<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 Fracture and can you explain it in depth? [/INST] Fracture is the separation of an object or material into two or more pieces under the action of stress. The fracture of a solid usually occurs due to the development of certain displacement discontinuity surfaces within the solid. If a displacement develops perpendicular to the surface, it is called a normal tensile crack or simply a crack; if a displacement develops tangentially, it is called a shear crack, slip band or dislocation.Brittle fractures occur with no apparent deformation before fracture. Ductile fractures occur after visible deformation. Fracture strength, or breaking strength, is the stress when a specimen fails or fractures. The detailed understanding of how a fracture occurs and develops in materials is the object of fracture mechanics.

Strength
Fracture strength, also known as breaking strength, is the stress at which a specimen fails via fracture. This is usually determined for a given specimen by a tensile test, which charts the stress–strain curve (see image). The final recorded point is the fracture strength.
Ductile materials have a fracture strength lower than the ultimate tensile strength (UTS), whereas in brittle materials the fracture strength is equivalent to the UTS. If a ductile material reaches its ultimate tensile strength in a load-controlled situation, it will continue to deform, with no additional load application, until it ruptures.  However, if the loading is displacement-controlled, the deformation of the material may relieve the load, preventing rupture.
The statistics of fracture in random materials have very intriguing behavior, and was noted by the architects and engineers quite early. Indeed, fracture or breakdown studies might be the oldest physical science studies, which still remain intriguing and very much alive. Leonardo da Vinci, more than 500 years ago, observed that the tensile strengths of nominally identical specimens of iron wire decrease with increasing length of the wires (see e.g., for a recent discussion). Similar observations were made by Galileo Galilei more than 400 years ago. This is the manifestation of the extreme statistics of failure (bigger sample volume can have larger defects due to cumulative fluctuations where failures nucleate and induce lower strength of the sample).

Types
There are two types of fractures: brittle and ductile fractures respectively without or with plastic deformation prior to failure.

Brittle
In brittle fracture, no apparent plastic deformation takes place before fracture. Brittle fracture typically involves little energy absorption and occurs at high speeds—up to 2,133.6 m/s (7,000 ft/s) in steel. In most cases brittle fracture will continue even when loading is discontinued.In brittle crystalline materials, fracture can occur by cleavage as the result of tensile stress acting normal to crystallographic planes with low bonding (cleavage planes). In amorphous solids, by contrast, the lack of a crystalline structure results in a conchoidal fracture, with cracks proceeding normal to the applied tension.
The fracture strength (or micro-crack nucleation stress) of a  material was first theoretically estimated by Alan Arnold Griffith in 1921:

          σ

              t
              h
              e
              o
              r
              e
              t
              i
              c
              a
              l

        =

                E
                γ

                r

                  o

    {\displaystyle \sigma _{\mathrm {theoretical} }={\sqrt {\frac {E\gamma }{r_{o}}}}}
  where: –

        E

    {\displaystyle E}
   is the Youngs modulus of the material,

        γ

    {\displaystyle \gamma }
   is the surface energy, and

          r

            o

    {\displaystyle r_{o}}
   is the micro-crack length (or equilibrium distance between atomic centers in a crystalline solid).On the other hand, a crack introduces a stress concentration modeled by

          σ

              e
              l
              l
              i
              p
              t
              i
              c
              a
              l

              c
              r
              a
              c
              k

        =

          σ

              a
              p
              p
              l
              i
              e
              d

          (

            1
            +
            2

                  a
                  ρ

          )

        =
        2

          σ

              a
              p
              p
              l
              i
              e
              d

              a
              ρ

    {\displaystyle \sigma _{\mathrm {elliptical\ crack} }=\sigma _{\mathrm {applied} }\left(1+2{\sqrt {\frac {a}{\rho }}}\right)=2\sigma _{\mathrm {applied} }{\sqrt {\frac {a}{\rho }}}}
   (For sharp cracks)where: –

          σ

              a
              p
              p
              l
              i
              e
              d

    {\displaystyle \sigma _{\mathrm {applied} }}
   is the loading stress,

        a

    {\displaystyle a}
   is half the length of the crack, and

        ρ

    {\displaystyle \rho }
   is the radius of curvature at the crack tip.Putting these two equations together gets

          σ

              f
              r
              a
              c
              t
              u
              r
              e

        =

                E
                γ
                ρ

                4
                a

                  r

                    o

        .

