<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 Chancroid and can you explain it in depth? [/INST] Chancroid ( SHANG-kroyd) is a bacterial sexually transmitted infection characterized by painful sores on the genitalia. Chancroid is known to spread from one individual to another solely through sexual contact. However, there have been reports of accidental infection through another route which is by the hand. While uncommon in the western world, it is the most common cause of genital ulceration worldwide.

Signs and symptoms
These are only local and no systemic manifestations are present.
The ulcer characteristically:

Ranges in size dramatically from 3 to 50 mm (1/8 inch to 2 inches) across
Is painful
Has sharply defined, undermined borders
Has irregular or ragged borders, described as saucer-shaped.
Has a base that is covered with a gray or yellowish-gray material
Has a base that bleeds easily if traumatized or scraped
Painful swollen lymph nodes occur in 30–60% of patients.
Dysuria (pain with urination) and dyspareunia (pain with intercourse) in femalesAbout half of infected men have only a single ulcer. Women frequently have four or more ulcers, with fewer symptoms. The ulcers are typically confined to the genital region most of the time.
The initial ulcer may be mistaken as a "hard" chancre, the typical sore of primary syphilis, as opposed to the "soft chancre" of chancroid.Approximately one-third of the infected individuals will develop enlargements of the inguinal lymph nodes, the nodes located in the fold between the leg and the lower abdomen.Half of those who develop swelling of the inguinal lymph nodes will progress to a point where the nodes rupture through the skin, producing draining abscesses. The swollen lymph nodes and abscesses are often referred to as buboes.

Complications
Extensive lymph node inflammation may develop.
Large inguinal abscesses may develop and rupture to form draining sinus or giant ulcer.
Superinfection by Fusarium and Bacteroides. These later require debridement and may result in disfiguring scars.
Phimosis can develop in long-standing lesion by scarring and thickening of foreskin, which may subsequently require circumcision.

Sites For Chancroid Lesions
Males
Internal and external surface of prepuce.
Coronal sulcus
Frenulum
Shaft of penis
Prepucial orifice
Urethral meatus
Glans penis
Perineum area

Females
Labia majora is most common site. "Kissing ulcers" may develop. These are ulcers that occur on opposing surfaces of the labia.
Labia minora
Fourchette
Vestibule
Clitoris
Perineal area
Inner thighs

Causes
Chancroid is a bacterial infection caused by the fastidious Gram-negative streptobacillus Haemophilus ducreyi. This pathogen is highly infectious. It is a disease found primarily in developing countries, most prevalent in low socioeconomic groups, associated with commercial sex workers.Chancroid, caused by H. ducreyi has infrequently been associated with cases of Genital Ulcer Disease in the US but has been isolated in up to 10% of genital ulcers diagnosed from STD clinics in Memphis and Chicago.Infection levels are very low in the Western world, typically around one case per two million of the population (Canada, France, Australia, UK and US). Most individuals diagnosed with chancroid have visited countries or areas where the disease is known to occur frequently, although outbreaks have been observed in association with crack cocaine use and prostitution.Chancroid is a risk factor for contracting HIV, due to their ecological association or shared risk of exposure, and biologically facilitated transmission of one infection by the other. Approximately 10% of people with chancroid will have a co-infection with syphilis and/or HIV.

Pathogenesis
H. ducreyi enters skin through microabrasions incurred during sexual intercourse. The incubation period of H. ducreyi infection is 10 to 14 days after which there is progression of the disease. A local tissue reaction leads to development of erythomatous papule, which progresses to pustule in 4–7 days. It then undergoes central necrosis to ulcerate.

Diagnosis
Variants
Some of clinical variants are as follows.

Laboratory findings
From bubo pus or ulcer secretions, H. ducreyi can be identified using special culture media; however, there is a <80% sensitivity. PCR-based identification of the organisms is available, but none in the United States are FDA-cleared. Simple, rapid, sensitive and inexpensive antigen detection methods for H. ducreyi identification are also popular. Serologic detection of H. ducreyi uses outer membrane protein and lipooligosaccharide. Most of the time, the diagnosis is based on presumptive approach using the symptomatology which in this case includes multiple painful genital ulcers.

Differential diagnosis
Despite many distinguishing features, the clinical spectrums of following diseases may overlap with chancroid:
Primary syphilis
Genital herpesPractical clinical approach for this STI as Genital Ulcer Disease is to rule out top differential diagnosis of Syphilis and Herpes and consider empirical treatment for Chancroid as testing is not commonly done for the latter.

Comparison with syphilis
There are many differences and similarities between the conditions syphilitic chancre and chancroid:
SimilaritiesBoth originate as pustules at the site of inoculation, and progress to ulcerated lesions
Both lesions are typically 1–2 cm in diameter
Both lesions are caused by sexually transmissible organisms
Both lesions typically appear on the genitals of infected individuals
Both lesions can be present at multiple sites and with multiple lesionsDifferencesChancre is a lesion typical of infection with the bacterium that causes syphilis, Treponema pallidum
Chancroid is a lesion typical of infection with the bacterium Haemophilus ducreyi
Chancres are typically painless, whereas chancroid are typically painful
Chancres are typically non-exudative, whereas chancroid typically have a grey or yellow purulent exudate
Chancres have a hard (indurated) edge, whereas chancroid have a soft edge
Chancres heal spontaneously within three to six weeks, even in the absence of treatment
Chancres can occur in the pharynx as well as on the genitals

Prevention
Chancroid spreads in populations with high sexual activity, such as prostitutes. Use of condom, prophylaxis by azithromycin, syndromic management of genital ulcers, treating patients with reactive syphilis serology are some of the strategies successfully tried in Thailand. Also, treatment of sexual partners is advocated whether they develop symptoms or not as long as there was unprotected sexual intercourse with the patient within 10 days of developing the symptoms.

Treatment
For the initial stages of the lesion, cleaning with soapy solution is recommended and sitz bath may be beneficial. Fluctuant nodules may require aspiration. Treatment may include more than one prescribed medication.

Antibiotics
Macrolides are often used to treat chancroid. The CDC recommendation is either a single oral dose (1 gram) of azithromycin, a single IM dose (250 mg) of ceftriaxone, oral (500 mg) of erythromycin three times a day for seven days, or oral (500 mg) of ciprofloxacin twice a day for three days. Due to a paucity of reliable empirical evidence it is not clear whether macrolides are actually more effective and/or better tolerated than other antibiotics when treating chancroid </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 Cholangiocarcinoma and can you explain it in depth? [/INST] Cholangiocarcinoma, also known as bile duct cancer, is a type of cancer that forms in the bile ducts. Symptoms of cholangiocarcinoma may include abdominal pain, yellowish skin, weight loss, generalized itching, and fever. Light colored stool or dark urine may also occur. Other biliary tract cancers include gallbladder cancer and cancer of the ampulla of Vater.Risk factors for cholangiocarcinoma include primary sclerosing cholangitis (an inflammatory disease of the bile ducts), ulcerative colitis, cirrhosis, hepatitis C, hepatitis B, infection with certain liver flukes, and some congenital liver malformations. However, most people have no identifiable risk factors. The diagnosis is suspected based on a combination of blood tests, medical imaging, endoscopy, and sometimes surgical exploration. The disease is confirmed by examination of cells from the tumor under a microscope. It is typically an adenocarcinoma (a cancer that forms glands or secretes mucin).Cholangiocarcinoma is typically incurable at diagnosis which is why early detection is ideal. In these cases palliative treatments may include surgical resection, chemotherapy, radiation therapy, and stenting procedures. In about a third of cases involving the common bile duct and less commonly with other locations the tumor can be completely removed by surgery offering a chance of a cure. Even when surgical removal is successful chemotherapy and radiation therapy are generally recommended. In certain cases surgery may include a liver transplantation. Even when surgery is successful the 5-year survival is typically less than 50%.Cholangiocarcinoma is rare in the Western world, with estimates of it occurring in 0.5–2 people per 100,000 per year. Rates are higher in Southeast Asia where liver flukes are common. Rates in parts of Thailand are 60 per 100,000 per year. It typically occurs in people in their 70s; however, in those with primary sclerosing cholangitis it often occurs in the 40s. Rates of cholangiocarcinoma within the liver in the Western world have increased.

