<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 Infective endocarditis and can you explain it in depth? [/INST] Infective endocarditis is an infection of the inner surface of the heart, usually the valves. Signs and symptoms may include fever, small areas of bleeding into the skin, heart murmur, feeling tired, and low red blood cell count. Complications may include backward blood flow in the heart, heart failure – the heart struggling to pump a sufficient amount of blood to meet the bodys needs, abnormal electrical conduction in the heart, stroke, and kidney failure.The cause is typically a bacterial infection and less commonly a fungal infection. Risk factors include valvular heart disease, including rheumatic disease, congenital heart disease, artificial valves, hemodialysis, intravenous drug use, and electronic pacemakers. The bacteria most commonly involved are streptococci or staphylococci. Diagnosis is suspected based on symptoms and supported by blood cultures or ultrasound of the heart. There is also a noninfective form of endocarditis.The usefulness of antibiotics following dental procedures for prevention is unclear. Some recommend them for people at high risk. Treatment is generally with intravenous antibiotics. The choice of antibiotics is based on the results of blood cultures. Occasionally heart surgery is required.The number of people affected is about 5 per 100,000 per year. Rates, however, vary between regions of the world. Infective endocarditis occurs in males more often than in females. The risk of death among those infected is about 25%. Without treatment, it is almost universally fatal.

Classification
Infective endocarditis is divided into the three categories of acute, subacute, and chronic based on the duration of symptoms. Acute infective endocarditis refers to the presence of signs and symptoms of infective endocarditis that are present for days up to six weeks. If these signs and symptoms persist for more than six weeks but less than three months, this is subacute infective endocarditis. Chronic infective endocarditis refers to the presence of such signs and symptoms when they persist for more than three months.
Subacute bacterial endocarditis (SBE) is often due to streptococci of low virulence (mainly viridans streptococci) and mild to moderate illness which progresses slowly over weeks and months (>2 weeks) and has low propensity to hematogenously seed extracardiac sites.
Acute bacterial endocarditis (ABE) is a fulminant illness over days to weeks (<2 weeks), and is more likely due to Staphylococcus aureus, which has much greater virulence or disease-producing capacity and frequently causes metastatic infection.This classification is now discouraged, because the ascribed associations (in terms of organism and prognosis) were not strong enough to be relied upon clinically. The terms short incubation (meaning less than about six weeks) and long incubation (greater than about six weeks) are preferred.

Culture results
Infective endocarditis may also be classified as culture-positive or culture-negative. By far the most common cause of "culture-negative" endocarditis is prior administration of antibiotics.Sometimes microorganisms can take a longer period of time to grow in the culture media, for example Cutibacterium spp. and the HACEK bacteria group. Some organisms are said to be fastidious because they have demanding growth requirements. Some examples include pathogens like Aspergillus species, Brucella species, Coxiella burnetii, Chlamydia species. Due to delay in growth and identification in these cases, patients may be erroneously classified as "culture-negative" endocarditis.

Heart side
Endocarditis can also be classified by the side of the heart affected:

People who intravenously inject opioids such as heroin or methamphetamine may introduce infection which can travel to the right side of the heart, classically affecting the tricuspid valve, and most often caused by S. aureus.
Regardless of cause, left-sided endocarditis is more common in people who inject IV drugs and people who do not use substances than right-sided endocarditis.

Infection setting
Another form of endocarditis is healthcare-associated endocarditis when the infecting organism is believed to be transmitted in a health care setting like hospital, dialysis unit or a residential nursing home. Nosocomial endocarditis is a form of healthcare associated endocarditis in which the infective organism is acquired during a stay in a hospital and it is usually secondary to presence of intravenous catheters, total parenteral nutrition lines, pacemakers, etc.

Valve type
Finally, the distinction between native-valve endocarditis and prosthetic-valve endocarditis is clinically important. Prosthetic valve endocarditis can be early (< 60 days of valvular surgery), intermediate (60 days to 1 year) or late (> 1 year following valvular surgery).
Early prosthetic valve endocarditis is usually due to intraoperative contamination or postoperative bacterial contamination which is usually nosocomial in nature.
Late prosthetic valve endocarditis is usually due to community-acquired microorganisms.Prosthetic valve endocarditis is commonly caused by Staphylococcus epidermidis as it is capable of growing as a biofilm on plastic surfaces. Cutibacterium acnes  almost exclusively causes endocarditis on prosthetic heart valves.

Signs and symptoms
Fever occurs in 97% of people; malaise and endurance fatigue in 90% of people.
A new or changing heart murmur, weight loss, and coughing occurs in 35% of people.
Vascular phenomena: septic embolism (a piece of infected debris or tissue breaking off and traveling through the bloodstream to a distant site) (causing thromboembolic problems such as a stroke or gangrene of the fingers), Janeway lesions (painless hemorrhagic cutaneous lesions on the palms and soles), bleeding in the brain, conjunctival hemorrhage, splinter hemorrhages, kidney infarcts, and splenic infarcts. Infective endocarditis can also lead to the formation of mycotic aneurysms.
Immunologic phenomena: glomerulonephritis which allows for blood and albumin to enter the urine, Oslers nodes ("ephemeral spots of a painful nodular erythema, chiefly in the skin of the hands and feet"), Roths spots on the retina, positive serum rheumatoid factor
Other signs may include night sweats, rigors, anemia, spleen enlargement

Cause
Many microorganisms can cause infective endocarditis. These are generally isolated by blood culture, where the patients blood is drawn and any growth is noted and identified. The term bacterial endocarditis (BE) commonly is used, reflecting the fact that most cases of IE are due to bacteria; however, infective endocarditis (IE) has become the preferred term.

Bacterial
Staphylococcus aureus is the leading cause of infective endocarditis in most parts of the world and is responsible for about 31% of cases. Staphylococcus aureus is the most common cause of endocarditis in people who use intravenous drugs. Viridans streptococci and Enterococci are the second and third most common organisms responsible for infective endocarditis. Viridans streptococci are a common cause of infective endocarditis in South America. Other Streptococci  are also a frequent cause. Infective endocarditis due to Streptococcus bovis occurs more commonly in Europe than in North America. HACEK group of bacteria are also rare causes of infective endocarditis in North America.The viridans group includes S. oralis, S. mitis, S. sanguis, S. gordonii and S. parasanguis. The primary habitats for these organisms are the oral cavity and upper respiratory tract. These bacteria are present in the normal oral flora and enter the bloodstream due to disruption of tissues in the mouth when dental surgical procedures are performed (tooth extractions) or genitourinary manipulation. Similarly, HACEK organisms are a group of bacteria that live on the dental gums and can be seen with people who inject drugs who contaminate their needles with saliva. Patients may also have a history of poor dental hygiene or pre-existing valvular disease.Viridans alpha-hemolytic streptococci, that are present in the mouth, are the most frequently isolated microorganisms when the infection is acquired in a community setting. In contrast, Staphylococcus bloodstream infections are frequently acquired in a health care setting where they can enter the bloodstream through procedures that cause breaks in the integrity of skin, such as surgery, catheterization, or during access of long term indwelling catheters or secondary to intravenous injection of recreational drugs.Enterococcus can enter the bloodstream as a consequence of abnormalities in the gastrointestinal or genitourinary tracts.Some organisms, when isolated, give valuable clues to the cause, as they tend to be specific.

Pseudomonas species, which are very resilient organisms that thrive in water, may contaminate street drugs that have been contaminated with drinking water. P. aeruginosa can infect a child through foot punctures, and can cause both endocarditis and septic arthritis.
S. bovis and Clostridium septicum, which are part of the natural flora of the bowel, are associated with colon cancers. When they present as the causative agent in endocarditis, it usually prompts a colonoscopy to be done immediately due to concerns regarding spread of bacteria from the colon through the bloodstream due to the cancer breaking down the barrier between the inside of the colon (lumen) and the blood vessels which drain the bowel.
Less commonly reported bacteria responsible for so called "culture negative endocarditis" include Bartonella, Chlamydia psittaci, and Coxiella. Such bacteria can be identified by serology, culture of the excised valve tissue, sputum, pleural fluid, and emboli, and by polymerase chain reaction or sequencing of bacterial 16S ribosomal RNA.Multiple case reports of infective endocarditis caused by unusual organisms have been published. Cutibacterium spp., which are normal skin flora, have been responsible for infective endocarditis, preferably in patients with prosthetic heart valves, in rare cases leading to death.Tropheryma whipplei has caused endocarditis without gastrointestinal involvement. Citrobacter koseri was found in an immunocompetent adult. Neisseria bacilliformis was found in a person with a bicuspid aortic valve.

Fungal
Fungal endocarditis (FE) is often fatal and one of the most serious forms of infective endocarditis. The types of fungi most seen associated with this disease are:
Candida albicans is found as a spherical or oval budding yeast. It is associated with endocarditis in people who inject drugs, patients with prosthetic valves, and immunocompromised patients. It forms biofilms around thick-walled resting structures like prosthetic heart valves and additionally colonizes and penetrates endothelial walls. C. albicans is responsible for 24-46% of all the cases of FE, and its mortality rate is 46.6–50%.Other fungi demonstrated to cause endocarditis are Histoplasma capsulatum and Aspergillus. Aspergillus contributes to roughly 25% of FE cases. Endocarditis with Tricosporon asahii has also been reported in a case report.