    {\displaystyle \sigma _{\mathrm {fracture} }={\sqrt {\frac {E\gamma \rho }{4ar_{o}}}}.}
  Sharp cracks (small

        ρ

    {\displaystyle \rho }
  ) and large defects (large

        a

    {\displaystyle a}
  ) both lower the fracture strength of the material.
Recently, scientists have discovered supersonic fracture, the phenomenon of crack propagation faster than the speed of sound in a material. This phenomenon was recently also verified by experiment of fracture in rubber-like materials.
The basic sequence in a typical brittle fracture is: introduction of a flaw either before or after the material is put in service, slow and stable crack propagation under recurring loading, and sudden rapid failure when the crack reaches critical crack length based on the conditions defined by fracture mechanics. Brittle fracture may be avoided by controlling three primary factors: material fracture toughness (Kc), nominal stress level (σ), and introduced flaw size (a). Residual stresses, temperature, loading rate, and stress concentrations also contribute to brittle fracture by influencing the three primary factors.Under certain conditions, ductile materials can exhibit brittle behavior. Rapid loading, low temperature, and triaxial stress constraint conditions may cause ductile materials to fail without prior deformation.

Ductile
In ductile fracture, extensive plastic deformation (necking) takes place before fracture. The terms "rupture" and "ductile rupture" describe the ultimate failure of ductile materials loaded in tension. The extensive plasticity causes the crack to propagate slowly due to the absorption of a large amount of energy before fracture.

Because ductile rupture involves a high degree of plastic deformation, the fracture behavior of a propagating crack as modelled above changes fundamentally. Some of the energy from stress concentrations at the crack tips is dissipated by plastic deformation ahead of the crack as it propagates.
The basic steps in ductile fracture are void formation, void coalescence (also known as crack formation), crack propagation, and failure, often resulting in a cup-and-cone shaped failure surface. Voids typically coalesce around precipitates, secondary phases, inclusions, and at grain boundaries in the material. Ductile fracture is typically transgranular and deformation due to dislocation slip can cause the shear lip characteristic of cup and cone fracture.

Characteristics
The manner in which a crack propagates through a material gives insight into the mode of fracture. With ductile fracture a crack moves slowly and is accompanied by a large amount of plastic deformation around the crack tip. A ductile crack will usually not propagate unless an increased stress is applied and generally cease propagating when loading is removed. In a ductile material, a crack may progress to a section of the material where stresses are slightly lower and stop due to the blunting effect of plastic deformations at the crack tip. On the other hand, with brittle fracture, cracks spread very rapidly with little or no plastic deformation. The cracks that propagate in a brittle material will continue to grow once initiated.
Crack propagation is also categorized by the crack characteristics at the microscopic level. A crack that passes through the grains within the material is undergoing transgranular fracture. A crack that propagates along the grain boundaries is termed an intergranular fracture.  Typically, the bonds between material grains are stronger at room temperature than the material itself, so transgranular fracture is more likely to occur. When temperatures increase enough to weaken the grain bonds, intergranular fracture is the more common fracture mode.

Testing
Fracture in materials is studied and quantified in multiple ways. Fracture is largely determined by the fracture toughness (

            K

              c

    {\textstyle \mathrm {K} _{\mathrm {c} }}
  ), so fracture testing is often done to determine this. The two most widely used techniques for determining fracture toughness are the Three-point flexural test and the compact tension test.
By performing the compact tension and three-point flexural tests, one is able to determine the fracture toughness through the following equation:

            K

              c

        =

          σ

              F

            π

              c

          f

          (
          c

            /

          a
          )

    {\displaystyle \mathrm {K_{c}} =\sigma _{\mathrm {F} }{\sqrt {\pi \mathrm {c} }}\mathrm {f\ (c/a)} }
  Where:-

          f

          (
          c

            /

          a
          )

    {\displaystyle \mathrm {f\ (c/a)} }
   is an empirically-derived equation to capture the test sample geometry

          σ

              F

    {\displaystyle \sigma _{\mathrm {F} }}
   is the fracture stress, and

          c

    {\displaystyle \mathrm {c} }
   is the crack length.To accurately attain

            K

              c

    {\textstyle \mathrm {K} _{\mathrm {c} }}
  , the value of

          c

    {\textstyle \mathrm {c} }
   must be precisely measured. This is done by taking the test piece with its fabricated notch of length

          c
          ′

    {\textstyle \mathrm {c\prime } }
   and sharpening this notch to better emulate a crack tip found in real-world materials. Cyclical prestressing the sample can then induce a fatigue crack which extends the crack from the fabricated notch length of

          c
          ′

    {\textstyle \mathrm {c\prime } }
    to

          c

    {\textstyle \mathrm {c} }
  . This value

          c

    {\textstyle \mathrm {c} }
   is used in the above equations for determining

            K

              c

    {\textstyle \mathrm {K} _{\mathrm {c} }}
  .Following this test, the sample can then be reoriented such that further loading of a load (F) will extend this crack and thus a load versus sample deflection curve can be obtained. With this curve, the slope of the linear portion, which is the inverse of the compliance of the material, can be obtained. This is then used to derive f(c/a) as defined above in the equation. With the knowledge of all these variables,

            K

              c

    {\textstyle \mathrm {K} _{\mathrm {c} }}
   can then be calculated.

