failed pregnancy, an ectopic pregnancy or rarely a persisting PUL.Because of frequent ambiguity on ultrasonography examinations, the following classification is proposed:
In women with a pregnancy of unknown location, between 6% and 20% have an ectopic pregnancy. In cases of pregnancy of unknown location and a history of heavy bleeding, it has been estimated that approximately 6% have an underlying ectopic pregnancy. Between 30% and 47% of women with pregnancy of unknown location are ultimately diagnosed with an ongoing intrauterine pregnancy, whereof the majority  (50–70%) will be found to have failing pregnancies where the location is never confirmed.

Persisting PUL is where the hCG level does not spontaneously decline and no intrauterine or ectopic pregnancy is identified on follow-up transvaginal ultrasonography. A persisting PUL is likely either a small ectopic pregnancy that has not been visualized, or a retained trophoblast in the endometrial cavity. Treatment should only be considered when a potentially viable intrauterine pregnancy has been definitively excluded. A treated persistent PUL is defined as one managed medically (generally with methotrexate) without confirmation of the location of the pregnancy such as by ultrasound, laparoscopy or uterine evacuation. A resolved persistent PUL is defined as serum hCG reaching a non-pregnant value (generally less than 5 IU/L) after expectant management, or after uterine evacuation without evidence of chorionic villi on histopathological examination. In contrast, a relatively low and unresolving level of serum hCG indicates the possibility of an hCG-secreting tumour.

Differential diagnosis
Other conditions that cause similar symptoms include: miscarriage, ovarian torsion, and acute appendicitis, ruptured ovarian cyst, kidney stone, and pelvic inflammatory disease, among others.

Treatment
Expectant management
Most women with a PUL are followed up with serum hCG measurements and repeat TVS examinations until a final diagnosis is confirmed. Low-risk cases of PUL that appear to be failing pregnancies may be followed up with a urinary pregnancy test after two weeks and get subsequent telephone advice. Low-risk cases of PUL that are likely intrauterine pregnancies may have another TVS in two weeks to access viability. High-risk cases of PUL require further assessment, either with a TVS within 48 h or additional hCG measurement.

Medical
Early treatment of an ectopic pregnancy with methotrexate is a viable alternative to surgical treatment which was developed in the 1980s. If administered early in the pregnancy, methotrexate terminates the growth of the developing embryo; this may cause an abortion, or the developing embryo may then be either resorbed by the womans body or pass with a menstrual period.  Contraindications include liver, kidney, or blood disease, as well as an ectopic embryonic mass > 3.5 cm.
Also, it may lead to the inadvertent termination of an undetected intrauterine pregnancy, or severe abnormality in any surviving pregnancy. Therefore, it is recommended that methotrexate should only be administered when hCG has been serially monitored with a rise less than 35% over 48 hours, which practically excludes a viable intrauterine pregnancy.For nontubal ectopic pregnancy, evidence from randomised clinical trials in women with CSP is uncertain regarding treatment success, complications and side effects of methotrexate compared with surgery (uterine arterial embolization or uterine arterial chemoembolization).The United States uses a multi dose protocol of methotrexate (MTX) which involves four doses of intramuscular along with an intramuscular injection of folinic acid to protect cells from the effects of the drugs and to reduce side effects. In France, the single dose protocol is followed, but a single dose has a greater chance of failure.

Surgery
If bleeding has already occurred, surgical intervention may be necessary. However, whether to pursue surgical intervention is an often difficult decision in a stable patient with minimal evidence of blood clot on ultrasound.Surgeons use laparoscopy or laparotomy to gain access to the pelvis and can either incise the affected Fallopian tube and remove only the pregnancy (salpingostomy) or remove the affected tube with the pregnancy (salpingectomy). The first successful surgery for an ectopic pregnancy was performed by Robert Lawson Tait in 1883. It is estimated that an acceptable rate of PULs that eventually undergo surgery is between 0.5 and 11%. People that undergo salpingectomy and salpingostomy have a similar recurrent ectopic pregnancy rate of 5% and 8% respectively. Additionally, their intrauterine pregnancy rates are also similar, 56% and 61%.Autotransfusion of a womans own blood as drained during surgery may be useful in those who have a lot of bleeding into their abdomen.Published reports that a re-implanted embryo survived to birth were debunked as false.

Prognosis
When ectopic pregnancies are treated, the prognosis for the mother is very good in Western countries; maternal death is rare, but all fetuses die or are aborted. For instance, in the UK, between 2003 and 2005 there were 32,100 ectopic pregnancies resulting in 10 maternal deaths (meaning that 1 in 3,210 women with an ectopic pregnancy died). In 2006–2008 the UK Confidential Enquiry into Maternal Deaths found that ectopic pregnancy is the cause of 6 maternal deaths (0.26/100,000 pregnancies).In the developing world, however, especially in Africa, the death rate is very high, and ectopic pregnancies are a major cause of death among women of childbearing age.
In women having had an ectopic pregnancy, the risk of another one in the next pregnancy is around 10%.