Risk factors
Risk factors for infective endocarditis are based on the premise that in a healthy individual, bacteremia (bacteria entering the bloodstream) is cleared quickly with no adverse consequences. However, if a heart valve is damaged, the bacteria can attach themselves to the valve, resulting in infective endocarditis. Additionally, in individuals with weakened immune systems, the concentration of bacteria in the blood can reach levels high enough to increase the probability that some will attach to the valve. Some significant risk factors are listed here:
Artificial heart valves
Intracardiac devices, such as implantable cardioverter-defibrillators
Unrepaired cyanotic congenital heart defects
History of infective endocarditis
Neoplastic disease
Chronic rheumatic heart disease, which is an autoimmune response to repeated Streptococcus pyogenes infection (mostly in the developing world)
Age-related degenerative valvular lesions
Congenital heart valve abnormalities
Hemodialysis, a medical procedure that filters the blood of individuals with kidney failure
Poor oral hygiene
Coexisting conditions, especially ones that suppress immunity. Diabetes mellitus, alcohol use disorder, chronic liver disease, HIV/AIDS, and intravenous drug use all fall in this categoryMore detailed descriptions of these and other risk factors are provided below.
Other conditions that result in large numbers of bacteria entering into the bloodstream include colorectal cancer (mostly Streptococcus bovis), serious urinary tract infections (mostly enterococci), and drug injection (Staphylococcus aureus). With a large number of bacteria, even a normal heart valve may become infected.
A more virulent organism (such as Staphylococcus aureus) can cause infective endocarditis by infecting even a normal heart valve.People who inject drugs tend to get their right-sided heart valves infected because the veins that are injected drain into the right side of the heart. In rheumatic heart disease, infection occurs on the aortic and the mitral valves on the left side of the heart.Other factors that increase the risk of developing infective endocarditis are low levels of white blood cells, immunodeficiency or immunosuppression, malignancy, diabetes mellitus, and excessive alcohol use.

Dental operations
In the past, one in eight cases of infective endocarditis was because of bacteremia caused by dental procedures (in most cases due to Streptococcus viridans, which reside in the oral cavity), such as cleaning or extraction of a tooth. This was thought to be more clinically significant than it actually was. However, it is important that a dentist or a dental hygienist be told of any heart problems before commencing treatment. Antibiotics are administered to patients with certain heart conditions as a precaution, although this practice has changed in the US, with new American Heart Association guidelines released in 2007, and in the UK as of March 2008 due to new NICE guidelines. Everyday tooth brushing and flossing will similarly cause bacteremia, so a high standard of oral health should be adhered to at all times.Although there is little evidence to support antibiotic prophylaxis for dental treatment, the current American Heart Association guidelines are highly accepted by clinicians and patients.

Pathogenesis
Damaged valves and endocardium contribute to the development of infective endocarditis. Specifically, the damaged part of a heart valve forms a local blood clot, a condition known as non-bacterial thrombotic endocarditis (NBTE). The platelet and fibrin deposits that form as part of the blood clotting process allow bacteria to take hold and form vegetations. As previously mentioned, the body has no direct methods of combating valvular vegetations because the valves do not have a dedicated blood supply. This combination of damaged valves, bacterial growth, and lack of a strong immune response results in infective endocarditis.Damage to the valves and endocardium can be caused by:
Altered, turbulent blood flow. The areas that fibrose, clot, or roughen as a result of this altered flow are known as jet lesions. Altered blood flow is more likely in high pressure areas, so ventricular septal defects or patent ductus arteriosus can create more susceptibility than atrial septal defects.
Catheters, electrodes, and other intracardiac prosthetic devices.
Solid particles from repeated intravenous injections.
Chronic inflammation. Examples include auto-immune mechanisms and degenerative valvular lesions.The risk factors for infective endocarditis provide a more extensive list of conditions that can damage the heart.

Diagnosis
In general, the Duke criteria should be fulfilled in order to establish the diagnosis of endocarditis. Although the Duke criteria are widely used, they have significant limitations. For example, the sensitivity of the Duke criteria for detecting infective endocarditis decreases when prosthetic heart valves are present.As the Duke criteria rely heavily on the results of echocardiography, research has addressed when to order an echocardiogram by using signs and symptoms to predict occult endocarditis among people who inject drugs and among non drug-abusing patients. However, this research is over twenty years old and it is possible that changes in the epidemiology of endocarditis and bacteria such as staphylococci make the following estimates incorrect.
The blood tests C reactive protein (CRP) and procalcitonin have not been found to be particularly useful in helping make or rule out the diagnosis.

Ultrasound
Echocardiography is the main type of diagnostic imaging used to establish the diagnosis of infective endocarditis. There are two main types of echocardiography used to assist with the diagnosis of IE: transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE).The transthoracic echocardiogram has a sensitivity and specificity of approximately 65% and 95% if the echocardiographer believes there is probable or almost certain evidence of endocarditis. However, in endocarditis involving a prosthetic valve, TTE has a sensitivity of approximately 50%, whereas TEE has a sensitivity exceeding 90%. The TEE also has an important diagnostic role when the TTE does not reveal IE but diagnostic suspicion remains high,  since TEE is more sensitive for infective endocarditis and is better able to characterize infection-related damage to the heart valves and surrounding tissues.Guidelines support the initial use of TTE over TEE in people with abnormal blood cultures, a new heart murmur, and suspected infective endocarditis. TEE is the preferred initial form of imaging in people with suspected infective endocarditis who have a moderate to high pretest probability of infective endocarditis, including people with prosthetic heart valves, blood cultures growing Staphylococcus,  or have an intracardiac device (such as a pacemaker).

Modified Duke criteria
Established in 1994 by the Duke Endocarditis Service and revised in 2000, the Duke criteria are a collection of major and minor criteria used to establish a diagnosis of infective endocarditis. According to the Duke criteria, diagnosis of infective endocarditis can be definite, possible, or rejected. A diagnosis of infective endocarditis is definite if either the following pathological or clinical criteria are met:
One of these pathological criteria:

Histology or culture of cardiac vegetation, embolized vegetation, or intracardiac abscess from the heart finds microorganisms
Active endocarditisOne of these combinations of clinical criteria

Two major clinical criteria
One major and three minor criteria
Five minor criteriaDiagnosis of infective endocarditis is possible if one of the following combinations of clinical criteria is met:

One major and one minor criteria
Three minor criteria are fulfilled

Major criteria
Positive blood culture with typical IE microorganism, defined as one of the following:
Typical microorganism consistent with IE from two separate blood cultures, as noted below:
Viridans-group streptococci, or
Streptococcus bovis including nutritional variant strains, or
HACEK group, or
Staphylococcus aureus, or
Community-acquired enterococci, in the absence of a primary focus
Microorganisms consistent with IE from persistently positive blood cultures defined as:
Two positive cultures of blood samples drawn >12 hours apart, or
Three or a majority of ≥four separate blood cultures (with first and last sample drawn at least one hour apart)
Coxiella burnetii detected by at least one positive blood culture or IgG antibody titer for Q fever phase 1 antigen >1:800. This was previously a minor criterionEvidence of endocardial involvement with positive echocardiogram is defined as

Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation, or
Abscess, or
New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing of preexisting murmur not sufficient)

Minor criteria
Predisposing factor: known cardiac lesion, recreational drug injection
Fever >38 °C
Vascular phenomena: arterial emboli, pulmonary infarcts, Janeway lesions, conjunctival hemorrhage
Immunological phenomena: glomerulonephritis, Oslers nodes, Roths spots, Rheumatoid factor
Microbiologic evidence: Positive blood culture (that doesnt meet a major criterion) or serologic evidence of infection with organism consistent with IE but not satisfying major criterion

Risk
Among people who do not use intravenous drugs and have a fever in the emergency department, there is a less than 5% chance of occult endocarditis. Mellors in 1987 found no cases of endocarditis nor of staphylococcal bacteremia among 135 febrile patients in the emergency room. The upper confidence interval for 0% of 135 is 5%, so for statistical reasons alone, there is up to a 5% chance of endocarditis among these patients. In contrast, Leibovici found that among 113 non-selected adults admitted to the hospital because of fever there were two cases (1.8% with 95%CI: 0% to 7%) of endocarditis.Among people who do use intravenous drugs and have a fever in the emergency department, there is about a 10% to 15% prevalence of endocarditis. This estimate is not substantially changed by whether the doctor believes the patient has a trivial explanation for their fever. Weisse found that 13% of 121 patients had endocarditis. Marantz also found a prevalence of endocarditis of 13% among such patients in the emergency department with fever. Samet found a 6% incidence among 283 such patients, but after excluding patients with initially apparent major illness to explain the fever (including 11 cases of manifest endocarditis), there was a 7% prevalence of endocarditis.Among people with staphylococcal bacteremia (SAB), one study found a 29% prevalence of endocarditis in community-acquired SAB versus 5% in nosocomial SAB. However, only 2% of strains were resistant to methicillin and so these numbers may be low in areas of higher resistance.

Prevention
Not all people with heart disease require antibiotics to prevent infective endocarditis. Heart diseases have been classified into high, medium and low risk of developing IE. Those falling into high risk category require IE prophylaxis before endoscopies and urinary tract procedures.
Diseases listed under high risk include:
Prior endocarditis
Unrepaired cyanotic congenital heart diseases
Completely repaired congenital heart disease in their first 6 months
Prosthetic heart valves
Incompletely repaired congenital heart diseases
Cardiac transplant valvulopathyFollowing are the antibiotic regimens recommended by the American Heart Association for antibiotic prophylaxis:
Oral amoxicillin one hour before the procedure
Intravenous or intramuscular ampicillin one hour before the procedure
In patients allergic to penicillins
Azithromycin or clarithromycin orally one hour before the procedure
Cephalexin orally one hour before the procedure
Clindamycin orally one hour before the procedureIn the UK, NICE clinical guidelines no longer advise prophylaxis because there is no clinical evidence that it reduces the incidence of IE and there are negative effects (e.g. allergy and increased bacterial resistance) of taking antibiotics that may outweigh the benefits.Antibiotics were historically commonly recommended to prevent IE in those with heart problems undergoing dental procedures (known as dental antibiotic prophylaxis). There is, however, insufficient evidence to support whether antibiotics are effective or ineffective at preventing IE when given prior to a dental procedures in people at high risk. They are less commonly recommended for this procedure.In some countries e.g. the US, high risk patients may be given prophylactic antibiotics such as penicillin or clindamycin for penicillin-allergic people prior to dental procedures. Prophylactics should be bactericidal rather than bacteriostatic. Such measures are not taken in certain countries e.g. Scotland due to the fear of antibiotic resistance. Because bacteria are the most common cause of infective endocarditis, antibiotics such as penicillin and amoxicillin (for beta lactamase-producing bacteria) are used in prophylaxis.