Ceramics and inorganic glasses
Ceramics and inorganic glasses have fracturing behavior that differ those of metallic materials. Ceramics have high strengths and perform well in high temperatures due to the material strength being independent of temperature. Ceramics have low toughness as determined by testing under a tensile load; often, ceramics have

            K

              c

    {\textstyle \mathrm {K} _{\mathrm {c} }}
   values that are ~5% of that found in metals. However, ceramics are usually loaded in compression in everyday use, so the compressive strength is often referred to as the strength; this strength can often exceed that of most metals. However, ceramics are brittle and thus most work done revolves around preventing brittle fracture. Due to how ceramics are manufactured and processed, there are often preexisting defects in the material introduce a high degree of variability in the Mode I brittle fracture. Thus, there is a probabilistic nature to be accounted for in the design of ceramics. The Weibull distribution predicts the survival probability of a fraction of samples with a certain volume that survive a tensile stress sigma, and is often used to better assess the success of a ceramic in avoiding fracture.

Fiber bundles
To model fracture of a bundle of fibers, the Fiber Bundle Model was introduced by Thomas Pierce  in 1926 as a model to understand the strength of composite materials. The bundle consists of a  large number of parallel Hookean springs of identical length and each having identical spring constants. They have however different breaking stresses. All these springs are suspended from a rigid horizontal platform. The load is attached  to a horizontal platform, connected to the lower ends of the springs. When this lower platform is absolutely rigid, the load at any point of time is shared equally (irrespective of how many fibers or springs have broken and where) by all the surviving fibers. This mode of load-sharing is called Equal-Load-Sharing mode. The lower platform can also be assumed to have finite rigidity, so that local deformation of the platform occurs wherever springs fail and the surviving neighbor fibers have to share a larger fraction of that transferred from the failed fiber. The extreme case is that of local load-sharing model, where load of the failed spring or fiber is shared (usually equally) by the surviving nearest neighbor fibers.

Disasters
Failures caused by brittle fracture have not been limited to any particular category of engineered structure. Though brittle fracture is less common than other types of failure, the impacts to life and property can be more severe </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 Stevens–Johnson syndrome and can you explain it in depth? [/INST] Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema multiforme (EM) is generally considered a separate condition. Early symptoms of SJS include fever and flu-like symptoms. A few days later, the skin begins to blister and peel, forming painful raw areas. Mucous membranes, such as the mouth, are also typically involved. Complications include dehydration, sepsis, pneumonia and multiple organ failure.The most common cause is certain medications such as lamotrigine, carbamazepine, allopurinol, sulfonamide antibiotics and nevirapine. Other causes can include infections such as Mycoplasma pneumoniae and cytomegalovirus, or the cause may remain unknown. Risk factors include HIV/AIDS and systemic lupus erythematosus.The diagnosis of Stevens–Johnson syndrome is based on involvement of less than 10% of the skin. It is known as TEN when more than 30% of the skin is involved and considered an intermediate form when 10–30% is involved. SJS/TEN reactions are believed to follow a type IV hypersensitivity mechanism. It is also included with drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis (AGEP) and toxic epidermal necrolysis in a group of conditions known severe cutaneous adverse reactions (SCARs).Treatment typically takes place in hospital such as in a burn unit or intensive care unit. Efforts may include stopping the cause, pain medication, antihistamines, antibiotics, intravenous immunoglobulins or corticosteroids. Together with TEN, SJS affects 1 to 2 people per million per year. Typical onset is under the age of 30. Skin usually regrows over two to three weeks; however, complete recovery can take months. Overall, the risk of death with SJS is 5 to 10%.

Signs and symptoms
SJS usually begins with fever, sore throat, and fatigue, which is commonly misdiagnosed and therefore treated with antibiotics. SJS, SJS/TEN, and TEN are often heralded by fever, sore throat, cough, and burning eyes for 1 to 3 days. Patients with these disorders frequently experience burning pain of their skin at the start of disease. Ulcers and other lesions begin to appear in the mucous membranes, almost always in the mouth and lips, but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patients ability to eat or drink. Conjunctivitis occurs in about 30% of children who develop SJS. A rash of round lesions about an inch across arises on the face, trunk, arms and legs, and soles of the feet, but usually not the scalp.

Causes
SJS is thought to arise from a disorder of the immune system.  The immune reaction can be triggered by drugs or infections. Genetic factors are associated with a predisposition to SJS. The cause of SJS is unknown in one-quarter to one-half of cases. SJS, SJS/TEN, and TEN are considered a single disease with common causes and mechanisms.Individuals expressing certain human leukocyte antigen (i.e. HLA) serotypes (i.e. genetic alleles), genetical-based T cell receptors, or variations in their efficiency to absorb, distribute to tissues, metabolize, or excrete (this combination is termed ADME) a drug are predisposed to develop SJS.