Signs and symptoms
The most common physical indications of cholangiocarcinoma are abnormal liver function tests, jaundice (yellowing of the eyes and skin occurring when bile ducts are blocked by tumor), abdominal pain (30–50%), generalized itching (66%), weight loss (30–50%), fever (up to 20%), and changes in the color of stool or urine. To some extent, the symptoms depend upon the location of the tumor: people with cholangiocarcinoma in the extrahepatic bile ducts (outside the liver) are more likely to have jaundice, while those with tumors of the bile ducts within the liver more often have pain without jaundice.Blood tests of liver function in people with cholangiocarcinoma often reveal a so-called "obstructive picture", with elevated bilirubin, alkaline phosphatase, and gamma glutamyl transferase levels, and relatively normal transaminase levels. Such laboratory findings suggest obstruction of the bile ducts, rather than inflammation or infection of the liver parenchyma, as the primary cause of the jaundice.

Risk factors
Although most people present without any known risk factors evident, a number of risk factors for the development of cholangiocarcinoma have been described. In the Western world, the most common of these is primary sclerosing cholangitis (PSC), an inflammatory disease of the bile ducts which is closely associated with ulcerative colitis (UC). Epidemiologic studies have suggested that the lifetime risk of developing cholangiocarcinoma for a person with PSC is on the order of 10–15%, although autopsy series have found rates as high as 30% in this population.  For inflammatory bowel disease patients with altered DNA repair functions, the progression from PSC to cholangiocarcinoma may be a consequence of DNA damage resulting from biliary inflammation and bile acids.Certain parasitic liver diseases may be risk factors as well. Colonization with the liver flukes Opisthorchis viverrini (found in Thailand, Laos PDR, and Vietnam) or Clonorchis sinensis (found in China, Taiwan, eastern Russia, Korea, and Vietnam) has been associated with the development of cholangiocarcinoma. Control programs (Integrated Opisthorchiasis Control Program) aimed at discouraging the consumption of raw and undercooked food have been successful at reducing the incidence of cholangiocarcinoma in some countries. People with chronic liver disease, whether in the form of viral hepatitis (e.g. hepatitis B or hepatitis C), alcoholic liver disease, or cirrhosis of the liver due to other causes, are at significantly increased risk of cholangiocarcinoma. HIV infection was also identified in one study as a potential risk factor for cholangiocarcinoma, although it was unclear whether HIV itself or other correlated and confounding factors (e.g. hepatitis C infection) were responsible for the association.Infection with the bacteria Helicobacter bilis and Helicobacter hepaticus species can cause biliary cancer.Congenital liver abnormalities, such as Caroli disease (a specific type of five recognized choledochal cysts), have been associated with an approximately 15% lifetime risk of developing cholangiocarcinoma. The rare inherited disorders Lynch syndrome II and biliary papillomatosis have also been found to be associated with cholangiocarcinoma. The presence of gallstones (cholelithiasis) is not clearly associated with cholangiocarcinoma. However, intrahepatic stones (called hepatolithiasis), which are rare in the West but common in parts of Asia, have been strongly associated with cholangiocarcinoma. Exposure to Thorotrast, a form of thorium dioxide which was used as a radiologic contrast medium, has been linked to the development of cholangiocarcinoma as late as 30–40 years after exposure; Thorotrast was banned in the United States in the 1950s due to its carcinogenicity.

Pathophysiology
Cholangiocarcinoma can affect any area of the bile ducts, either within or outside the liver. Tumors occurring in the bile ducts within the liver are referred to as intrahepatic, those occurring in the ducts outside the liver are extrahepatic, and tumors occurring at the site where the bile ducts exit the liver may be referred to as perihilar. A cholangiocarcinoma occurring at the junction where the left and right hepatic ducts meet to form the common hepatic duct may be referred to eponymously as a Klatskin tumor.Although cholangiocarcinoma is known to have the histological and molecular features of an adenocarcinoma of epithelial cells lining the biliary tract, the actual cell of origin is unknown. Recent evidence has suggested that the initial transformed cell that generates the primary tumor may arise from a pluripotent hepatic stem cell. Cholangiocarcinoma is thought to develop through a series of stages – from early hyperplasia and metaplasia, through dysplasia, to the development of frank carcinoma – in a process similar to that seen in the development of colon cancer. Chronic inflammation and obstruction of the bile ducts, and the resulting impaired bile flow, are thought to play a role in this progression.Histologically, cholangiocarcinomas may vary from undifferentiated to well-differentiated. They are often surrounded by a brisk fibrotic or desmoplastic tissue response; in the presence of extensive fibrosis, it can be difficult to distinguish well-differentiated cholangiocarcinoma from normal reactive epithelium. There is no entirely specific immunohistochemical stain that can distinguish malignant from benign biliary ductal tissue, although staining for cytokeratins, carcinoembryonic antigen, and mucins may aid in diagnosis. Most tumors (>90%) are adenocarcinomas.

Diagnosis
Blood tests
There are no specific blood tests that can diagnose cholangiocarcinoma by themselves. Serum levels of carcinoembryonic antigen (CEA) and CA19-9 are often elevated, but are not sensitive or specific enough to be used as a general screening tool. However, they may be useful in conjunction with imaging methods in supporting a suspected diagnosis of cholangiocarcinoma.

Abdominal imaging
Ultrasound of the liver and biliary tree is often used as the initial imaging modality in people with suspected obstructive jaundice. Ultrasound can identify obstruction and ductal dilatation and, in some cases, may be sufficient to diagnose cholangiocarcinoma. Computed tomography (CT) scanning may also play an important role in the diagnosis of cholangiocarcinoma.

Imaging of the biliary tree
While abdominal imaging can be useful in the diagnosis of cholangiocarcinoma, direct imaging of the bile ducts is often necessary. Endoscopic retrograde cholangiopancreatography (ERCP), an endoscopic procedure performed by a gastroenterologist or specially trained surgeon, has been widely used for this purpose. Although ERCP is an invasive procedure with attendant risks, its advantages include the ability to obtain biopsies and to place stents or perform other interventions to relieve biliary obstruction. Endoscopic ultrasound can also be performed at the time of ERCP and may increase the accuracy of the biopsy and yield information on lymph node invasion and operability. As an alternative to ERCP, percutaneous transhepatic cholangiography (PTC) may be utilized. Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive alternative to ERCP. Some authors have suggested that MRCP should supplant ERCP in the diagnosis of biliary cancers, as it may more accurately define the tumor and avoids the risks of ERCP.

Surgery
Surgical exploration may be necessary to obtain a suitable biopsy and to accurately stage a person with cholangiocarcinoma. Laparoscopy can be used for staging purposes and may avoid the need for a more invasive surgical procedure, such as laparotomy, in some people.

Pathology
Histologically, cholangiocarcinomas are classically well to moderately differentiated adenocarcinomas. Immunohistochemistry is useful in the diagnosis and may be used to help differentiate a cholangiocarcinoma from hepatocellular carcinoma and metastasis of other gastrointestinal tumors. Cytological scrapings are often nondiagnostic, as these tumors typically have a desmoplastic stroma and, therefore, do not release diagnostic tumor cells with scrapings.