Treatment
High-dose antibiotics are the cornerstone of treatment for infective endocarditis. These antibiotics are administered by the intravenous (IV) route to maximize diffusion of antibiotic molecules into vegetation(s) from the blood filling the chambers of the heart. This is necessary because neither the heart valves nor the vegetations adhering to them are supplied by blood vessels. Antibiotics are typically continued for two to six weeks depending on the characteristics of the infection and the causative microorganisms. Antibiotic treatment lowers the risk of embolic complications in people with infective endocarditis.In acute endocarditis, due to the fulminant inflammation, empirical antibiotic therapy is started immediately after the blood has been drawn for culture to clarify the bacterial organisms responsible for the infection. This usually includes vancomycin and ceftriaxone IV infusions until the infecting organism is identified and the susceptibility report with the minimum inhibitory concentration becomes available. Once this information is available, this allows the supervising healthcare professional to modify the antimicrobial therapy to target the specific infecting microorganism. The routine use of gentamicin to treat endocarditis has fallen out of favor due to the lack of evidence to support its use (except in infections caused by Enterococcus and nutritionally variant streptococci) and the high rate of complications. In cases of subacute endocarditis, where the persons hemodynamic status is usually stable, antibiotic treatment can be delayed until the causative microorganism can be identified.Viridans group streptococci and Streptococcus bovis are usually highly susceptible to penicillin and can be treated with penicillin or ceftriaxone. Relatively resistant strains of viridans group streptococci and Streptococcus bovis are treated with penicillin or ceftriaxone along with a shorter two-week course of an aminoglycoside during the initial phase of treatment. Highly penicillin-resistant strains of viridans group streptococci, nutritionally variant streptococci like Granulicatella sp., Gemella sp., Abiotrophia defectiva, and Enterococci are usually treated with a combination therapy consisting of penicillin and an aminoglycoside for the entire duration of 4–6 weeks.Some people may be treated with a relatively shorter course of treatment (two weeks) with benzyl penicillin IV if infection is caused by viridans group streptococci or Streptococcus bovis as long as the following conditions are met:

Endocarditis of a native valve, not of a prosthetic valve
A MIC ≤ 0.12 mg/l
A complication such as heart failure, arrhythmia, or pulmonary embolism occurs
No evidence of extracardiac complication like septic thromboembolism
No vegetations > 5 mm in diameter conduction defects
Rapid clinical response and clearance of bloodstream infectionAdditionally, oxacillin-susceptible Staphylococcus aureus native valve endocarditis of the right side can also be treated with a short 2-week course of a beta-lactam antibiotic such as nafcillin with or without aminoglycosides.

The main indication for surgical treatment is regurgitation or stenosis. In active infective endocarditis, the surgery should remove enough leaflet tissue to ensure eradication of the infectious process. Subsequent valve repair can be performed in limited disease. Replacement of the valve with a mechanical or bioprosthetic artificial heart valve is necessary in certain situations:
Patients with significant valve stenosis or regurgitation causing heart failure
Evidence of hemodynamic compromise in the form of elevated end-diastolic left ventricular or left atrial pressure or moderate to severe pulmonary hypertension
Presence of intracardiac complications like paravalvular abscess, conduction defects or destructive penetrating lesions
Recurrent septic emboli despite appropriate antibiotic treatment
Large vegetations (> 10 mm)
Persistently positive blood cultures despite appropriate antibiotic treatment
Prosthetic valve dehiscence
Relapsing infection in the presence of a prosthetic valve
Abscess formation
Early closure of mitral valve
Infection caused by fungi or resistant Gram-negative bacteria.The guidelines were recently updated by both the American College of Cardiology and the European Society of Cardiology. There was a recent meta-analysis published that showed surgical intervention at seven days or less is associated with lower mortality.

Prognosis
Infective endocarditis is associated with 18% in-hospital mortality. As many as 50% of people with infective endocarditis may experience embolic complications.

Epidemiology
In developed countries, the annual incidence of infective endocarditis is 3 to 9 cases per 100,000 persons. Infective endocarditis occurs more often in men than in women. There is an increased incidence of infective endocarditis in persons 65 years of age and older, which is probably because people in this age group have a larger number of risk factors for infective endocarditis </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 De Quervains thyroiditis and can you explain it in depth? [/INST] De Quervains thyroiditis, also  known as subacute granulomatous thyroiditis or giant cell thyroiditis, is a member of the group of thyroiditis conditions known as resolving thyroiditis. People of all ages and genders may be affected.

Presentation
Patients will experience a hyperthyroid period as the cellular lining of colloid spaces fails, allowing abundant colloid into the circulation, with neck pain and fever. Patients typically then become hypothyroid as the pituitary reduces TSH production and the inappropriately released colloid is depleted before resolving to euthyroid. The symptoms are those of hyperthyroidism and hypothyroidism. In addition, patients may suffer from painful dysphagia.  There are multi-nucleated giant cells on histology. Thyroid antibodies can be present in some cases </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 Rhinitis and can you explain it in depth? [/INST] Rhinitis, also known as coryza, is irritation and inflammation of the mucous membrane inside the nose. Common symptoms are a stuffy nose, runny nose, sneezing, and post-nasal drip.The inflammation is caused by viruses, bacteria, irritants or allergens. The most common kind of rhinitis is allergic rhinitis, which is usually triggered by airborne allergens such as pollen and dander. Allergic rhinitis may cause additional symptoms, such as sneezing and nasal itching, coughing, headache, fatigue, malaise, and cognitive impairment. The allergens may also affect the eyes, causing watery, reddened, or itchy eyes and puffiness around the eyes. The inflammation results in the generation of large amounts of mucus, commonly producing a runny nose, as well as a stuffy nose and post-nasal drip. In the case of allergic rhinitis, the inflammation is caused by the degranulation of mast cells in the nose. When mast cells degranulate, they release histamine and other chemicals, starting an inflammatory process that can cause symptoms outside the nose, such as fatigue and malaise. In the case of infectious rhinitis, it may occasionally lead to pneumonia, either viral or bacterial. Sneezing also occurs in infectious rhinitis to expel bacteria and viruses from the respiratory tract.
Rhinitis is very common. Allergic rhinitis is more common in some countries than others; in the United States, about 10–30% of adults are affected annually. Mixed rhinitis (MR) refers to patients with nonallergic rhinitis and allergic rhinitis. MR is a specific rhinitis subtype. It may represent between 50 and 70% of all AR patients. However, true prevalence of MR has not been confirmed yet.

Types
Rhinitis is categorized into three types (although infectious rhinitis is typically regarded as a separate clinical entity due to its transient nature): (i) infectious rhinitis includes acute and chronic bacterial infections; (ii) nonallergic rhinitis includes vasomotor, idiopathic, hormonal, atrophic, occupational, and gustatory rhinitis, as well as rhinitis medicamentosa (rebound congestion); (iii) allergic rhinitis, triggered by pollen, mold, animal dander, dust, Balsam of Peru, and other inhaled allergens.

Infectious
Rhinitis is commonly caused by a viral or bacterial infection, including the common cold, which is caused by Rhinoviruses, Coronaviruses, and influenza viruses, others caused by adenoviruses, human parainfluenza viruses, human respiratory syncytial virus, enteroviruses other than rhinoviruses, metapneumovirus, and measles virus, or bacterial sinusitis, which is commonly caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Symptoms of the common cold include rhinorrhea, sneezing, sore throat (pharyngitis), cough, congestion, and slight headache.

Nonallergic rhinitis
Nonallergic rhinitis refers to rhinitis that is not due to an allergy. The category was formerly referred to as vasomotor rhinitis, as the first cause discovered was vasodilation due to an overactive parasympathetic nerve response. As additional causes were identified, additional types of nonallergic rhinitis were recognized. Vasomotor rhinitis is now included among these under the more general classification of nonallergic rhinitis. The diagnosis is made upon excluding allergic causes. It is an umbrella term of rhinitis of multiple causes, such as occupational (chemical), smoking, gustatory, hormonal, senile (rhinitis of the elderly), atrophic, medication-induced (including rhinitis medicamentosa), local allergic rhinitis, non-allergic rhinitis with eosinophilia syndrome (NARES) and idiopathic (vasomotor or non-allergic, non-infectious perennial allergic rhinitis (NANIPER), or non-infectious non-allergic rhinitis (NINAR).In vasomotor rhinitis, certain nonspecific stimuli, including changes in environment (temperature, humidity, barometric pressure, or weather), airborne irritants (odors, fumes), dietary factors (spicy food, alcohol), sexual arousal, exercise, and emotional factors trigger rhinitis. There is still much to be learned about this, but it is thought that these non-allergic triggers cause dilation of the blood vessels in the lining of the nose, which results in swelling and drainage.
Non-allergic rhinitis can co-exist with allergic rhinitis, and is referred to as "mixed rhinitis". The pathology of vasomotor rhinitis appears to involve neurogenic inflammation and is as yet not very well understood. The role of transient receptor potential ion channels on the non-neuronal nasal epithelial cells has also been suggested. Overexpression of these receptors have influence the nasal airway hyper-responsiveness to non-allergic irritant environmental stimuli (e.g., extremes of temperature, changes in osmotic or barometric pressure). Vasomotor rhinitis appears to be significantly more common in women than men, leading some researchers to believe that hormone imbalance plays a role. In general, age of onset occurs after 20 years of age, in contrast to allergic rhinitis which can be developed at any age. Individuals with vasomotor rhinitis typically experience symptoms year-round, though symptoms may be exacerbated in the spring and autumn when rapid weather changes are more common. An estimated 17 million United States citizens have vasomotor rhinitis.Drinking alcohol may cause rhinitis as well as worsen asthma (see alcohol-induced respiratory reactions).  In certain populations, particularly those of East Asian countries such as Japan, these reactions have a nonallergic basis. In other populations, particularly those of European descent, a genetic variant in the gene that metabolizes ethanol to acetaldehyde, ADH1B, is associated with alcohol-induced rhinitis.  It is suggested that this variant metabolizes ethanol to acetaldehyde too quickly for further processing by ALDH2 and thereby leads to the accumulation of acetaldehyde and rhinitis symptoms. In these cases, alcohol-induced rhinitis may be of the mixed rhinitis type and, it seems likely, most cases of alcohol-induced rhinitis in non-Asian populations reflect true allergic response to the non-ethanol and/or contaminants in alcoholic beverages, particularly when these beverages are wines or beers. Alcohol-exacerbated rhinitis is more frequent in individuals with a history of rhinitis exacerbated by aspirin.Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), particularly those that inhibit cyclooxygenase 1 (COX1), can worsen rhinitis and asthma symptoms in individuals with a history of either one of these diseases. These exacerbations most often appear due to NSAID hypersensitivity reactions rather than NSAID-induced allergic reactions.The antihistamine azelastine, applied as a nasal spray, may be effective for vasomotor rhinitis. Fluticasone propionate or budesonide (both are steroids) in nostril spray form may also be used for symptomatic treatment. The antihistamine cyproheptadine is also effective, probably due to its antiserotonergic effects.
A systematic review on non-allergic rhinitis reports improvement of overall function after treatment with capsaicin (the active component of chili peppers). The quality of evidence is low, however.