Medications
Although SJS can be caused by viral infections and malignancies, the main cause is medications. A leading cause appears to be the use of antibiotics, particularly sulfa drugs. Between 100 and 200 different drugs may be associated with SJS. No reliable test exists to establish a link between a particular drug and SJS for an individual case. Determining what drug is the cause is based on the time interval between first use of the drug and the beginning of the skin reaction. Drugs discontinued more than 1 month prior to onset of mucocutaneous physical findings are highly unlikely to cause SJS and TEN. SJS and TEN most often begin between 4 and 28 days after culprit drug administration. A published algorithm (ALDEN) to assess drug causality gives structured assistance in identifying the responsible medication.SJS may be caused by the medications rivaroxaban, vancomycin, allopurinol, valproate, levofloxacin, diclofenac, etravirine, isotretinoin, fluconazole, valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil, lamotrigine, nevirapine, pyrimethamine, ibuprofen, ethosuximide, carbamazepine, bupropion, telaprevir, and nystatin.Medications that have traditionally been known to lead to SJS, erythema multiforme, and toxic epidermal necrolysis include sulfonamide antibiotics, penicillin antibiotics, cefixime (antibiotic), barbiturates (sedatives), lamotrigine, phenytoin (e.g., Dilantin) (anticonvulsants) and trimethoprim. Combining lamotrigine with sodium valproate increases the risk of SJS.Nonsteroidal anti-inflammatory drugs (NSAIDs) are a rare cause of SJS in adults; the risk is higher for older patients, women, and those initiating treatment. Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. Similar to NSAIDs, paracetamol (acetaminophen) has also caused rare cases of SJS.  People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.

Infections
The second most common cause of SJS and TEN is infection, particularly in children. This includes upper respiratory infections, otitis media, pharyngitis, and Epstein–Barr virus, Mycoplasma pneumoniae and cytomegalovirus infections. The routine use of medicines such as antibiotics, antipyretics and analgesics to manage infections can make it difficult to identify if cases were caused by the infection or medicines taken.Viral diseases reported to cause SJS include: herpes simplex virus (possibly; is debated), AIDS, coxsackievirus, influenza, hepatitis, and mumps.In pediatric cases, Epstein–Barr virus and enteroviruses have been associated with SJS.Recent upper respiratory tract infections have been reported by more than half of patients with SJS.Bacterial infections linked to SJS include group A beta-hemolytic streptococci, diphtheria, brucellosis, lymphogranuloma venereum, mycobacteria, Mycoplasma pneumoniae, rickettsial infections, tularemia, and typhoid.Fungal infections with coccidioidomycosis, dermatophytosis and histoplasmosis are also considered possible causes. Malaria and trichomoniasis, protozoal infections, have also been reported as causes.

Pathophysiology
SJS is a type IV hypersensitivity reaction in which a drug or its metabolite stimulates cytotoxic T cells (i.e. CD8+ T cells) and T helper cells (i.e. CD4+ T cells) to initiate autoimmune reactions that attack self tissues. In particular, it is a type IV, subtype IVc, delayed hypersensitivity reaction dependent in part on the tissue-injuring actions of natural killer cells. This contrasts with the other types of SCARs disorders, i.e., the DRESS syndrome which is a Type IV, Subtype IVb, hypersensitivity drug reaction dependent in part on the tissue-injuring actions of eosinophils and acute generalized exanthematous pustulosis which is a Type IV, subtype IVd, hypersensitivity reaction dependent in part on the tissue-injuring actions of neutrophils.Like other SCARs-inducing drugs, SJS-inducing drugs or their metabolites stimulate CD8+ T cells or CD4+ T cells to initiate autoimmune responses. Studies indicate that the mechanism by which a drug or its metabolites accomplishes this involves subverting the antigen presentation pathways of the innate immune system. The drug or metabolite covalently binds with a host protein to form a non-self, drug-related epitope. An antigen presenting cell (APC) takes up these alter proteins; digests them into small peptides; places the peptides in a groove on the human leukocyte antigen (i.e. HLA) component of their major histocompatibility complex (i.e. MHC); and presents the MHC-associated peptides to T-cell receptors on CD8+ T cells or CD4+ T cells. Those peptides expressing a drug-related, non-self epitope on one of their various HLA protein forms (HLA-A, HLA-B, HLA-C, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, or HLA-DR) can bind to a T-cell receptor and thereby stimulate the receptor-bearing parent T cell to initiate attacks on self tissues. Alternatively, a drug or its metabolite may stimulate these T cells by inserting into the groove on a HLA protein to serve as a non-self epitope or bind outside of this groove to alter a HLA protein so that it forms a non-self epitope. In all these cases, however, a non-self epitope must bind to a specific HLA serotype (i.e. variation) in order to stimulate T cells. Since the human population expresses some 13,000 different HLA serotypes while an individual expresses only a fraction of them and since a SJS-inducing drug or metabolite interacts with only one or a few HLA serotypes, a drugs ability to induce SCARs is limited to those individuals who express HLA serotypes targeted by the drug or its metabolite. Accordingly, only rare individuals are predisposed to develop a SCARs in response to a particular drug on the bases of their expression of HLA serotypes: Studies have identified several HLA serotypes associated with development of SJS, SJS/TEN, or TEN in response to certain drugs. In general, these associations are restricted to the cited populations.In some East Asian populations studied (Han Chinese and Thai), carbamazepine- and phenytoin-induced SJS is strongly associated with HLA-B*1502 (HLA-B75), an HLA-B serotype of the broader serotype HLA-B15. A study in Europe suggested the gene marker is only relevant for East Asians. This has clinical relevance as it is agreed upon that prior to starting a medication such as allopurinol in a patient of Chinese descent, HLA-B*58:01 testing should be considered.Based on the Asian findings, similar studies in Europe showed 61% of allopurinol-induced SJS/TEN patients carried the HLA-B58 (phenotype frequency of the B*5801 allele in Europeans is typically 3%). One study concluded: "Even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease."Other HLA associations with the development of SJS, SJS/TEN, or TEN and the intake of specific drugs as determined in certain populations are given in HLA associations with SCARs.