Staging
Although there are at least three staging systems for cholangiocarcinoma (e.g. those of Bismuth, Blumgart, and the American Joint Committee on Cancer), none have been shown to be useful in predicting survival. The most important staging issue is whether the tumor can be surgically removed, or whether it is too advanced for surgical treatment to be successful. Often, this determination can only be made at the time of surgery.General guidelines for operability include:
Absence of lymph node or liver metastases
Absence of involvement of the portal vein
Absence of direct invasion of adjacent organs
Absence of widespread metastatic disease

Treatment
Cholangiocarcinoma is considered to be an incurable and rapidly lethal disease unless all the tumors can be fully resected (cut out surgically). Since the operability of the tumor can only be assessed during surgery in most cases, a majority of people undergo exploratory surgery unless there is already a clear indication that the tumor is inoperable. However, the Mayo Clinic has reported significant success treating early bile duct cancer with liver transplantation using a protocolized approach and strict selection criteria.Adjuvant therapy followed by liver transplantation may have a role in treatment of certain unresectable cases. Locoregional therapies including transarterial chemoembolization (TACE), transarterial radioembolization (TARE) and ablation therapies have a role in intrahepatic variants of cholangiocarcinoma to provide palliation or potential cure in people who are not surgical candidates.

Adjuvant chemotherapy and radiation therapy
If the tumor can be removed surgically, people may receive adjuvant chemotherapy or radiation therapy after the operation to improve the chances of cure. If the tissue margins are negative (i.e. the tumor has been totally excised), adjuvant therapy is of uncertain benefit. Both positive and negative results have been reported with adjuvant radiation therapy in this setting, and no prospective randomized controlled trials have been conducted as of March 2007. Adjuvant chemotherapy appears to be ineffective in people with completely resected tumors. The role of combined chemoradiotherapy in this setting is unclear. However, if the tumor tissue margins are positive, indicating that the tumor was not completely removed via surgery, then adjuvant therapy with radiation and possibly chemotherapy is generally recommended based on the available data.

Treatment of advanced disease
The majority of cases of cholangiocarcinoma present as inoperable (unresectable) disease in which case people are generally treated with palliative chemotherapy, with or without radiotherapy. Chemotherapy has been shown in a randomized controlled trial to improve quality of life and extend survival in people with inoperable cholangiocarcinoma. There is no single chemotherapy regimen which is universally used, and enrollment in clinical trials is often recommended when possible. Chemotherapy agents used to treat cholangiocarcinoma include 5-fluorouracil with leucovorin, gemcitabine as a single agent, or gemcitabine plus cisplatin, irinotecan, or capecitabine. A small pilot study suggested possible benefit from the tyrosine kinase inhibitor erlotinib in people with advanced cholangiocarcinoma.
Radiation therapy appears to prolong survival in people with resected extrahepatic cholangiocarcinoma, and the few reports of its use in unresectable cholangiocarcinoma appear to show improved survival, but numbers are small.Infigratinib (Truseltiq) is a tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR) that was approved for medical use in the United States in May 2021. It is indicated for the treatment of people with previously treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement.Pemigatinib (Pemazyre) is a kinase inhibitor of fibroblast growth factor receptor 2 (FGFR2) that was approved for medical use in the United States in April 2020. It is indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.
Ivodesinib (Tibsovo) is a small molecule inhibitor of isocitrate dehydrogenase 1. The FDA approved ivosidenib in August 2021 for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an isocitrate dehydrogenase-1 (IDH1) mutation as detected by an FDA-approved test.Durvalumab, (Imfinzi) is an immune checkpoint inhibitor that blocks the PD-L1 protein on the surface of immune cells, thereby allowing the immune system to recognize and attack tumor cells. In Phase III clinical trials, durvalumab, in combination with standard-of-care chemotherapy, demonstrated a statistically significant and clinically meaningful improvement in overall survival and progression-free survival versus chemotherapy alone as a 1st-line treatment for patients with advanced biliary tract cancer.

Prognosis
Surgical resection offers the only potential chance of cure in cholangiocarcinoma. For non-resectable cases, the five-year survival rate is 0% where the disease is inoperable because distal lymph nodes show metastases, and less than 5% in general. Overall mean duration of survival is less than 6 months in people with metastatic disease.For surgical cases, the odds of cure vary depending on the tumor location and whether the tumor can be completely, or only partially, removed. Distal cholangiocarcinomas (those arising from the common bile duct) are generally treated surgically with a Whipple procedure; long-term survival rates range from 15 to 25%, although one series reported a five-year survival of 54% for people with no involvement of the lymph nodes. Intrahepatic cholangiocarcinomas (those arising from the bile ducts within the liver) are usually treated with partial hepatectomy </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 Cholera and can you explain it in depth? [/INST] Cholera is an infection of the small intestine by some strains of the bacterium Vibrio cholerae. Symptoms may range from none, to mild, to severe. The classic symptom is large amounts of watery diarrhea that lasts a few days. Vomiting and muscle cramps may also occur. Diarrhea can be so severe that it leads within hours to severe dehydration and electrolyte imbalance. This may result in sunken eyes, cold skin, decreased skin elasticity, and wrinkling of the hands and feet. Dehydration can cause the skin to turn bluish. Symptoms start two hours to five days after exposure.Cholera is caused by a number of types of Vibrio cholerae, with some types producing more severe disease than others. It is spread mostly by unsafe water and unsafe food that has been contaminated with human feces containing the bacteria. Undercooked shellfish is a common source. Humans are the only known host for the bacteria. Risk factors for the disease include poor sanitation, not enough clean drinking water, and poverty. Cholera can be diagnosed by a stool test. A rapid dipstick test is available but is not as accurate.Prevention methods against cholera include improved sanitation and access to clean water. Cholera vaccines that are given by mouth provide reasonable protection for about six months. They have the added benefit of protecting against another type of diarrhea caused by E. coli. By 2017 the US Food and Drug Administration (FDA) had approved a single-dose, live, oral cholera vaccine called Vaxchora for adults aged 18–64 who are travelling to an area of active cholera transmission. It offers limited protection to young children. People who survive an episode of cholera have long-lasting immunity for at least 3 years (the period tested.)The primary treatment for affected individuals is oral rehydration salts (ORS), the replacement of fluids and electrolytes by using slightly sweet and salty solutions. Rice-based solutions are preferred. Zinc supplementation is useful in children. In severe cases, intravenous fluids, such as Ringers lactate, may be required, and antibiotics may be beneficial. Testing to see which antibiotic the cholera is susceptible to can help guide the choice.Cholera continues to affect an estimated 3–5 million people worldwide and causes 28,800–130,000 deaths a year. The most recent of seven cholera pandemics and associated outbreaks, since the early 19th century, started about 1961. As of 2010, it is rare in high income countries. Children are mostly affected. Cholera occurs as both outbreaks and chronically in certain areas. Areas with an ongoing risk of disease include Africa and Southeast Asia. The risk of death among those affected is usually less than 5%, given improved treatment, but may be as high as 50% without such access to treatment. Descriptions of cholera are found as early as the 5th century BC in Sanskrit. In Europe, cholera was a term initially used to describe any kind of gastroenteritis, and was not used for this disease until the early 19th century. The study of cholera in England by John Snow between 1849 and 1854 led to significant advances in the field of epidemiology because of his insights about transmission via contaminated water.