Allergic
Allergic rhinitis or hay fever may follow when an allergen such as pollen, dust, or Balsam of Peru is inhaled by an individual with a sensitized immune system, triggering antibody production. These antibodies mostly bind to mast cells, which contain histamine. When the mast cells are stimulated by an allergen, histamine (and other chemicals) are released. This causes itching, swelling, and mucus production.
Symptoms vary in severity between individuals. Very sensitive individuals can experience hives or other rashes. Particulate matter in polluted air and chemicals such as chlorine and detergents, which can normally be tolerated, can greatly aggravate the condition.Characteristic physical findings in individuals who have allergic rhinitis include conjunctival swelling and erythema, eyelid swelling, lower eyelid venous stasis, lateral crease on the nose, swollen nasal turbinates, and middle ear effusion.Even if a person has negative skin-prick, intradermal and blood tests for allergies, they may still have allergic rhinitis, from a local allergy in the nose. This is called local allergic rhinitis. Many people who were previously diagnosed with nonallergic rhinitis may actually have local allergic rhinitis.A patch test may be used to determine if a particular substance is causing the rhinitis.

Rhinitis medicamentosa
Rhinitis medicamentosa is a form of drug-induced nonallergic rhinitis which is associated with nasal congestion brought on by the use of certain oral medications (primarily sympathomimetic amine and 2-imidazoline derivatives) and topical decongestants (e.g., oxymetazoline, phenylephrine, xylometazoline, and naphazoline nasal sprays) that constrict the blood vessels in the lining of the nose.

Chronic atrophic rhinitis
Chronic rhinitis is a form of atrophy of the mucous membrane and glands of the nose.

Rhinitis sicca
Chronic form of dryness of the mucous membranes.

Polypous rhinitis
Chronic rhinitis associated with polyps in the nasal cavity.

Pathophysiology
Most prominent pathological changes observed are nasal airway epithelial metaplasia in which goblet cells replace ciliated columnar epithelial cells in the nasal mucous membrane. This results in mucin hypersecretion by goblet cells and decreased mucociliary activity. Nasal secretion are not adequately cleared with clinical manifestation of nasal congestion, sinus pressure, post-nasal dripping, and headache. Over-expression of transient receptor potential (TRP) ion channels, such as TRPA1 and TRPV1, may be involved in the pathogenesis of non-allergic rhinitis.

Association between rhinitis and asthma
Neurogenic inflammation produced by neuropeptides released from sensory nerve endings to the airways is a proposed common mechanism of association between both allergic and non-allergic rhinitis with asthma. This may explain higher association of rhinitis with asthma developing later in life. Environmental irritants acts as modulators of airway inflammation in these contiguous airways </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 Ganglion cyst and can you explain it in depth? [/INST] A ganglion cyst is a fluid-filled bump associated with a joint or tendon sheath. It most often occurs at the back of the wrist, followed by the front of the wrist. Onset is often over several months, typically with no further symptoms. Occasionally, pain or numbness may occur. Complications may include carpal tunnel syndrome.The cause is unknown. The underlying mechanism is believed to involve an outpouching of the synovial membrane. Risk factors include gymnastics activity. Diagnosis is typically based on examination with light shining through the lesion being supportive. Medical imaging may be done to rule out other potential causes.Treatment options include watchful waiting, splinting the affected joint, needle aspiration, or surgery. About half the time, they resolve on their own. About three per 10,000 people newly develop ganglion of the wrist or hand a year. They most commonly occur in young and middle-aged females.

Presentation
The average size of these cysts is 2.0 cm, but excised cysts of more than 5 cm have been reported. The size of the cyst may vary over time and may increase after activity. Between 50 and 70% of all masses on the hand and wrist are expected to be ganglion cysts.

Sites
Ganglion cysts most frequently occur around the dorsum of the wrist and on the fingers. A common site of the occurrence is along the extensor carpi radialis brevis, as it passes over the dorsum of the wrist joint. Although most commonly found in the wrist, ganglion cysts also may occur in the foot.Ganglion cysts are "commonly observed in association with the joints and tendons of the appendicular skeleton, with 88% in communication with the multiple small joints of the hand and wrist and 11% with those of the foot and ankle".

Wrist
They commonly are found near the wrist joint, especially at the scapholunate area.Common wrist ganglions include:

dorsal wrist ganglion
volar wrist ganglion
volar retinaculum ganglion
extensor retinaculum ganglion
occult ganglion
intraosseous ganglion
mucous cyst

Foot
In a 2007 study of patients in Glasgow whose foot lumps were removed surgically, 39 of 101 cases were ganglion cysts. The study replicated earlier findings that no ganglion cysts were found on the sole or heel. The authors wrote, "Although lumps in these areas may be ganglia, the surgeon should probably consider other diagnoses in the first instance." The researchers noted a preponderance of occurrence among females (85%) and that 11 of the other cases had been misdiagnosed as ganglion cysts before surgery.Ganglion cysts are not limited to the hands and feet. They may occur near the knee, commonly near the cruciate ligaments, but they may occur at the origins of the gastrocnemius tendon, and anteriorly on Hoffas infrapatellar fat pad. At the shoulder, they typically occur at the acromioclavicular joint or along the biceps tendon.

Other
From their common origin at a joint or tendon, ganglion cysts may form in a wide range of locations. Rarely, intraosseous ganglion cysts occur, sometimes in combination with a cyst in the overlying soft tissue. Rare cases of intramuscular ganglion cysts in the gastrocnemius muscle of the calf have been reported. It is possible for a cyst to be considerably displaced from the joint. In one extreme case, a ganglion cyst was observed to propagate extensively via the conduit of the common peroneal nerve sheath to a location in the thigh; in such cases surgery to the proximal joint to remove the articular connection may remove the need for a riskier, more extensive surgery in the neural tissue of the thigh. The cysts may intrude into the spine, which may cause pain and dysesthesia in distant extremities.Cystic adventitial disease, in which a cyst occurs within the popliteal artery near the knee, has been proposed recently to occur by an articular mechanism, with a conduit leading from the joint, similar to the development of ganglion cysts, that spreads within the peroneal nerve.Cysts that were compressing one or more nerves and causing bone erosions have been reported to occur near the shoulder joint.

Causes
The most commonly accepted probable cause of ganglion cysts is the "herniation hypothesis", by which they are thought to occur as "an out-pouching or distention of a weakened portion of a joint capsule or tendon sheath." This description is based on the observations that the cysts occur close to tendons and joints.  The microscopic anatomy of the cyst resembles that of tenosynovial tissue. The fluid is similar in composition to synovial fluid. Dye injected into the joint capsule frequently ends up in the cyst, which may become enlarged after activity. Dye injected into the cyst rarely enters the joint, however, which has been attributed to the apparent formation of an effective and one-way "check valve", allowing fluid out of the joint, but not back in.In synovials, post-traumatic degeneration of connective tissue and inflammation have been considered as causes. Other possible mechanisms for the development of ganglion cysts include repeated mechanical stress, facet arthrosis, myxoid degeneration of periarticular fibrous tissues and liquefaction with chronic damage, increased production of hyaluronic acid by fibroblasts, and a proliferation of mesenchymal cells.

Diagnosis
Ganglion cysts are diagnosed easily, as they are visible and pliable to touch.
Radiographs in anteroposterior and lateral views should be obtained to exclude any more serious underlying pathology. Ultrasonography (US) may be used to increase diagnostic confidence in clinically suspected lesions or to depict occult cysts, because intratendinous ganglia are readily distinguished from extratendinous ganglia during dynamic ultrasonography, as microscopically, ganglionic cysts are thin-walled cysts containing clear, mucinous fluid.