T-cell receptors
In addition to acting through HLA proteins to bind with a T-cell receptor, a drug or its metabolite may bypass HLA proteins to bind directly to a T-cell receptor and thereby stimulate CD8+ T or CD4+ T cells to initiate autoimmune responses. In either case, this binding appears to develop only on certain T cell receptors. Since the genes for these receptors are highly edited, i.e. altered to encode proteins with different amino acid sequences, and since the human population may express more than 100 trillion different (i.e. different amino acid sequences) T-cell receptors while an individual express only a fraction of these, a drugs or its metabolites ability to induce the DRESS syndrome by interacting with a T cell receptor is limited to those individuals whose T cells express a T cell receptor(s) that can interact with the drug or its metabolite. Thus, only rare individuals are predisposed to develop SJS in response to a particular drug on the bases of their expression of specific T-cell receptor types. While the evidence supporting this T-cell receptor selectivity is limited, one study identified the preferential presence of the TCR-V-b and complementarity-determining region 3 in T-cell receptors found on the T cells in the blisters of patients with allopurinol-induced DRESS syndrome. This finding is compatible with the notion that specific types of T cell receptors are involved in the development of specific drug-induced SCARs.

ADME
Variations in ADME, i.e. an individuals efficiency in absorbing, tissue-distributing, metabolizing, or excreting a drug, have been found to occur in various severe cutaneous adverse reactions (SCARS) as well as other types of adverse drug reactions. These variations influence the levels and duration of a drug or its metabolite in tissues and thereby impact the drugs or metabolites ability to evoke these reactions. For example, CYP2C9 is an important drug-metabolizing cytochrome P450; it metabolizes and thereby inactivates phenytoin. Taiwanese, Japanese, and Malaysian individuals expressing the CYP2C9*3 variant of CYP2C9, which has reduced metabolic activity compared to the wild type (i.e. CYP2c9*1) cytochrome, have increased blood levels of phenytoin and a high incidence of SJS (as well as SJS/TEN and TEN) when taking the drug. In addition to abnormalities in drug-metabolizing enzymes, dysfunctions of the kidney, liver, or GI tract which increase a SCARs-inducing drug or metabolite levels are suggested to promote SCARs responses. These ADME abnormalities, it is also suggested, may interact with particular HLA proteins and T cell receptors to promote a SCARs disorder.

Diagnosis
The diagnosis is based on involvement of less than 10% of the skin. It is known as TEN when more than 30% of the skin is involved and an intermediate form with 10 to 30% involvement. A positive Nikolskys sign is helpful in the diagnosis of SJS and TEN. A skin biopsy is helpful, but not required, to establish a diagnosis of SJS and TEN.

Pathology
SJS, like TEN and erythema multiforme, is characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum.

Classification
Stevens–Johnson syndrome (SJS) is a milder form of toxic epidermal necrolysis (TEN). These conditions were first recognised in 1922. A classification first published in 1993, that has been adopted as a consensus definition, identifies Stevens–Johnson syndrome, toxic epidermal necrolysis, and SJS/TEN overlap. All three are part of a spectrum of severe cutaneous reactions (SCAR) which affect skin and mucous membranes. The distinction between SJS, SJS/TEN overlap, and TEN is based on the type of lesions and the amount of the body surface area with blisters and erosions. It is agreed that the most reliable method to classify EM, SJS, and TEN is based on lesion morphology and extent of epidermal detachment. Blisters and erosions cover between 3% and 10% of the body in SJS, 11–30% in SJS/TEN overlap, and over 30% in TEN. The skin pattern most commonly associated with SJS is widespread, often joined or touching (confluent), papuric spots (macules) or flat small blisters or large blisters which may also join. These occur primarily on the torso.SJS, TEN, and SJS/TEN overlap can be mistaken for erythema multiforme. Erythema multiforme, which is also within the SCAR spectrum, differs in clinical pattern and etiology.