Signs and symptoms
The primary symptoms of cholera are profuse diarrhea and vomiting of clear fluid. These symptoms usually start suddenly, half a day to five days after ingestion of the bacteria. The diarrhea is frequently described as "rice water" in nature and may have a fishy odor. An untreated person with cholera may produce 10 to 20 litres (3 to 5 US gal) of diarrhea a day. Severe cholera, without treatment, kills about half of affected individuals. If the severe diarrhea is not treated, it can result in life-threatening dehydration and electrolyte imbalances. Estimates of the ratio of asymptomatic to symptomatic infections have ranged from 3 to 100. Cholera has been nicknamed the "blue death" because a persons skin may turn bluish-gray from extreme loss of fluids.Fever is rare and should raise suspicion for secondary infection. Patients can be lethargic and might have sunken eyes, dry mouth, cold clammy skin, or wrinkled hands and feet. Kussmaul breathing, a deep and labored breathing pattern, can occur because of acidosis from stool bicarbonate losses and lactic acidosis associated with poor perfusion. Blood pressure drops due to dehydration, peripheral pulse is rapid and thready, and urine output decreases with time. Muscle cramping and weakness, altered consciousness, seizures, or even coma due to electrolyte imbalances are common, especially in children.

Cause
Transmission
Cholera bacteria have been found in shellfish and plankton.Transmission is usually through the fecal-oral route of contaminated food or water caused by poor sanitation. Most cholera cases in developed countries are a result of transmission by food, while in developing countries it is more often water. Food transmission can occur when people harvest seafood such as oysters in waters infected with sewage, as Vibrio cholerae accumulates in planktonic crustaceans and the oysters eat the zooplankton.People infected with cholera often have diarrhea, and disease transmission may occur if this highly liquid stool, colloquially referred to as "rice-water", contaminates water used by others.  A single diarrheal event can cause a one-million fold increase in numbers of V. cholerae in the environment. The source of the contamination is typically other people with cholera when their untreated diarrheal discharge is allowed to get into waterways, groundwater or drinking water supplies. Drinking any contaminated water and eating any foods washed in the water, as well as shellfish living in the affected waterway, can cause a person to contract an infection. Cholera is rarely spread directly from person to person.V. cholerae also exists outside the human body in natural water sources, either by itself or through interacting with phytoplankton, zooplankton, or biotic and abiotic detritus. Drinking such water can also result in the disease, even without prior contamination through fecal matter. Selective pressures exist however in the aquatic environment that may reduce the virulence of V. cholerae. Specifically, animal models indicate that the transcriptional profile of the pathogen changes as it prepares to enter an aquatic environment. This transcriptional change results in a loss of ability of V. cholerae to be cultured on standard media, a phenotype referred to as viable but non-culturable (VBNC) or more conservatively active but non-culturable (ABNC). One study indicates that the culturability of V. cholerae drops 90% within 24 hours of entering the water, and furthermore that this loss in culturability is associated with a loss in virulence.Both toxic and non-toxic strains exist. Non-toxic strains can acquire toxicity through a temperate bacteriophage.

Susceptibility
About 100 million bacteria must typically be ingested to cause cholera in a normal healthy adult. This dose, however, is less in those with lowered gastric acidity (for instance those using proton pump inhibitors). Children are also more susceptible, with two- to four-year-olds having the highest rates of infection. Individuals susceptibility to cholera is also affected by their blood type, with those with type O blood being the most susceptible. Persons with lowered immunity, such as persons with AIDS or malnourished children, are more likely to suffer a severe case if they become infected. Any individual, even a healthy adult in middle age, can undergo a severe case, and each persons case should be measured by the loss of fluids, preferably in consultation with a professional health care provider.The cystic fibrosis genetic mutation known as delta-F508 in humans has been said to maintain a selective heterozygous advantage: heterozygous carriers of the mutation (who are not affected by cystic fibrosis) are more resistant to V. cholerae infections. In this model, the genetic deficiency in the cystic fibrosis transmembrane conductance regulator channel proteins interferes with bacteria binding to the intestinal epithelium, thus reducing the effects of an infection.

Mechanism
When consumed, most bacteria do not survive the acidic conditions of the human stomach. The few surviving bacteria conserve their energy and stored nutrients during the passage through the stomach by shutting down protein production. When the surviving bacteria exit the stomach and reach the small intestine, they must propel themselves through the thick mucus that lines the small intestine to reach the intestinal walls where they can attach and thrive.Once the cholera bacteria reach the intestinal wall, they no longer need the flagella to move. The bacteria stop producing the protein flagellin to conserve energy and nutrients by changing the mix of proteins that they express in response to the changed chemical surroundings. On reaching the intestinal wall, V. cholerae start producing the toxic proteins that give the infected person a watery diarrhea. This carries the multiplying new generations of V. cholerae bacteria out into the drinking water of the next host if proper sanitation measures are not in place.The cholera toxin (CTX or CT) is an oligomeric complex made up of six protein subunits: a single copy of the A subunit (part A), and five copies of the B subunit (part B), connected by a disulfide bond. The five B subunits form a five-membered ring that binds to GM1 gangliosides on the surface of the intestinal epithelium cells. The A1 portion of the A subunit is an enzyme that ADP-ribosylates G proteins, while the A2 chain fits into the central pore of the B subunit ring. Upon binding, the complex is taken into the cell via receptor-mediated endocytosis. Once inside the cell, the disulfide bond is reduced, and the A1 subunit is freed to bind with a human partner protein called ADP-ribosylation factor 6 (Arf6). Binding exposes its active site, allowing it to permanently ribosylate the Gs alpha subunit of the heterotrimeric G protein. This results in constitutive cAMP production, which in turn leads to the secretion of water, sodium, potassium, and bicarbonate into the lumen of the small intestine and rapid dehydration. The gene encoding the cholera toxin was introduced into V. cholerae by horizontal gene transfer. Virulent strains of V. cholerae carry a variant of a temperate bacteriophage called CTXφ.
Microbiologists have studied the genetic mechanisms by which the V. cholerae bacteria turn off the production of some proteins and turn on the production of other proteins as they respond to the series of chemical environments they encounter, passing through the stomach, through the mucous layer of the small intestine, and on to the intestinal wall. Of particular interest have been the genetic mechanisms by which cholera bacteria turn on the protein production of the toxins that interact with host cell mechanisms to pump chloride ions into the small intestine, creating an ionic pressure which prevents sodium ions from entering the cell. The chloride and sodium ions create a salt-water environment in the small intestines, which through osmosis can pull up to six liters of water per day through the intestinal cells, creating the massive amounts of diarrhea. The host can become rapidly dehydrated unless treated properly.By inserting separate, successive sections of V. cholerae DNA into the DNA of other bacteria, such as E. coli that would not naturally produce the protein toxins, researchers have investigated the mechanisms by which V. cholerae responds to the changing chemical environments of the stomach, mucous layers, and intestinal wall. Researchers have discovered a complex cascade of regulatory proteins controls expression of V. cholerae virulence determinants. In responding to the chemical environment at the intestinal wall, the V. cholerae bacteria produce the TcpP/TcpH proteins, which, together with the ToxR/ToxS proteins, activate the expression of the ToxT regulatory protein. ToxT then directly activates expression of virulence genes that produce the toxins, causing diarrhea in the infected person and allowing the bacteria to colonize the intestine. Current research aims at discovering "the signal that makes the cholera bacteria stop swimming and start to colonize (that is, adhere to the cells of) the small intestine."