Treatment
If persons are not in pain, they should simply be reassured that the lump is not cancerous, and wait for the lump to disappear on its own. At least 33% resolve without treatment within six years, and 50% within 10 years.Surgical treatments remain the primary elective option for treatment of ganglion cysts. The progression of ganglion surgery worldwide is to use an arthroscopic or miniopening method. Alternatively, a hypodermic needle may be used to drain the fluid from the cyst (via aspiration) and a corticosteroid may be injected after the cyst is empty; however, if the fluid has thickened, owing to the passage of time, this treatment is not always effective. The recurrence rate is about 50% following needle drainage (via aspiration) of ganglion cysts.
A historical method of treatment for a ganglion cyst was to strike the lump with a large and heavy book, causing the cyst to rupture and drain into the surrounding tissues. Historically, a Bible was the largest or only book in any given household, and was employed for this treatment </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 Pseudohypoparathyroidism and can you explain it in depth? [/INST] Pseudohypoparathyroidism is a condition associated primarily with resistance to the parathyroid hormone. Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) is appropriately high (due to the low level of calcium in the blood). Its pathogenesis has been linked to dysfunctional G Proteins (in particular, Gs alpha subunit). Pseudohypoparathyroidism is a very rare disorder, with estimated prevalence between 0.3 and 1.1 cases per 100000 population depending on geographic location.

Types
Types include:

Type 1a (OMIM  103580)
Has a characteristic phenotypic appearance (Albrights hereditary osteodystrophy), including short fourth and fifth metacarpals and a rounded facies. It is most likely an autosomal dominant disorder. It is also associated with thyroid stimulating hormone resistance. Caused by GNAS1 mutation.
Type 1b (OMIM  603233)
Lacks the physical appearance of type 1a, but is biochemically similar. It is associated with a methylation defect in the A/B exon of GNAS1, caused by STX16 disruption.
Type 2 (OMIM  203330)
Also lacks the physical appearance of type 1a. Since the genetic defect in type 2 is further down the signalling pathway than in type 1, there is a normal cAMP response to PTH stimulation despite the inherent abnormality in calcium regulation. The specific gene is not identified.While biochemically similar, type 1 and 2 disease may be distinguished by the differing urinary excretion of cyclic AMP in response to exogenous PTH.Some sources also refer to a "type 1c" (OMIM  612462). The phenotype is the same as in type 1a, but red blood cells show normal Gs activity. As it is also caused by a GNAS mutation, it is not clear whether it should be considered an entity separate from Ia.

Presentation
Patients may present with features of hypocalcaemia including carpo-pedal muscular spasms, cramping, tetany, and if the calcium deficit is severe, generalized seizures. IQ is typically mildly depressed or unaffected </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 Foodborne illness and can you explain it in depth? [/INST] Foodborne illness (also foodborne disease and food poisoning) is any illness resulting from the spoilage of contaminated food by pathogenic bacteria, viruses, or parasites that contaminate food, as well as prions (the agents of mad cow disease), and toxins such as aflatoxins in peanuts, poisonous mushrooms, and various species of beans that have not been boiled for at least 10 minutes.
Symptoms vary depending on the cause but often include vomiting, fever, and aches, and may include diarrhea. Bouts of vomiting can be repeated with an extended delay in between, because even if infected food was eliminated from the stomach in the first bout, microbes, like bacteria (if applicable), can pass through the stomach into the intestine and begin to multiply. Some types of microbes stay in the intestine.
For contaminants requiring an incubation period, symptoms may not manifest for hours to days, depending on the cause and on quantity of consumption. Longer incubation periods tend to cause those affected to not associate the symptoms with the item consumed, so they may misattribute the symptoms to gastroenteritis, for example.

Causes
Foodborne illness usually arises from improper handling, preparation, or food storage. Good hygiene practices before, during, and after food preparation can reduce the chances of contracting an illness. There is a consensus in the public health community that regular hand-washing is one of the most effective defenses against the spread of foodborne illness. The action of monitoring food to ensure that it will not cause foodborne illness is known as food safety. Foodborne disease can also be caused by a large variety of toxins that affect the environment.Furthermore, foodborne illness can be caused by a number of chemicals, such as pesticides, medicines, and natural toxic substances such as vomitoxin, poisonous mushrooms or reef fish.

Bacteria
Bacteria are a common cause of foodborne illness. The United Kingdom, in 2000, reported the individual bacteria involved as the following: Campylobacter jejuni 77.3%, Salmonella 20.9%, Escherichia coli O157:H7 1.4%, and all others less than 0.56%.  In the past, bacterial infections were thought to be more prevalent because few places had the capability to test for norovirus and no active surveillance was being done for this particular agent. Toxins from bacterial infections are delayed because the bacteria need time to multiply. As a result, symptoms associated with intoxication are usually not seen until 12–72 hours or more after eating contaminated food. However, in some cases, such as Staphylococcal food poisoning, the onset of illness can be as soon as 30 minutes after ingesting contaminated food.

Most common bacterial foodborne pathogens are:

Campylobacter jejuni which can lead to secondary Guillain–Barré syndrome and periodontitis
Clostridium perfringens, the "cafeteria germ"
Salmonella spp. – its S. typhimurium infection is caused by consumption of eggs or poultry that are not adequately cooked or by other interactive human-animal pathogens
Escherichia coli O157:H7 enterohemorrhagic (EHEC) which can cause hemolytic-uremic syndromeOther common bacterial foodborne pathogens are:
Bacillus cereus
Escherichia coli, other virulence properties, such as enteroinvasive (EIEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enteroaggregative (EAEC or EAgEC)
Listeria monocytogenes
Shigella spp.
Staphylococcus aureus
Staphylococcal enteritis
Streptococcus
Vibrio cholerae, including O1 and non-O1
Vibrio parahaemolyticus
Vibrio vulnificus
Yersinia enterocolitica and Yersinia pseudotuberculosisLess common bacterial agents:
Brucella spp.
Corynebacterium ulcerans
Coxiella burnetii or Q fever
Plesiomonas shigelloides

Enterotoxins
In addition to disease caused by direct bacterial infection, some foodborne illnesses are caused by enterotoxins (exotoxins targeting the intestines). Enterotoxins can produce illness even when the microbes that produced them have been killed. Symptom appearance varies with the toxin but may be rapid in onset, as in the case of enterotoxins of Staphylococcus aureus in which symptoms appear in one to six hours. This causes intense vomiting including or not including diarrhea (resulting in staphylococcal enteritis), and staphylococcal enterotoxins (most commonly staphylococcal enterotoxin A but also including staphylococcal enterotoxin B) are the most commonly reported enterotoxins although cases of poisoning are likely underestimated. It occurs mainly in cooked and processed foods due to competition with other biota in raw foods, and humans are the main cause of contamination as a substantial percentage of humans are persistent carriers of S. aureus. The CDC has estimated about 240,000 cases per year in the United States.
Clostridium botulinum
Clostridium perfringens
Bacillus cereusThe rare but potentially deadly disease botulism occurs when the anaerobic bacterium Clostridium botulinum grows in improperly canned low-acid foods and produces botulin, a powerful paralytic toxin.
Pseudoalteromonas tetraodonis, certain species of Pseudomonas and Vibrio, and some other bacteria, produce the lethal tetrodotoxin, which is present in the tissues of some living animal species rather than being a product of decomposition.

Emerging foodborne pathogens
Aeromonas hydrophila, Aeromonas caviae, Aeromonas sobriaScandinavian outbreaks of Yersinia enterocolitica have recently increased to an annual basis, connected to the non-canonical contamination of pre-washed salad.

Preventing bacterial food poisoning
Prevention is mainly the role of the state, through the definition of strict rules of hygiene and a public services of veterinary surveying of animal products in the food chain, from farming to the transformation industry and delivery (shops and restaurants). This regulation includes:

traceability: in a final product, it must be possible to know the origin of the ingredients (originating farm, identification of the harvesting or of the animal) and where and when it was processed; the origin of the illness can thus be tracked and solved (and possibly penalized), and the final products can be removed from the sale if a problem is detected;
enforcement of hygiene procedures such as HACCP and the "cold chain";
power of control and of law enforcement of veterinarians.In August 2006, the United States Food and Drug Administration approved phage therapy which involves spraying meat with viruses that infect bacteria, and thus preventing infection. This has raised concerns, because without mandatory labelling consumers would not be aware that meat and poultry products have been treated with the spray.At home, prevention mainly consists of good food safety practices. Many forms of bacterial poisoning can be prevented by cooking food sufficiently, and either eating it quickly or refrigerating it effectively. Many toxins, however, are not destroyed by heat treatment.
Techniques that help prevent food borne illness in the kitchen are hand washing, rinsing produce, preventing cross-contamination, proper storage, and maintaining cooking temperatures. In general, freezing or refrigerating prevents virtually all bacteria from growing, and heating food sufficiently kills parasites, viruses, and most bacteria. Bacteria grow most rapidly at the range of temperatures between 40 and 140 °F (4 and 60 °C), called the "danger zone". Storing food below or above the "danger zone" can effectively limit the production of toxins. For storing leftovers, the food must be put in shallow containers
for quick cooling and must be refrigerated within two hours. When food is reheated, it must reach an internal temperature of 165 °F (74 °C) or until hot or steaming to kill bacteria.