Future fertility
Fertility following ectopic pregnancy depends upon several factors, the most important of which is a prior history of infertility. The treatment choice does not play a major role; a randomized study in 2013 concluded that the rates of intrauterine pregnancy two years after treatment of ectopic pregnancy are approximately 64% with radical surgery, 67% with medication, and 70% with conservative surgery. In comparison, the cumulative pregnancy rate of women under 40 years of age in the general population over two years is over 90%.Methotrexate does not affect future fertility treatments. The number of oocytes that were retrieved before and after treatment with methotrexate does not change.In case of ovarian ectopic pregnancy, the risk of subsequent ectopic pregnancy or infertility is low.There is no evidence that massage improves fertility after ectopic pregnancy.

Epidemiology
The rate of ectopic pregnancy is about 1% and 2% of that of live births in developed countries, though it is as high as 4% in pregnancies involving assisted reproductive technology. Between 93% and 97% of ectopic pregnancies are located in a fallopian tube. Of these, in turn, 13% are located in the isthmus, 75% are located in the ampulla, and 12% in the fimbriae. Ectopic pregnancy is responsible for 6% of maternal deaths during the first trimester of pregnancy making it the leading cause of maternal death during this stage of pregnancy.Between 5% and 42% of women seen for ultrasound assessment with a positive pregnancy test have a pregnancy of unknown location, that is a positive pregnancy test but no pregnancy visualized at transvaginal ultrasonography. Between 6% and 20% of pregnancy of unknown location are subsequently diagnosed with actual ectopic pregnancy.

Society and culture
Salpingectomy as a treatment for ectopic pregnancy is one of the common cases when the principle of double effect can be used to justify accelerating the death of the embryo by doctors and patients opposed to outright abortions.In the Catholic Church, there are moral debates on certain treatments.  A significant number of Catholic moralists consider use of methotrexate and the salpingostomy procedure to be not "morally permissible" because they destroy the embryo; however, situations are considered differently in which the mothers health is endangered, and the whole fallopian tube with the developing embryo inside is removed.Organisations exist that provide information and support to help those who experience ectopic pregnancy. Studies show that people can experience post-traumatic stress, depression, and anxiety for which they would need specialist therapies. Partners can also experience post-traumatic stress.

Live birth
There have been cases where ectopic pregnancy lasted many months and ended in a live baby delivered by laparotomy.
In July 1999, Lori Dalton gave birth by caesarean section in Ogden, Utah, United States, to a healthy baby girl, Saige, who had developed outside of the uterus. Previous ultrasounds had not discovered the problem. "[Dalton]s delivery was slated as a routine Caesarean birth at Ogden Regional Medical Center in Utah. When Dr </s>


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<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 Somatic symptom disorder and can you explain it in depth? [/INST] A somatic symptom disorder, formerly known as a somatoform disorder, is any mental disorder that manifests as physical symptoms that suggest illness or injury, but cannot be explained fully by a general medical condition or by the direct effect of a substance, and are not attributable to another mental disorder (e.g., panic disorder). Somatic symptom disorders, as a group, are included in a number of diagnostic schemes of mental illness, including the Diagnostic and Statistical Manual of Mental Disorders. (Before DSM-5 this disorder was split into somatization disorder and undifferentiated somatoform disorder.)
In people who have been diagnosed with a somatic symptom disorder, medical test results are either normal or do not explain the persons symptoms (medically unexplained physical symptoms), and history and physical examination do not indicate the presence of a known medical condition that could cause them, though the DSM-5 cautions that this alone is not sufficient for diagnosis. The patient must also be excessively worried about their symptoms, and this worry must be judged to be out of proportion to the severity of the physical complaints themselves. A diagnosis of somatic symptom disorder requires that the subject have recurring somatic complaints for at least six months.Symptoms are sometimes similar to those of other illnesses and may last for years. Usually, the symptoms begin appearing during adolescence, and patients are diagnosed before the age of 30 years. Symptoms may occur across cultures and gender. Other common symptoms include anxiety and depression. However, since anxiety and depression are also very common in persons with confirmed medical illnesses, it remains unproven whether such symptoms are a consequence of the physical impairment or a cause. Somatic symptom disorders are not the result of conscious malingering (fabricating or exaggerating symptoms for secondary motives) or factitious disorders (deliberately producing, feigning, or exaggerating symptoms). Somatic symptom disorder is difficult to diagnose and treat. Some advocates of the diagnosis believe this is because proper diagnosis and treatment requires psychiatrists to work with neurologists on patients with this disorder.

History
Somitisation disorder was first described by Paul Briquet in 1859 and was subsequently known as Briquets syndrome. He described patients who had been sickly most of their lives and complained of multiple symptoms from different organ systems. Symptoms persist despite multiple consultations,  hospitalisations and investigations.

Definition
Somatic symptom disorders are a group of disorders, all of which fit the definition of physical symptoms similar to those observed in physical disease or injury for which there is no identifiable physical cause. As such, they are a diagnosis of exclusion. Somatic symptoms may be generalized in four major medical categories: neurological, cardiac, pain, and gastrointestinal somatic symptoms.

Diagnostic and Statistical Manual of Mental Disorders
Somatic symptom disorders used to be recognized as Somatoform disorders in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association </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 Blood blister and can you explain it in depth? [/INST] A blood blister is a type of blister that forms when subdermal tissues and blood vessels are damaged without piercing the skin </s>