Genetic structure
Amplified fragment length polymorphism fingerprinting of the pandemic isolates of V. cholerae has revealed variation in the genetic structure. Two clusters have been identified: Cluster I and Cluster II. For the most part, Cluster I consists of strains from the 1960s and 1970s, while Cluster II largely contains strains from the 1980s and 1990s, based on the change in the clone structure. This grouping of strains is best seen in the strains from the African continent.

Antibiotic resistance
In many areas of the world, antibiotic resistance is increasing within cholera bacteria. In Bangladesh, for example, most cases are resistant to tetracycline, trimethoprim-sulfamethoxazole, and erythromycin. Rapid diagnostic assay methods are available for the identification of multi-drug resistant cases. New generation antimicrobials have been discovered which are effective against cholera bacteria in in vitro studies.

Diagnosis
A rapid dipstick test is available to determine the presence of V. cholerae. In those samples that test positive, further testing should be done to determine antibiotic resistance. In epidemic situations, a clinical diagnosis may be made by taking a patient history and doing a brief examination. Treatment via hydration and over-the-counter hydration solutions can be started without or before confirmation by laboratory analysis, especially where cholera is a common problem.Stool and swab samples collected in the acute stage of the disease, before antibiotics have been administered, are the most useful specimens for laboratory diagnosis. If an epidemic of cholera is suspected, the most common causative agent is V. cholerae O1. If V. cholerae serogroup O1 is not isolated, the laboratory should test for V. cholerae O139. However, if neither of these organisms is isolated, it is necessary to send stool specimens to a reference laboratory.Infection with V. cholerae O139 should be reported and handled in the same manner as that caused by V. cholerae O1. The associated diarrheal illness should be referred to as cholera and must be reported in the United States.

Prevention
The World Health Organization (WHO) recommends focusing on prevention, preparedness, and response to combat the spread of cholera. They also stress the importance of an effective surveillance system. Governments can play a role in all of these areas.

Water, sanitation and hygiene
Although cholera may be life-threatening, prevention of the disease is normally straightforward if proper sanitation practices are followed. In developed countries, due to their nearly universal advanced water treatment and sanitation practices, cholera is rare. For example, the last major outbreak of cholera in the United States occurred in 1910–1911. Cholera is mainly a risk in developing countries in those areas where access to WASH (water, sanitation and hygiene) infrastructure is still inadequate.
Effective sanitation practices, if instituted and adhered to in time, are usually sufficient to stop an epidemic. There are several points along the cholera transmission path at which its spread may be halted:
Sterilization: Proper disposal and treatment of all materials that may have come into contact with the feces of other people with cholera (e.g., clothing, bedding, etc.) are essential. These should be sanitized by washing in hot water, using chlorine bleach if possible. Hands that touch cholera patients or their clothing, bedding, etc., should be thoroughly cleaned and disinfected with chlorinated water or other effective antimicrobial agents.
Sewage and fecal sludge management: In cholera-affected areas, sewage and fecal sludge need to be treated and managed carefully in order to stop the spread of this disease via human excreta. Provision of sanitation and hygiene is an important preventative measure. Open defecation, release of untreated sewage, or dumping of fecal sludge from pit latrines or septic tanks into the environment need to be prevented. In many cholera affected zones, there is a low degree of sewage treatment. Therefore, the implementation of dry toilets that do not contribute to water pollution, as they do not flush with water, may be an interesting alternative to flush toilets.
Sources: Warnings about possible cholera contamination should be posted around contaminated water sources with directions on how to decontaminate the water (boiling, chlorination etc.) for possible use.
Water purification: All water used for drinking, washing, or cooking should be sterilized by either boiling, chlorination, ozone water treatment, ultraviolet light sterilization (e.g., by solar water disinfection), or antimicrobial filtration in any area where cholera may be present. Chlorination and boiling are often the least expensive and most effective means of halting transmission. Cloth filters or sari filtration, though very basic, have significantly reduced the occurrence of cholera when used in poor villages in Bangladesh that rely on untreated surface water. Better antimicrobial filters, like those present in advanced individual water treatment hiking kits, are most effective. Public health education and adherence to appropriate sanitation practices are of primary importance to help prevent and control transmission of cholera and other diseases.Handwashing with soap or ash after using a toilet and before handling food or eating is also recommended for cholera prevention by WHO Africa.

Surveillance
Surveillance and prompt reporting allow for containing cholera epidemics rapidly. Cholera exists as a seasonal disease in many endemic countries, occurring annually mostly during rainy seasons. Surveillance systems can provide early alerts to outbreaks, therefore leading to coordinated response and assist in preparation of preparedness plans. Efficient surveillance systems can also improve the risk assessment for potential cholera outbreaks. Understanding the seasonality and location of outbreaks provides guidance for improving cholera control activities for the most vulnerable. For prevention to be effective, it is important that cases be reported to national health authorities.

Vaccination
Spanish physician Jaume Ferran i Clua developed a cholera inoculation in 1885, the first to immunize humans against a bacterial disease. However, his vaccine and inoculation was rather controversial and was rejected by his peers and several investigation commissions. Russian-Jewish bacteriologist Waldemar Haffkine successfully developed the first human cholera vaccine in July 1892. He conducted a massive inoculation program in British India.Persons who survive an episode of cholera have long-lasting immunity for at least 3 years (the period tested.) A number of safe and effective oral vaccines for cholera are available.  The World Health Organization (WHO) has three prequalified oral cholera vaccines (OCVs): Dukoral, Sanchol, and Euvichol. Dukoral, an orally administered, inactivated whole cell vaccine, has an overall efficacy of about 52% during the first year after being given and 62% in the second year, with minimal side effects.  It is available in over 60 countries. However, it is not currently recommended by the Centers for Disease Control and Prevention (CDC) for most people traveling from the United States to endemic countries. The vaccine that the US Food and Drug Administration (FDA) recommends, Vaxchora, is an oral attenuated live vaccine,  that is effective for adults aged 18-64 as a single dose.One injectable vaccine was found to be effective for two to three years. The protective efficacy was 28% lower in children less than five years old. However, as of 2010, it has limited availability. Work is under way to investigate the role of mass vaccination. The WHO recommends immunization of high-risk groups, such as children and people with HIV, in countries where this disease is endemic.  If people are immunized broadly, herd immunity results, with a decrease in the amount of contamination in the environment.WHO recommends that oral cholera vaccination be considered in areas where the disease is endemic (with seasonal peaks), as part of the response to outbreaks, or in a humanitarian crisis during which the risk of cholera is high. Oral Cholera Vaccine (OCV) has been recognized as an adjunct tool for prevention and control of cholera. The World Health Organization (WHO) has prequalified three bivalent cholera vaccines—Dukoral (SBL Vaccines), containing a non-toxic B-subunit of cholera toxin and providing protection against V. cholerae O1; and two vaccines developed using the same transfer of technology—ShanChol (Shantha Biotec) and Euvichol (EuBiologics Co.), which have bivalent O1 and O139 oral killed cholera vaccines. Oral cholera vaccination could be deployed in a diverse range of situations from cholera-endemic areas and locations of humanitarian crises, but no clear consensus exists.

Sari filtration
Developed for use in Bangladesh, the "sari filter" is a simple and cost-effective appropriate technology method for reducing the contamination of drinking water. Used sari cloth is preferable but other types of used cloth can be used with some effect, though the effectiveness will vary significantly. Used cloth is more effective than new cloth, as the repeated washing reduces the space between the fibers. Water collected in this way has a greatly reduced pathogen count—though it will not necessarily be perfectly safe, it is an improvement for poor people with limited options. In Bangladesh this practice was found to decrease rates of cholera by nearly half. It involves folding a sari four to eight times. Between uses the cloth should be rinsed in clean water and dried in the sun to kill any bacteria on it. A nylon cloth appears to work as well but is not as affordable.