Mycotoxins and alimentary mycotoxicoses
The term alimentary mycotoxicosis refers to the effect of poisoning by mycotoxins through food consumption.  The term mycotoxin is usually reserved for the toxic chemical products produced by fungi that readily colonize crops. Mycotoxins sometimes have important effects on human and animal health.  For example, an outbreak which occurred in the UK in 1960 caused the death of 100,000 turkeys which had consumed aflatoxin-contaminated peanut meal.  In the USSR in World War II, 5,000 people died due to alimentary toxic aleukia (ALA). The common foodborne Mycotoxins include:

Aflatoxins – originating from Aspergillus parasiticus and Aspergillus flavus. They are frequently found in tree nuts, peanuts, maize, sorghum and other oilseeds, including corn and cottonseeds. The pronounced forms of Aflatoxins are those of B1, B2, G1, and G2, amongst which Aflatoxin B1 predominantly targets the liver, which will result in necrosis, cirrhosis, and carcinoma. In the US, the acceptable level of total aflatoxins in foods is less than 20 μg/kg, except for Aflatoxin M1 in milk, which should be less than 0.5 μg/kg. The official document can be found at FDAs website.
Altertoxins – are those of alternariol (AOH), alternariol methyl ether (AME), altenuene (ALT), altertoxin-1 (ATX-1), tenuazonic acid (TeA), and radicinin (RAD), originating from Alternaria spp. Some of the toxins can be present in sorghum, ragi, wheat and tomatoes. Some research has shown that the toxins can be easily cross-contaminated between grain commodities, suggesting that manufacturing and storage of grain commodities is a critical practice.
Citrinin
Citreoviridin
Cyclopiazonic acid
Cytochalasins
Ergot alkaloids / ergopeptine alkaloids – ergotamine
Fumonisins – Crop corn can be easily contaminated by the fungi Fusarium moniliforme, and its fumonisin B1 will cause leukoencephalomalacia (LEM) in horses, pulmonary edema syndrome (PES) in pigs, liver cancer in rats and esophageal cancer in humans. For human and animal health, both the FDA and the EC have regulated the content levels of toxins in food and animal feed.
Fusaric acid
Fusarochromanone
Kojic acid
Lolitrem alkaloids
Moniliformin
3-Nitropropionic acid
Nivalenol
Ochratoxins – In Australia, The Limit of Reporting (LOR) level for ochratoxin A (OTA) analyses in 20th Australian Total Diet Survey was 1 µg/kg, whereas the EC restricts the content of OTA to 5 µg/kg in cereal commodities, 3 µg/kg in processed products and 10 µg/kg in dried vine fruits.
Oosporeine
Patulin – Currently, this toxin has been advisably regulated on fruit products.  The EC and the FDA have limited it to under 50 µg/kg for fruit juice and fruit nectar, while limits of 25 µg/kg for solid-contained fruit products and 10 µg/kg for baby foods were specified by the EC.
Phomopsins
Sporidesmin A
Sterigmatocystin
Tremorgenic mycotoxins – Five of them have been reported to be associated with molds found in fermented meats. These are fumitremorgen B, paxilline, penitrem A, verrucosidin, and verruculogen.
Trichothecenes – sourced from Cephalosporium, Fusarium, Myrothecium, Stachybotrys, and Trichoderma. The toxins are usually found in molded maize, wheat, corn, peanuts and rice, or animal feed of hay and straw. Four trichothecenes, T-2 toxin, HT-2 toxin, diacetoxyscirpenol (DAS), and deoxynivalenol (DON) have been most commonly encountered by humans and animals. The consequences of oral intake of, or dermal exposure to, the toxins will result in alimentary toxic aleukia, neutropenia, aplastic anemia, thrombocytopenia and/or skin irritation. In 1993, the FDA issued a document for the content limits of DON in food and animal feed at an advisory level. In 2003, US published a patent that is very promising for farmers to produce a trichothecene-resistant crop.
Zearalenone
Zearalenols

Viruses
Viral infections make up perhaps one third of cases of food poisoning in developed countries. In the US, more than 50% of cases are viral and noroviruses are the most common foodborne illness, causing 57% of outbreaks in 2004. Foodborne viral infection are usually of intermediate (1–3 days) incubation period, causing illnesses which are self-limited in otherwise healthy individuals; they are similar to the bacterial forms described above.
Enterovirus
Hepatitis A is distinguished from other viral causes by its prolonged (2–6 week) incubation period and its ability to spread beyond the stomach and intestines into the liver. It often results in jaundice, or yellowing of the skin, but rarely leads to chronic liver dysfunction. The virus has been found to cause infection due to the consumption of fresh-cut produce which has fecal contamination.
Hepatitis E
Norovirus
Rotavirus

Parasites
Most foodborne parasites are zoonoses.
Platyhelminthes:Diphyllobothrium sp.
Nanophyetus sp.
Taenia saginata
Taenia solium
Fasciola hepatica
See also: Tapeworm and Flatworm
Nematode:Anisakis sp.
Ascaris lumbricoides
Eustrongylides sp.
Toxocara
Trichinella spiralis
Trichuris trichiura
Protozoa:Acanthamoeba and other free-living amoebae
Cryptosporidiosis
Cyclospora cayetanensis
Entamoeba histolytica
Giardia lamblia
Sarcocystis hominis
Sarcocystis suihominis
Toxoplasma

Natural toxins
Several foods can naturally contain toxins, many of which are not produced by bacteria. Plants in particular may be toxic; animals which are naturally poisonous to eat are rare. In evolutionary terms, animals can escape being eaten by fleeing; plants can use only passive defenses such as poisons and distasteful substances, for example capsaicin in chili peppers and pungent sulfur compounds in garlic and onions. Most animal poisons are not synthesised by the animal, but acquired by eating poisonous plants to which the animal is immune, or by bacterial action.
Alkaloids
Ciguatera poisoning
Grayanotoxin (honey intoxication)
Hormones from the thyroid glands of slaughtered animals (especially Triiodothyronine in cases of hamburger thyrotoxicosis or alimentary thyrotoxicosis)
Mushroom toxins
Phytohaemagglutinin (red kidney bean poisoning; destroyed by boiling)
Pyrrolizidine alkaloids
Shellfish toxin, including paralytic shellfish poisoning, diarrhetic shellfish poisoning, neurotoxic shellfish poisoning, amnesic shellfish poisoning and ciguatera fish poisoning
Scombrotoxin
Tetrodotoxin (fugu fish poisoning)Some plants contain substances which are toxic in large doses, but have therapeutic properties in appropriate dosages.

Foxglove contains cardiac glycosides.
Poisonous hemlock (conium) has medicinal uses.

Other pathogenic agents
Prions, resulting in Creutzfeldt–Jakob disease (CJD) and its variant (vCJD)

"Ptomaine poisoning"
Ptomaine poisoning was a myth that persisted in the public consciousness, in newspaper headlines, and legal cases as an official diagnosis, decades after it had been disproven scientifically in the 1910s.In the 19th century, the Italian chemist Francesco Selmi, of Bologna, introduced the generic name ptomaine (from Greek ptōma,  "fall, fallen body, corpse") for alkaloids found in decaying animal and vegetable matter, especially (as reflected in their names) putrescine and cadaverine.  The 1892 Mercks Bulletin stated, "We name such products of bacterial origin ptomaines; and the special alkaloid produced by the comma bacillus is variously named Cadaverine, Putrescine, etc." While The Lancet stated, "The chemical ferments produced in the system, the... ptomaines which may exercise so disastrous an influence." It is now known that the "disastrous... influence" is due to the direct action of bacteria and only slightly due to the alkaloids. Thus, the use of the phrase "ptomaine poisoning" is now obsolete.
Tainted potato salad sickening hundreds at a Communist political convention in Massillon, Ohio, and aboard a Washington DC cruise boat in separate incidents during a single week in 1932 drew national attention to the dangers of so-called "ptomaine poisoning" in the pages of the American news weekly, Time.
Another newspaper article from 1944 told of more than 150 persons being hospitalized in Chicago with ptomaine poisoning apparently from rice pudding served by a chain of restaurants.

Mechanism
Incubation period
The delay between the consumption of contaminated food and the appearance of the first symptoms of illness is called the incubation period. This ranges from hours to days (and rarely months or even years, such as in the case of listeriosis or bovine spongiform encephalopathy), depending on the agent, and on how much was consumed. If symptoms occur within one to six hours after eating the food, it suggests that it is caused by a bacterial toxin or a chemical rather than live bacteria.
The long incubation period of many foodborne illnesses tends to cause those affected to attribute their symptoms to gastroenteritis.During the incubation period, microbes pass through the stomach into the intestine, attach to the cells lining the intestinal walls, and begin to multiply there. Some types of microbes stay in the intestine, some produce a toxin that is absorbed into the bloodstream, and some can directly invade the deeper body tissues. The symptoms produced depend on the type of microbe.

Infectious dose
The infectious dose is the amount of agent that must be consumed to give rise to symptoms of foodborne illness, and varies according to the agent and the consumers age and overall health. Pathogens vary in minimum infectious dose; for example, Shigella sonnei has a low estimated minimum dose of < 500 colony-forming units (CFU) while Staphylococcus aureus has a relatively high estimate.In the case of Salmonella a relatively large inoculum of 1 million to 1 billion organisms is necessary to produce symptoms in healthy human volunteers, as Salmonellae are very sensitive to acid. An unusually high stomach pH level (low acidity) greatly reduces the number of bacteria required to cause symptoms by a factor of between 10 and 100.

Gut microbiota unaccustomed to endemic organisms
Foodborne illness often occurs as travelers diarrhea in persons whose gut microbiota is unaccustomed to organisms endemic to the visited region. This effect of microbiologic naivete is compounded by any food safety lapses in the foods preparation.

Epidemiology
Asymptomatic subclinical infection may help spread these diseases, particularly Staphylococcus aureus, Campylobacter, Salmonella, Shigella, Enterobacter, Vibrio cholerae, and Yersinia. For example, as of 1984 it was estimated that in the United States, 200,000 people were asymptomatic carriers of Salmonella.

Infants
Globally, infants are a group that is especially vulnerable to foodborne disease. The World Health Organization has issued recommendations for the preparation, use and storage of prepared formulas. Breastfeeding remains the best preventive measure for protection from foodborne infections in infants.

United States
In the United States, using FoodNet data from 2000 to 2007, the CDC estimated there were 47.8 million foodborne illnesses per year (16,000 cases for 100,000 inhabitants) with 9.4 million of these caused by 31 known identified pathogens.
127,839 were hospitalized (43 per 100,000 inhabitants per year).
3,037 people died (1.0 per 100,000 inhabitants per year).