Prevention
Screening individuals for certain predisposing gene variants before initiating treatment with particular SJS-, TEN/SJS-, or TEN-inducing drugs is recommended or under study. These recommendations are typically limited to specific populations that show a significant chance of having the indicated gene variant since screening of populations with extremely low incidences of expressing the variant is considered cost-ineffective. Individuals expressing the HLA allele associated with sensitivity to an indicated drug should not be treated with the drug. These recommendations include the following. Before treatment with carbamazepine, the Taiwan and USA Food and Drug Administrations recommend screening for HLA-B*15:02 in certain Asian groups. This has been implemented in Taiwan, Hong Kong, Singapore, and many medical centers in Thailand and Mainland China. Before treatment with allopurinol, the American College of Rheumatology guidelines for managing gout recommend HLA-B*58:01 screening. This is provided in many medical centers in Taiwan, Hong Kong, Thailand, and Mainland China. Before treatment with abacavir, the USA Food and Drug Administration recommends screening for HLA-B*57:01 in Caucasian populations. This screening is widely implemented. It has also been suggested that all individuals found to express this HLA serotype avoid treatment with abacovir. Current trials are underway in Taiwan to define the cost-effectiveness of avoiding phenytoin in SJS, SJS/TEN, and TEN for individuals expressing the CYP2C9*3 allele of CYP2C9.

Treatment
SJS constitutes a dermatological emergency. Patients with documented Mycoplasma infections can be treated with oral macrolide or oral doxycycline.Initially, treatment is similar to that for patients with thermal burns, and continued care can only be supportive (e.g., intravenous fluids and nasogastric or parenteral feeding) and symptomatic (e.g., analgesic mouth rinse for mouth ulcer). Dermatologists and surgeons tend to disagree about whether the skin should be debrided.Beyond this kind of supportive care, no treatment for SJS is accepted. Treatment with corticosteroids is controversial. Early retrospective studies suggested corticosteroids increased hospital stays and complication rates. No randomized trials of corticosteroids have been conducted for SJS, and it can be managed successfully without them.Other agents have been used, including cyclophosphamide and ciclosporin, but none have exhibited much therapeutic success. Intravenous immunoglobulin treatment has shown some promise in reducing the length of the reaction and improving symptoms. Other common supportive measures include the use of topical pain anesthetics and antiseptics, maintaining a warm environment, and intravenous analgesics.
An ophthalmologist should be consulted immediately, as SJS frequently causes the formation of scar tissue inside the eyelids, leading to corneal vascularization, impaired vision, and a host of other ocular problems. Those with chronic ocular surface disease caused by SJS may find some improvement with PROSE treatment (prosthetic replacement of the ocular surface ecosystem treatment).

Prognosis
SJS (with less than 10% of body surface area involved) has a mortality rate of around 5%. The mortality for toxic epidermal necrolysis (TEN) is 30–40%. The risk for death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account. It is helpful to calculate a SCORTEN within the first 3 days of hospitalization. Other outcomes include organ damage/failure, cornea scratching, and blindness.. Restrictive lung disease may develop in patients with SJS and TEN after initial acute pulmonary involvement </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 Axenfeld–Rieger syndrome and can you explain it in depth? [/INST] Axenfeld–Rieger syndrome is a rare  autosomal dominant disorder, which affects the development of the teeth, eyes, and abdominal region.Axenfeld–Rieger syndrome is part of the so-called iridocorneal or anterior segment dysgenesis syndromes, which were formerly known as anterior segment cleavage syndromes, anterior chamber segmentation syndromes or mesodermal dysgenesis. Although the exact classification of this set of signs and symptoms is somewhat confusing in current scientific literature, most authors agree with the classification cited here. Axenfeld Anomaly is known as the development of a posterior embryotoxon, associated with strands of the iris adhered to a Schwalbe line that has been displaced anteriorly, which when added to glaucoma is called Axenfeld Syndrome. Riegers Anomaly is defined by a universe of congenital anomalies of the iris, such as iris hypoplasia, corectopia or polycoria. When systemic findings are added to Riegers anomaly, such as bone, facial and/or dental defects, it is known as Rieger syndrome. The combination of both entities gives rise to the Axenfeld-Rieger Anomaly when there are no systemic abnormalities and Axenfeld-Rieger Syndrome when there are.Axenfeld-Rieger Syndrome, is a rare disease that affects the eye bilaterally, with an estimated prevalence of 1/200,000 people, without gender predilection, and is characterized by autosomal dominant inheritance with complete penetrance of variable expressivity. The genes that have been identified in approximately 50% of cases are PITX2 and FOXC1. Given the important hereditary factor, it is important to evaluate the most direct members of the family.To explain the ocular alterations, there is a theory of the mechanism postulated by Shields et al., which implies an arrest in the migration of neural crest cells towards the third trimester of gestation, which leads to the persistence of primordial endothelial tissue in the iris and anterior chamber angle. Contraction of these membranes after birth lead to the progressive changes seen in some patients. This primordial endothelium also generates an excessive and atypical basement membrane, especially near the limbal corneal junction, which accounts for the prominent Schwalbe line. In the case of secondary glaucoma, it would be the consequence of dysgenesis in the chamber sinus.