Treatment
Continued eating speeds the recovery of normal intestinal function. The WHO recommends this generally for cases of diarrhea no matter what the underlying cause. A CDC training manual specifically for cholera states: "Continue to breastfeed your baby if the baby has watery diarrhea, even when traveling to get treatment. Adults and older children should continue to eat frequently."

Fluids
The most common error in caring for patients with cholera is to underestimate the speed
and volume of fluids required. In most cases, cholera can be successfully treated with oral rehydration therapy (ORT), which is highly effective, safe, and simple to administer. Rice-based solutions are preferred to glucose-based ones due to greater efficiency. In severe cases with significant dehydration, intravenous rehydration may be necessary. Ringers lactate is the preferred solution, often with added potassium. Large volumes and continued replacement until diarrhea has subsided may be needed. Ten percent of a persons body weight in fluid may need to be given in the first two to four hours. This method was first tried on a mass scale during the Bangladesh Liberation War, and was found to have much success.  Despite widespread beliefs, fruit juices and commercial fizzy drinks like cola are not ideal for rehydration of people with serious infections of the intestines, and their excessive sugar content may even harm water uptake.If commercially produced oral rehydration solutions are too expensive or difficult to obtain, solutions can be made. One such recipe calls for 1 liter of boiled water, 1/2 teaspoon of salt, 6 teaspoons of sugar, and added mashed banana for potassium and to improve taste.

Electrolytes
As there frequently is initially acidosis, the potassium level may be normal, even though large losses have occurred. As the dehydration is corrected, potassium levels may decrease rapidly, and thus need to be replaced.  This may be done by consuming foods high in potassium, like bananas or coconut water.

Antibiotics
Antibiotic treatments for one to three days shorten the course of the disease and reduce the severity of the symptoms. Use of antibiotics also reduces fluid requirements. People will recover without them, however, if sufficient hydration is maintained. The WHO only recommends antibiotics in those with severe dehydration.Doxycycline is typically used first line, although some strains of V. cholerae have shown resistance. Testing for resistance during an outbreak can help determine appropriate future choices. Other antibiotics proven to be effective include cotrimoxazole, erythromycin, tetracycline, chloramphenicol, and furazolidone. Fluoroquinolones, such as ciprofloxacin, also may be used, but resistance has been reported.Antibiotics improve outcomes in those who are both severely and not severely dehydrated. Azithromycin and tetracycline may work better than doxycycline or ciprofloxacin.

Zinc supplementation
In Bangladesh zinc supplementation reduced the duration and severity of diarrhea in children with cholera when given with antibiotics and rehydration therapy as needed. It reduced the length of disease by eight hours and the amount of diarrhea stool by 10%. Supplementation appears to be also effective in both treating and preventing infectious diarrhea due to other causes among children in the developing world.

Prognosis
If people with cholera are treated quickly and properly, the mortality rate is less than 1%; however, with untreated cholera, the mortality rate rises to 50–60%.For certain genetic strains of cholera, such as the one present during the 2010 epidemic in Haiti and the 2004 outbreak in India, death can occur within two hours of becoming ill.

Epidemiology
Cholera affects an estimated 2.8 million people worldwide, and causes approximately 95,000 deaths a year (uncertainty range: 21,000–143,000) as of 2015. This occurs mainly in the developing world.In the early 1980s, death rates are believed to have still been higher than three million a year. It is difficult to calculate exact numbers of cases, as many go unreported due to concerns that an outbreak may have a negative impact on the tourism of a country. As of 2004, cholera remained both epidemic and endemic in many areas of the world.Recent major outbreaks are the 2010s Haiti cholera outbreak and the 2016–2021 Yemen cholera outbreak. In October 2016, an outbreak of cholera began in war-ravaged Yemen. WHO called it "the worst cholera outbreak in the world". In 2019, 93% of the reported 923,037 cholera cases were from Yemen (with 1911 deaths reported). Between September 2019 and September 2020, a global total of over 450,000 cases and over 900 deaths was reported; however, the accuracy of these numbers suffer from over-reporting from countries that report suspected cases (and not laboratory confirmed cases), as well as under-reporting from countries that do not report official cases (such as Bangladesh, India and Philippines).Although much is known about the mechanisms behind the spread of cholera, researchers still do not have a full understanding of what makes cholera outbreaks happen in some places and not others. Lack of treatment of human feces and lack of treatment of drinking water greatly facilitate its spread. Bodies of water have been found to serve as a reservoir of infection, and seafood shipped long distances can spread the disease.
Cholera had disappeared from the Americas for most of the 20th century, but it reappeared toward the end of that century, beginning with a severe outbreak in Peru. Following the end of the 2010s Haiti cholera outbreak, there have not been any cholera cases in the Americas since February 2019. As of August 2021 the disease is endemic in Africa and some areas of eastern and western Asia (Bangladesh, India and Yemen). Cholera is not endemic in Europe; all reported cases had a travel history to endemic areas.

History of outbreaks
The word cholera is from Greek: χολέρα kholera from χολή kholē "bile". Cholera likely has its origins in the Indian subcontinent as evidenced by its prevalence in the region for centuries.References to cholera appear in the European literature as early as 1642, from the Dutch physician Jakob de Bondts description in his De Medicina Indorum. (The "Indorum" of the title refers to the East Indies. He also gave first European descriptions of other diseases.) But at the time, the word "cholera" was historically used by European physicians to refer to any gastrointestinal upset resulting in yellow diarrhea. De Bondt thus used a common word already in regular use to describe the new disease. This was a frequent practice of the time. It was not until the 1830s that the name for severe yellow diarrhea changed in English from "cholera" to "cholera morbus" to differentiate it from what was then known as "Asiatic cholera", or that associated with origins in India and the East.
Early outbreaks in the Indian subcontinent are believed to have been the result of crowded, poor living conditions, as well as the presence of pools of still water, both of which provide ideal conditions for cholera to thrive. The disease first spread by travelers along trade routes (land and sea) to Russia in 1817, later to the rest of Europe, and from Europe to North America and the rest of the world, (hence the name "Asiatic cholera"). Seven cholera pandemics have occurred since the early 19th century; the first one did not reach the Americas. The seventh pandemic originated in Indonesia in 1961.The first cholera pandemic occurred in the Bengal region of India, near Calcutta starting in 1817 through 1824. The disease dispersed from India to Southeast Asia, the Middle East, Europe, and Eastern Africa. The movement of British Army and Navy ships and personnel is believed to have contributed to the range of the pandemic, since the ships carried people with the disease to the shores of the Indian Ocean, from Africa to Indonesia, and north to China and Japan.The second pandemic lasted from 1826 to 1837 and particularly affected North America and Europe. Advancements in transportation and global trade, and increased human migration, including soldiers, meant that more people were carrying the disease more widely.  The third pandemic erupted in 1846, persisted until 1860, extended to North Africa, and reached North and South America. It was introduced to North America at Quebec, Canada, via Irish immigrants from the Great Famine. In this pandemic, Brazil was affected for the first time. The fourth pandemic lasted from 1863 to 1875, spreading from India to Naples and Spain, and reaching the United States at New Orleans, Louisiana in 1873. It spread throughout the Mississippi River system on the continent.
The fifth pandemic was from 1881 to 1896. It started in India and spread to Europe, Asia, and South America. The sixth pandemic ran from 1899–1923. These epidemics had a lower number of fatalities because physicians and researchers had a greater understanding of the cholera bacteria. Egypt, the Arabian peninsula, Persia, India, and the Philippines were hit hardest during these epidemics. Other areas, such as Germany in 1892 (primarily the city of Hamburg, where more than 8.600 people died) and Naples from 1910 to 1911, also suffered severe outbreaks.
The seventh pandemic originated in 1961 in Indonesia and is marked by the emergence of a new strain, nicknamed El Tor, which still persists (as of 2018) in developing countries. This pandemic had initially subsided about 1975 and was thought to have ended, but, as noted, it has persisted. There were a rise in cases in the 1990s and since.
Cholera became widespread in the 19th century. Since then it has killed tens of millions of people. In Russia alone, between 1847 and 1851, more than one million people died from the disease. It killed 150,000 Americans during the second pandemic. Between 1900 and 1920, perhaps eight million people died of cholera in India. Cholera officially became the first reportable disease in the United States due to the significant effects it had on health. John Snow, in England, in 1854 was the first to identify the importance of contaminated water as its source of transmission. Cholera is now no longer considered a pressing health threat in Europe and North America due to filtering and chlorination of water supplies, but it still strongly affects populations in developing countries.
In the past, vessels flew a yellow quarantine flag if any crew members or passengers had cholera. No one aboard a vessel flying a yellow flag would be allowed ashore for an extended period, typically 30 to 40 days.Historically many different claimed remedies have existed in folklore. Many of the older remedies were based on the miasma theory, that the disease was transmitted by bad air. Some believed that abdominal chilling made one more susceptible, and flannel and cholera belts were included in army kits. In the 1854–1855 outbreak in Naples, homeopathic camphor was used according to Hahnemann. T. J. Ritters Mothers Remedies book lists tomato syrup as a home remedy from northern America. Elecampane was recommended in the United Kingdom, according to William Thomas Fernie. The first effective human vaccine was developed in 1885, and the first effective antibiotic was developed in 1948.
Cholera cases are much less frequent in developed countries where governments have helped to establish water sanitation practices and effective medical treatments. In the 19th century the United States, for example, had a severe cholera problem similar to those in some developing countries. It had three large cholera outbreaks in the 1800s, which can be attributed to Vibrio choleraes spread through interior waterways such as the Erie Canal and the extensive Mississippi River valley system, as well as the major ports along the Eastern Seaboard and their cities upriver. The island of Manhattan in New York City touches the Atlantic Ocean, where cholera collected from river waters and ship discharges just off the coast. At this time, New York City did not have as effective a sanitation system as it developed in the later 20th century, so cholera spread through the citys water supply.Cholera morbus is a historical term that was used to refer to gastroenteritis rather than specifically to what is now defined as the disease of cholera.