United Kingdom
According to a 2012 report from the Food Standards Agency, there were around a million cases of foodborne illness per year (1,580 cases for 100,000 inhabitants).
20,000 were hospitalized (32 per 100,000 inhabitants);
500 people died (0.80 per 100,000 inhabitants).

France
This data pertains to reported medical cases of 23 specific pathogens in the 1990s, as opposed to total population estimates of all foodborne illness for the United States.In France, for 750,000 cases (1,210 per 100,000 inhabitants):
70,000 people consulted in the emergency department of a hospital (113 per 100,000 inhabitants);
113,000 people were hospitalized (182 per 100,000 inhabitants);
460 people died (0.75 per 100,000 inhabitants).

Australia
A study by the Australian National University, published in November 2014, found in 2010 that there were an estimated 4.1 million cases of foodborne gastroenteritis acquired in Australia on average each year, along with 5,140 cases of non-gastrointestinal illness. The study was funded by the Australian Department of Health, Food Standards Australia New Zealand and the NSW Food Authority.The main causes were Norovirus, pathogenic Escherichia coli, Campylobacter spp. and non-typhoidal Salmonella spp., although the causes of approximately 80% of illnesses were unknown. Approximately 25% (90% CrI: 13%–42%) of the 15.9 million episodes of gastroenteritis that occur in Australia were estimated to be transmitted by contaminated food. This equates to an average of approximately one episode of foodborne gastroenteritis every five years per person. Data on the number of hospitalisations and deaths represent the occurrence of serious foodborne illness. Including gastroenteritis, non-gastroenteritis and sequelae, there were an estimated annual 31,920 (90% CrI: 29,500–35,500) hospitalisations due to foodborne illness and 86 (90% CrI: 70–105) deaths due to foodborne illness circa 2010. This study concludes that these rates are similar to recent estimates in the US and Canada.A main aim of this study was to compare if foodborne illness incidence had increased over time. In this study, similar methods of assessment were applied to data from circa 2000, which showed that the rate of foodborne gastroenteritis had not changed significantly over time. Two key estimates were the total number of gastroenteritis episodes each year, and the proportion considered foodborne. In circa 2010, it was estimated that 25% of all episodes of gastroenteritis were foodborne. By applying this proportion of episodes due to food to the incidence of gastroenteritis circa 2000, there were an estimated 4.3 million (90% CrI: 2.2–7.3 million) episodes of foodborne gastroenteritis circa 2000, although credible intervals overlap with 2010. Taking into account changes in population size, applying these equivalent methods suggests a 17% decrease in the rate of foodborne gastroenteritis between 2000 and 2010, with considerable overlap of the 90% credible intervals.This study replaces a previous estimate of 5.4 million cases of foodborne illness in Australia every year, causing:
18,000 hospitalizations
120 deaths (0.5 deaths per 100,000 inhabitants)
2.1 million lost days off work
1.2 million doctor consultations
300,000 prescriptions for antibiotics.Most foodborne disease outbreaks in Australia have been linked to raw or minimally cooked eggs or poultry. The Australian Food Safety Information Council estimates that one third of cases of food poisoning occur in the home.

Comparison between countries
Outbreaks
The vast majority of reported cases of foodborne illness occur as individual or sporadic cases. The origin of most sporadic cases is undetermined. In the United States, where people eat outside the home frequently, 58% of cases originate from commercial food facilities (2004 FoodNet data). An outbreak is defined as occurring when two or more people experience similar illness after consuming food from a common source.Often, a combination of events contributes to an outbreak, for example, food might be left at room temperature for many hours, allowing bacteria to multiply which is compounded by inadequate cooking which results in a failure to kill the dangerously elevated bacterial levels.Outbreaks are usually identified when those affected know each other. Outbreaks can also be identified by public health staff when there are unexpected increases in laboratory results for certain strains of bacteria. Outbreak detection and investigation in the United States is primarily handled by local health jurisdictions and is inconsistent from district to district. It is estimated that 1–2% of outbreaks are detected.

Society and culture
United Kingdom
In postwar Aberdeen (1964) a large-scale (>400 cases) outbreak of typhoid occurred, caused by contaminated corned beef which had been imported from Argentina. The corned beef was placed in cans and because the cooling plant had failed, cold river water from the Plate estuary was used to cool the cans. One of the cans had a defect and the meat inside was contaminated. This meat was then sliced using a meat slicer in a shop in Aberdeen, and a lack of cleaning the machinery led to spreading the contamination to other meats cut in the slicer. These meats were then eaten by the people of Aberdeen who then became ill.Serious outbreaks of foodborne illness since the 1970s prompted key changes in UK food safety law. These included the death of 19 patients in the Stanley Royd Hospital outbreak and the bovine spongiform encephalopathy (BSE, mad cow disease) outbreak identified in the 1980s. The death of 21 people in the 1996 Wishaw outbreak of E. coli O157 was a precursor to the establishment of the Food Standards Agency which, according to Tony Blair in the 1998 white paper A Force for Change Cm 3830, "would be powerful, open and dedicated to the interests of consumers".In May 2015, for the second year running, Englands Food Standards Agency devoted its annual Food Safety Week to – "The Chicken Challenge". The focus was on the handling of raw chicken in the home and in catering facilities in a drive to reduce the high levels of food poisoning from the campylobacter bacterium. Anne Hardy argues that widespread public education of food hygiene can be useful, particularly through media (TV cookery programmes) and advertisement. She points to the examples set by Scandinavian societies.

United States
In 2001, the Center for Science in the Public Interest petitioned the United States Department of Agriculture to require meat packers to remove spinal cords before processing cattle carcasses for human consumption, a measure designed to lessen the risk of infection by variant Creutzfeldt–Jakob disease. The petition was supported by the American Public Health Association, the Consumer Federation of America, the Government Accountability Project, the National Consumers League, and Safe Tables Our Priority.None of the US Department of Health and Human Services targets regarding incidence of foodborne infections were reached in 2007.A report issued in June 2018 by NBCs Minneapolis station using research by both the CDC and the Minnesota Department of Health concluded that foodborne illness is on the rise in the U.S.

Organizations
The World Health Organization Department of Food Safety and Zoonoses (FOS) provides scientific advice for organizations and the public on issues concerning the safety of food. Its mission is to lower the burden of foodborne disease, thereby strengthening the health security and sustainable development of Member States. Foodborne and waterborne diarrhoeal diseases kill an estimated 2.2 million people annually, most of whom are children. WHO works closely with the Food and Agriculture Organization of the United Nations (FAO) to address food safety issues along the entire food production chain—from production to consumption—using new methods of risk analysis. These methods provide efficient, science-based tools to improve food safety, thereby benefiting both public health and economic development.

International Food Safety Authorities Network (INFOSAN)
The International Food Safety Authorities Network (INFOSAN) is a joint program of the WHO and FAO. INFOSAN has been connecting national authorities from around the globe since 2004, with the goal of preventing the international spread of contaminated food and foodborne disease and strengthening food safety systems globally. This is done by:
Promoting the rapid exchange of information during food safety events;
Sharing information on important food safety issues of global interest;
Promoting partnership and collaboration between countries; and
Helping countries strengthen their capacity to manage food safety risks.Membership to INFOSAN is voluntary, but is restricted to representatives from national and regional government authorities and requires an official letter of designation. INFOSAN seeks to reflect the multidisciplinary nature of food safety and promote intersectoral collaboration by requesting the designation of Focal Points in each of the respective national authorities with a stake in food safety, and a single Emergency Contact Point in the national authority with the responsibility for coordinating national food safety emergencies; countries choosing to be members of INFOSAN are committed to sharing information between their respective food safety authorities and other INFOSAN members. The operational definition of a food safety authority includes those authorities involved in: food policy; risk assessment; food control and management; food inspection services; foodborne disease surveillance and response; laboratory services for monitoring and surveillance of foods and foodborne diseases; and food safety information, education and communication across the farm-to-table continuum.

Prioritisation of foodborne pathogens
The Food and Agriculture Organization of the United Nations and The World Health Organization have published a global ranking of foodborne parasites using a multicriteria ranking tool concluding that Taenia solium was the most relevant, followed by Echinococcus granulosus, Echinococcus multilocularis, and Toxoplasma gondii. The same method was used regionally to rank the most important foodborne parasites in Europe ranking Echinococcus multilocularis of highest relevance, followed by Toxoplasma gondii and Trichinella spiralis.

Regulatory steps
Food may be contaminated during all stages of food production and retailing. In order to prevent viral contamination, regulatory authorities in Europe have enacted several measures:
European Commission Regulation (EC) No 2073/2005 of November 15, 2005
European Committee for Standardization (CEN): Standard method for the detection of norovirus and hepatitis A virus in food products (shellfish, fruits and vegetables, surfaces and bottled water)
CODEX Committee on Food Hygiene (CCFH): Guideline for the application of general principles of food hygiene for the control of viruses in food

See also
References
This article incorporates public domain material from websites or documents of the Centers for Disease Control and Prevention.