Signs and symptoms
Disease manifestations:
Regarding the age of diagnosis, this differs according to the intensity of the symptoms, ranging from asymptomatic to florid symptoms, characterized by ocular and systemic diseases, affecting multiple organs that have in common their origin in the neural crest.
Eye manifestations:
Bilateral ocular manifestations are usually pathognomonic of the disease. In the case of children who develop glaucoma, they may attend the consultation with signs and symptoms of buphthalmos, photosensitivity, tearing, corneal decompensation, which associated with poor vision, can be completed with a strabismus. In the case of the adult, there is a greater chance of not presenting symptoms, so an ophthalmological control may be required to detect the problem. Using a slit lamp, a posterior embryotoxon characterized by a prominent anteriorly displaced Schwalbes ring near the temporal corneal limbus can be revealed. The unexpected finding of a posterior embryotoxon as a single whitish irregular arcuate ridge, on routine examination, is not necessarily a diagnosis of ARS, as this occurs in a percentage estimated in the literature from 8% to 15% of the normal population. In the case of gonioscopy, we can observe that the extension of the posterior embryotoxon can be greater and be present in the 360○, with a variable thickness of the annulus and unusually detached and hanging within the anterior chamber. Regarding the iris, we can observe peripheral extensions to Schwalbes line, which can be thin or thick and extend over the trabecular meshwork, obscuring the scleral spur and even pulling the iris and producing corectopia in iris tissue that can range from atrophy mild stromal to the presence of uveal ectropion, pseudopolycoria or even absence of iris. These chamber sinus anomalies predispose half of the cases to open-angle glaucoma, which can manifest throughout life and therefore require regular ophthalmological check-ups. Other related anomalies are strabismus due to alteration in the insertions of the extraocular muscles or secondary to amblyopia, and with a predisposition to exotropia and retinal detachment.Systemic manifestations:
In the case of pathologies that affect the extraocular organs, greater attention must be paid to anomalies in the cardiovascular system, since they represent the most worrying associations due to their repercussions at the systemic level. These are present in different structures that make it up, such as heart valve defects, the presence of Fallots tetralogy, atrial septal defects or persistent truncus arteriosus. Other alterations described are craniofacial anomalies associated with hypoplasia of the midface, hypertelorism, telecanthus, maxillary hypoplasia, short nasolabial fold, thin upper lip and larger everted lower lip, which are typical facial characteristics although expressed in a variable way. Maxillary hypoplasia and poor tooth development produce a prognathic profile. Inspection of the oral cavity may show microdontia, hypodontia, oligodontia, and a thickened frenulum. The crowns of the anterior teeth may be conical or peg-shaped and the roots may be shortened, the gingival attachments may be reduced, and the enamel may be hypoplastic, contributing to poor dental health. There are other described associations such as umbilical, auditory, pituitary, psychomotor, size, urethral and anal anomalies as well as albinism.

Pathophysiology
The molecular genetics of Axenfeld–Rieger syndrome are poorly understood, but center on three genes identified by cloning of chromosomal breakpoints from patients.This disorder is inheritable as an autosomal dominant trait, which means the defective gene is located on an autosome, and only one copy of the gene is sufficient to cause the disorder when inherited from a parent who has the disorder.  As shown in the diagram, this gives a 50/50 chance of offspring inheriting the condition from an affected parent.

Diagnosis
Although most recognized for its correlation with the onset of glaucoma, the malformation is not limited to the eye, as Axenfeld–Rieger syndrome when associated with the PITX2 genetic mutation usually presents congenital malformations of the face, teeth, and skeletal system.The most characteristic feature affecting the eye is a distinct corneal posterior arcuate ring, known as an "embryotoxon". In severe cases, iris may be adherent to the cornea anterior to the Schwalbes line.One of the three known genetic mutations which cause Rieger syndrome can be identified through genetic samples analysis. About 40% of people with Axenfeld–Rieger have displayed mutations in genes PITX2, FOXC1, and PAX6. The difference between Type 1, 2, and 3 Axenfeld–Rieger syndrome is the genetic cause, all three types display the same symptoms and abnormalities.