Research
One of the major contributions to fighting cholera was made by the physician and pioneer medical scientist John Snow (1813–1858), who in 1854 found a link between cholera and contaminated drinking water. Dr. Snow proposed a microbial origin for epidemic cholera in 1849. In his major "state of the art" review of 1855, he proposed a substantially complete and correct model for the cause of the disease. In two pioneering epidemiological field studies, he was able to demonstrate human sewage contamination was the most probable disease vector in two major epidemics in London in 1854. His model was not immediately accepted, but it was increasingly seen as plausible as medical microbiology developed over the next 30 years or so. For his work on cholera, John Snow is often regarded as the "Father of Epidemiology".The bacterium was isolated in 1854 by Italian anatomist Filippo Pacini, but its exact nature and his results were not widely known. In the same year, the Catalan Joaquim Balcells i Pascual discovered the bacterium. In 1856 António Augusto da Costa Simões and José Ferreira de Macedo Pinto, two Portuguese researchers, are believed to have done the same.Between the mid-1850s and the 1900s, cities in developed nations made massive investment in clean water supply and well-separated sewage treatment infrastructures. This eliminated the threat of cholera epidemics from the major developed cities in the world. In 1883, Robert Koch identified V. cholerae with a microscope as the bacillus causing the disease.Hemendra Nath Chatterjee, a Bengali scientist, was the first to formulate and demonstrate the effectiveness of oral rehydration salt (ORS) to treat diarrhea.  In his 1953 paper, published in The Lancet, he states that promethazine can stop vomiting during cholera and then oral rehydration is possible. The formulation of the fluid replacement solution was 4 g of sodium chloride, 25 g of glucose and 1000 ml of water.

Indian medical scientist Sambhu Nath De discovered the cholera toxin, the animal model of cholera, and successfully demonstrated the method of transmission of cholera pathogen Vibrio cholerae.Robert Allan Phillips, working at US Naval Medical Research Unit Two in Southeast Asia, evaluated the pathophysiology of the disease using modern laboratory chemistry techniques. He developed a protocol for rehydration. His research led the Lasker Foundation to award him its prize in 1967.More recently, in 2002, Alam, et al., studied stool samples from patients at the International Centre for Diarrhoeal Disease in Dhaka, Bangladesh. From the various experiments they conducted, the researchers found a correlation between the passage of V. cholerae through the human digestive system and an increased infectivity state. Furthermore, the researchers found the bacterium creates a hyperinfected state where genes that control biosynthesis of amino acids, iron uptake systems, and formation of periplasmic nitrate reductase complexes were induced just before defecation. These induced characteristics allow the cholera vibrios to survive in the "rice water" stools, an environment of limited oxygen and iron, of patients with a cholera infection.

Global Strategy
In 2017, the WHO launched the "Ending Cholera: a global roadmap to 2030" strategy which aims to reduce cholera deaths by 90% by 2030. The strategy was developed by the Global Task Force on Cholera Control (GTFCC) which develops country-specific plans and monitors progress. The approach to achieve this goal combines surveillance, water sanitation, rehydration treatment and oral vaccines. Specifically, the control strategy focuses on three approaches: i) early detection and response to outbreaks to contain outbreaks, ii) stopping cholera transmission through improved sanitation and vaccines in hotspots, and iii) a global framework for cholera control through the GTFCC.The WHO and the GTFCC do not consider global cholera eradication a viable goal. Even though humans are the only host of cholera, the bacterium can persist in the environment without a human host. While global eradication is not possible, elimination of human to human transmission may be possible. Local elimination is possible, which has been underway most recently during the 2010s Haiti cholera outbreak. Haiti aims to achieve certification of elimination by 2022.The GTFCC targets 47 countries, 13 of which have established vaccination campaigns.

Society and culture
Health policy
In many developing countries, cholera still reaches its victims through contaminated water sources, and countries without proper sanitation techniques have greater incidence of the disease. Governments can play a role in this. In 2008, for example, the Zimbabwean cholera outbreak was due partly to the governments role, according to a report from the James Baker Institute. The Haitian governments inability to provide safe drinking water after the 2010 earthquake led to an increase in cholera cases as well.Similarly, South Africas cholera outbreak was exacerbated by the governments policy of privatizing water programs. The wealthy elite of the country were able to afford safe water while others had to use water from cholera-infected rivers.According to Rita R. Colwell of the James Baker Institute, if cholera does begin to spread, government preparedness is crucial. A governments ability to contain the disease before it extends to other areas can prevent a high death toll and the development of an epidemic or even pandemic. Effective disease surveillance can ensure that cholera outbreaks are recognized as soon as possible and dealt with appropriately. Oftentimes, this will allow public health programs to determine and control the cause of the cases, whether it is unsanitary water or seafood that have accumulated a lot of Vibrio cholerae specimens. Having an effective surveillance program contributes to a governments ability to prevent cholera from spreading. In the year 2000 in the state of Kerala in India, the Kottayam district was determined to be "Cholera-affected"; this pronouncement led to task forces that concentrated on educating citizens with 13,670 information sessions about human health. These task forces promoted the boiling of water to obtain safe water, and provided chlorine and oral rehydration salts. Ultimately, this helped to control the spread of the disease to other areas and minimize deaths. On the other hand, researchers have shown that most of the citizens infected during the 1991 cholera outbreak in Bangladesh lived in rural areas, and were not recognized by the governments surveillance program. This inhibited physicians abilities to detect cholera cases early.According to Colwell, the quality and inclusiveness of a countrys health care system affects the control of cholera, as it did in the Zimbabwean cholera outbreak. While sanitation practices are important, when governments respond quickly and have readily available vaccines, the country will have a lower cholera death toll. Affordability of vaccines can be a problem; if the governments do not provide vaccinations, only the wealthy may be able to afford them and there will be a greater toll on the countrys poor. The speed with which government leaders respond to cholera outbreaks is important.Besides contributing to an effective or declining public health care system and water sanitation treatments, government can have indirect effects on cholera control and the effectiveness of a response to cholera. A countrys government can impact its ability to prevent disease and control its spread. A speedy government response backed by a fully functioning health care system and financial resources can prevent choleras spread. This limits choleras ability to cause death, or at the very least a decline in education, as children are kept out of school to minimize the risk of infection.