Further reading
Periodicals
International Journal of Food Microbiology, ISSN 0168-1605, Elsevier
Foodborne Pathogens and Disease, ISSN 1535-3141, Mary Ann Liebert, Inc.
Mycopathologia, ISSN 1573-0832 (electronic), ISSN 0301-486X (paper), Springer

Books
Hocking AD, Pitt JI, Samson RA, Thrane U (2005). Advances in Food Mycology. Springer. ISBN 978-0-387-28385-2. ISBN 978-0-387-28391-3 (electronic).
Hobbs BC (1993). Food Poisoning and Food Hygiene. British Medical Bulletin. Vol. 7. Edward Arnold. pp. 167–70 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Primary ovarian insufficiency and can you explain it in depth? [/INST] Primary ovarian insufficiency (POI) (also called premature ovarian insufficiency, premature menopause, and premature ovarian failure) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of folliclular (egg producing area) dysfunction or early loss of eggs. POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. A medical triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism.Physical and emotional symptoms include hot flashes, night sweats, dry skin, vaginal dryness, irregular or absent menstruation, anxiety, depression, mental fog, irritability, nervousness, decreased libido, and increased autoimmune disruption. The sense of  shock and distress on being informed of the diagnosis can be overwhelming. The general treatment is for symptoms, bone protection, and mental health. Although 5 to 10% of women with POI may ovulate sporadically and become pregnant without treatment, others may use assisted reproductive technology including in vitro fertilization and egg donation or decide to adopt or remain childless.The causes of POI are heterogeneous and are unknown in 90% of cases. It can be associated with genetic causes, autoimmune disease, enzyme deficiency, infection, environmental factors, radiation, or surgery in 10%. Two to 5% of women with POI and a premutation in FMR1, a genetic abnormality, are at risk of having a child with fragile X syndrome, the most common cause of inherited intellectual disability.The diagnosis is based on ages less than 40, amenorrhea, and  elevated serum follicle-stimulating hormone (FSH) levels. Typical serum FSH levels in POI patients is in the post-menopausal range. Treatment will vary depending on the symptoms. It can include hormone replacement therapy, fertility management, and psychosocial support, as well as annual screenings of thyroid and adrenal function.

Signs and symptoms
The signs and symptoms of POI can be seen as part of a continuum of changes leading to menopause. POI contrasts with age-appropriate menopause in the age of onset, degree of symptoms and sporadic return to normal ovarian function. As some women retain partial ovarian function, symptoms may not be as severe as regular menopause. In others, particularly with coexistent depression, symptoms such as decreased quality of life can be severe.Hormonally, POI is defined by abnormally low levels of estrogen and high levels of FSH, which demonstrate that the ovaries are no longer responding to circulating FSH by producing estrogen and developing fertile eggs. The ovaries will likely appear smaller than normal. The age of onset can be as early as 11 years. POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. A contrasting problem can be when a girl never begins menstruation due to a genetic condition causing primary amenorrhea.

Causes
The cause of POI is idiopathic in 90% of cases. Some cases of POI are attributed to autoimmune disorders such as autoimmune oophoritis, Hashimoto thyroiditis, Addison disease, type I diabetes mellitus, pernicious anemia, genetic disorders such as Turner syndrome and Fragile X syndrome, metabolic defects, and enzyme defects. One study showed a strong correlation between incidence of POI and certain variants in the inhibin alpha gene. Chemotherapy and radiation treatments for cancer can sometimes cause POI. The effect of chemotherapy or radiation is variable and in a mouse model, with results consistent with observations in humans, cyclophosphamide can result in an 87% reduction in primordial follicles 72 hours after administration.  Women who have had a hysterectomy tend to go through menopause early and have a nearly twofold increased risk of POI. Almost any pelvic surgery has the potential to damage the ovary by affecting its blood supply or causing inflammation in the area resulting in POI.

Galactosemia
Women who have inherited classic galactosemia (galactose intolerance) may develop primary ovarian insufficiency.

Mechanism
The pathogenic mechanisms of POI are highly heterogeneous and can be divided into four major categories: follicular migration defect early in embryogenesis; an early decrease in the primordial follicles; increased follicular death; and altered maturation or recruitment of primordial follicles.  These result in a decrease of the ovaries general supply of eggs that normally lasts until an average age of 51 for age of age-appropriate menopause.Genetic causes such as Turner syndrome have initial ovarian development but then ovaries degenerate rapidly during prenatal life, often leading to gonadal dysgenesis with streak ovaries. In those cases where POI is associated with adrenal autoimmunity, histological examination almost always confirms the presence of an autoimmune oophoritis in which follicles are infiltrated by lymphocytes, plasma cells, and macrophages that attack mainly steroid-producing cells and eventually result in follicular depletion.In some women FSH may bind to the FSH receptor site, but be inactive. By lowering the endogenous FSH levels with ethinylestradiol (EE) or with a GnRH-a the receptor sites are free and treatment with exogenous recombinant FSH activates the receptors and normal follicle growth and ovulation can occur. (Since the serum Anti-Müllerian hormone (AMH) level is correlated with the number of remaining primordial follicles some researchers believe the above two phenotypes can be distinguished by measuring serum AMH levels.Genetic associations include genetic disorders, autoimmune diseases, enzyme defects, and resistant ovaries.Mutations in FOXL2 cause Blepharophimosis Ptosis Epicanthus inversus Syndrome (BPES). Premature ovarian failure is part of the BPES Type I variant of the syndrome but not of the BPES Type II variant.

DNA repair deficiency
BRCA1 protein plays an essential role in the repair of DNA double-strand breaks by homologous recombination. Women with a germline BRCA1 mutation tend to have premature menopause as evidenced by the final menorrhea appearing at a younger age. BRCA1 mutations are associated with occult POI. Impairment of the repair of DNA double-strand breaks due to a BRCA1 defect leads to premature ovarian aging in both mice and humans.In addition to BRCA1, the MCM8-MCM9 protein complex also plays a crucial role in the recombinational repair of DNA double-strand breaks. In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability. MCM9, as well as MCM8, mutations are also associated with ovarian failure and chromosomal instability. The MCM8-MCM9 complex is likely required for the homologous recombinational repair of DNA double-strand breaks that are present during the pachytene stage of meiosis I. In women homozygous for MCM8 or MCM9 mutations, failure to repair breaks apparently leads to oocyte death and small or absent ovaries.

Diagnosis
The diagnosis is based on age less than forty, amenorrhea for four months or more, and two elevated serum follicle-stimulating hormone (FSH) measurements at one-month intervals. The anterior pituitary secretes FSH and LH at high levels to try to increase the low estrogen levels that are due to the dysfunction of the ovaries. Typical FSH in POI patients is over 40 mlU/ml (post-menopausal range).

Treatment
Fertility
Between 5 and 10 percent of women with POI may become pregnant with no treatment. As of 2016 no fertility treatment has been found to effectively increase fertility in women with POI, and the use of donor eggs with in-vitro fertilization (IVF) and adoption are a means of achieving parenthood for women with POI. Some women with POI choose to live child-free.Researchers have investigated the use of a hormone called dehydroepiandrosterone (DHEA) in women with POI to increase spontaneous pregnancy rates. Results from studies on DHEA in 2010 indicated that DHEA may increase spontaneously conceived pregnancies, decrease spontaneous miscarriage rates and improve IVF success rates in women with POI. This includes women referred for donor eggs or surrogacy in 2009. In 2018, there was no significant improvement in ovarian function by 12-month on DHEA supplementation in women with POI. Given the inconclusiveness of potential benefits and risks of testosterone and DHEA supplementation, longer-term, randomized studies are warranted for women and girls with POI.Ovarian tissue cryopreservation can be performed on prepubertal girls at risk for premature ovarian failure, and this procedure is as feasible and safe as comparable operative procedures in children.In 2013, Kawamura in Japan and his collaborators at Stanford University published treatment of infertility of POI patients by fragmenting ovaries followed by in vitro treatment of ovarian fragments with phosphatidylinositol-3 kinase activators to enhance the AKT pathway followed by autografting. They successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. A  2020 review covered variations including phosphatidylinositol-3 kinase activators to enhance the AKT pathway, fragmentation of ovarian cortex, combining those two into in-vitro activation (IVA), and drug-free IVA. Two laparoscopies are needed in conventional IVA and one with drug-free IVA.

Hormonal replacement
Women with POI can develop symptoms of estrogen deficiency, including vasomotor flushes and vaginal dryness that respond to physiologic replacement of hormones. Most authorities recommend that this hormone replacement continue until age 50 years, the normal age of menopause. The leading hormone replacement regimen recommended involves the administration of estradiol daily by either skin patch or vaginal ring. This approach reduces the risk of pulmonary embolism and deep venous thrombosis by avoiding the first pass effect on the liver that is induced by oral estrogen therapy.  The transdermal estradiol patch also provides the replacement by steady infusion rather than by bolus when taking daily pills.Concerns of estrogen supplement are addressed in The US Medical Eligibility Criteria for Contraceptive Use, 2010 provides guidance for safety of contraceptive methods and include guidance for conditions associated with increased risk of thrombosis such as postpartum, history of thrombosis, thrombogenic mutations, systemic lupus erythematosus, diabetes, and hypertension. There is also an increased risk with valvular heart disease and cardiomyopathy.To avoid the development of endometrial cancer young women taking estradiol replacement need also to take a progestin in a regular cyclic fashion. The most evidence supports the use of medroxyprogesterone acetate per day for days one through 12 of each calendar month. This will induce regular and predictable menstrual cycles. It is important that women taking this regimen keep a menstrual calendar. If the next expected menses is late it is important to get a pregnancy test. It this is positive, the woman should stop taking the hormone replacement. Approximately 5 to 10% of women with confirmed POI conceive a pregnancy after the diagnosis without medical intervention.

Prognosis
Infertility can be a result of this condition and is the most discussed problem resulting from it, but there are additional health implications of the problem, and studies are ongoing. For example, osteoporosis (decreased bone density) affects almost all women with POI due to an insufficiency of estrogen. There is also an increased risk of heart disease, hypothyroidism such as Hashimotos thyroiditis, Addisons disease, and other autoimmune disorders.

Emotional health
The most common words women use to describe how they felt in the two hours after being given the diagnosis of POI are "devastated", "shocked," and "confused."  The diagnosis is more than infertility and affects a womans physical and emotional well-being. Patients face the acute shock of the diagnosis, associated stigma of infertility, grief from the death of dreams, anxiety and depression from the disruption of life plans, confusion around the cause, shame, insecurity and lowered self-esteem, anger in reflection of being letdown by the medical system, symptoms of estrogen deficiency, worry over the associated potential medical sequelae such as reduced bone density and cardiovascular risk, and the uncertain future that all of these factors create </s>