Classification
The OMIM classification is as follows:

Detection of any of these mutations can give patients a clear diagnosis and prenatal procedures such as preimplantation genetic diagnosis, chorionic villus sampling and amniocentesis can be offered to patients and prospective parents.

Management
One of the surgical techniques used to treat this rare disease is the Phakic Retroiridian Pupilloplasty is an original surgical technique involving the creation of a sclerocorneal incision through a peripheral iridotomy, with the surgeon working behind the iris and creating a neopupil with an anterior chamber vitrectome. It requires very few follow-up visits and the patients recovery is fast.

Eponym
It is named after the German ophthalmologist Theodor Axenfeld who studied anterior segment disorders, especially those such as Rieger syndrome and the Axenfeld anomaly.
Axenfeld–Rieger syndrome is characterized by abnormalities of the eyes, teeth, and facial structure. Rieger syndrome, by medical definition, is determined by the presence of malformed teeth, underdeveloped anterior segment of the eyes, and cardiac problems associated with the Axenfeld anomaly. The term "Rieger syndrome" is sometimes used to indicate an association with glaucoma. Glaucoma occurs in up to 50% of patients with Rieger syndrome. Glaucoma develops during adolescence or late childhood, but often occurs in infancy. In addition, a prominent Schwalbes line, an opaque ring around the cornea known as posterior embryotoxon, may arise with hypoplasia of the iris. Below average height and stature, stunted development of the mid-facial features and mental deficiencies may also be observed in patients.

References
Further reading
Amendt, Brad A., ed. (2005). The Molecular Mechanisms of Axenfeld-Rieger Syndrome. Medical Intelligence Unit. Springer. doi:10.1007/0-387-28672-1. ISBN 978-0-387-28672-3.
Agarwal, Sunita; Agarwal, Athiya; Apple, David J., eds. (2002). "Axenfeld-Rieger Syndrome". Textbook of Ophthalmology. Jaypee Brothers. pp. 1049–51. ISBN 978-81-7179-884-1.
Shields, M.Bruce; Buckley, Edward; Klintworth, Gordon K.; Thresher, Randy (1985). "Axenfeld-Rieger syndrome. A spectrum of developmental disorders" </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 Sodoku and can you explain it in depth? [/INST] Sodoku (鼠毒) is a bacterial zoonotic disease. It is caused by the Gram-negative rod Spirillum minus (also known as Spirillum minor). It is a form of rat-bite fever (RBF).

Signs and symptoms
The initial scratch or wound caused by a bite from a carrier rodent results in mild inflammatory reactions and ulcerations </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 Wheeze and can you explain it in depth? [/INST] A wheeze is a continuous, coarse, whistling sound produced in the respiratory airways during breathing. For wheezes to occur, some part of the respiratory tree must be narrowed or obstructed (for example narrowing of the lower respiratory tract in an asthmatic attack), or airflow velocity within the respiratory tree must be heightened. Wheezing is commonly experienced by persons with a lung disease; the most common cause of recurrent wheezing is asthma, though it can also be a symptom of lung cancer, congestive heart failure, and certain types of heart diseases.
The differential diagnosis of wheezing is wide, and the reason for  wheezing in a given patient is determined by considering the characteristics of the wheezes and the historical and clinical findings made by the examining physician.

Characteristics
Wheeze
Wheezes occupy different portions of the respiratory cycle depending on the site of airway obstruction and its nature. The fraction of the respiratory cycle during which a wheeze is produced roughly corresponds to the degree of airway obstruction. Bronchiolar disease usually causes wheezing that occurs in the expiratory phase of respiration. As a rule, extrathoracic airway obstruction produce inspiratory sounds. Intrathoracic major airway obstruction produces inspiratory as well as expiratory sounds. Distal airway obstruction predominantly produces expiratory sounds.The presence of expiratory phase wheezing signifies that the patients peak expiratory flow rate is less than 50% of normal. Wheezing heard in the inspiratory phase, on the other hand, is often a sign of a stiff stenosis, usually caused by tumors, foreign bodies or scarring. This is especially true if the wheeze is monotonal, occurs throughout the inspiratory phase (i.e. is "holoinspiratory"), and is heard more proximally, in the trachea. Inspiratory wheezing also occurs in hypersensitivity pneumonitis. Wheezes heard at the end of both expiratory and inspiratory phases usually signify the periodic opening of deflated alveoli, as occurs in some diseases that lead to collapse of parts of the lungs.
The location of the wheeze can also be an important clue to the diagnosis. Diffuse processes that affect most parts of the lungs are more likely to produce wheezing that may be heard throughout the chest via a stethoscope. Localized processes, such as the occlusion of a portion of the respiratory tree, are more likely to produce wheezing at that location, hence the sound will be loudest and radiate outwardly. The pitch of a wheeze does not reliably predict the degree of narrowing in the affected airway.

Stridor
A special type of wheeze is stridor </s>