Notable cases
Tchaikovskys death has traditionally been attributed to cholera, most probably contracted through drinking contaminated water several days earlier. Tchaikovskys mother died of cholera, and his father became sick with cholera at this time but made a full recovery. Some scholars, however, including English musicologist and Tchaikovsky authority David Brown and biographer Anthony Holden, have theorized that his death was a suicide.
2010s Haiti cholera outbreak. Ten months after the 2010 earthquake, an outbreak swept over Haiti, traced to a United Nations base of peacekeepers from Nepal. This marks the worst cholera outbreak in recent history, as well as the best documented cholera outbreak in modern public health.
Adam Mickiewicz, Polish poet and novelist, is thought to have died of cholera in Istanbul in 1855.
Sadi Carnot, physicist, a pioneer of thermodynamics (d. 1832)
Charles X, King of France (d. 1836)
James K. Polk, eleventh president of the United States (d. 1849)
Carl von Clausewitz, Prussian soldier and German military theorist (d. 1831)
Elliot Bovill, Chief Justice of the Straits Settlements (1893)
Nikola Tesla, Serbian-American inventor, engineer and futurist known for his contributions to the design of the modern alternating current (AC) electricity supply system, contracted cholera in 1873 at the age of 17. He was bedridden for nine months, and near death multiple times, but survived and fully recovered.

In popular culture
Unlike tuberculosis ("consumption") which in literature and the arts was often romanticized as a disease of denizens of the demimonde or those with an artistic temperament, cholera is a disease which almost entirely affects the lower-classes living in filth and poverty.  This, and the unpleasant course of the disease – which includes voluminous "rice-water" diarrhea, the hemorrhaging of liquids from the mouth, and violent muscle contractions which continue even after death – has discouraged the disease from being romanticized, or even the actual factual presentation of the disease in popular culture.
The 1889 novel Mastro-don Gesualdo by Giovanni Verga presents the course of a cholera epidemic across the island of Sicily, but does not show the suffering of those affected.
In Thomas Manns novella Death in Venice, first published in 1912 as Der Tod in Venedig, Mann "presented the disease as emblematic of the final bestial degradation of the sexually transgressive author Gustav von Aschenbach." Contrary to the actual facts of how violently cholera kills, Mann has his protagonist die peacefully on a beach in a deck chair.  Luchino Viscontis 1971 film version also hid from the audience the actual course of the disease.  Manns novella was also made into an opera by Benjamin Britten in 1973, his last one, and into a ballet by John Neumeier for his Hamburg Ballet company, in December 2003.*
In Gabriel Garcia Márquezs 1985 novel Love in the Time of Cholera, cholera is "a looming background presence rather than a central figure requiring vile description."  The novel was adapted in 2007 for the film of the same name directed by Mike Newell.

Country examples
Zambia
In Zambia, widespread cholera outbreaks have occurred since 1977, most commonly in the capital city of Lusaka. In 2017, an outbreak of cholera was declared in Zambia after laboratory confirmation of Vibrio cholerae O1, biotype El Tor, serotype Ogawa, from stool samples from two patients with acute watery diarrhea. There was a rapid increase in the number of cases from several hundred cases in early December 2017 to approximately 2,000 by early January 2018. With intensification of the rains, new cases increased on a daily basis reaching a peak on the first week of January 2018 with over 700 cases reported.In collaboration with partners, the Zambia Ministry of Health (MoH) launched a multifaceted public health response that included increased chlorination of the Lusaka municipal water supply, provision of emergency water supplies, water quality monitoring and testing, enhanced surveillance, epidemiologic investigations, a cholera vaccination campaign, aggressive case management and health care worker training, and laboratory testing of clinical samples.The Zambian Ministry of Health implemented a reactive one-dose Oral Cholera Vaccine (OCV) campaign in April 2016 in three Lusaka compounds, followed by a pre-emptive second-round in December.

India
The city of Kolkata, India in the state of West Bengal in the Ganges delta has been described as the "homeland of cholera", with regular outbreaks and pronounced seasonality. In India, where the disease is endemic, cholera outbreaks occur every year between dry seasons and rainy seasons. India is also characterized by high population density, unsafe drinking water, open drains, and poor sanitation which provide an optimal niche for survival, sustenance and transmission of Vibrio cholerae.

Democratic Republic of Congo
In Goma in the Democratic Republic of Congo, cholera has left an enduring mark on human and medical history. Cholera pandemics in the 19th and 20th centuries led to the growth of epidemiology as a science and in recent years it has continued to press advances in the concepts of disease ecology, basic membrane biology, and transmembrane signaling and in the use of scientific information and treatment design.

Notes
References
Further reading
Arnold, David (1986). "Cholera and Colonialism in British India". Past & Present. 113 (113): 118–151. doi:10.1093/past/113.1.118. JSTOR 650982. PMID 11617906.
Azizi, MH; Azizi, F (January 2010). "History of Cholera Outbreaks in Iran during the 19th and 20th Centuries". Middle East Journal of Digestive Diseases. 2 (1): 51–55. PMC 4154910. PMID 25197514.
Bilson, Geoffrey. A Darkened House: Cholera in Nineteenth-Century Canada (U of Toronto Press, 1980).
Cooper, Donald B. (1986). "The New Black Death: Cholera in Brazil, 1855-1856". Social Science History. 10 (4): 467–488. doi:10.2307/1171027. JSTOR 1171027. PMID 11618140.
Echenberg, Myron (2011). Africa in the Time of Cholera: A History of Pandemics from 1817 to the Present. ISBN 978-0-521-18820-3.
Evans, Richard J. (1988). "Epidemics and Revolutions: Cholera in Nineteenth-Century Europe". Past & Present. 120 (120): 123–146. doi:10.1093/past/120.1.123. JSTOR 650924. PMID 11617908.
Evans, Richard J. (2005). Death in Hamburg: Society and Politics in the Cholera Years. ISBN 978-0-14-303636-4.
Gilbert, Pamela K. Cholera and Nation: Doctoring the Social Body in Victorian England" (SUNY Press, 2008).
Hamlin, Christopher (2009). Cholera: The Biography. Oxford University Press.
Huber, Valeska (November 2020). "Pandemics and the politics of difference: rewriting the history of internationalism through nineteenth-century cholera". Journal of Global History. 15 (3): 394–407. doi:10.1017/S1740022820000236. S2CID 228940685.
Huber, Valeska (June 2006). "THE UNIFICATION OF THE GLOBE BY DISEASE? THE INTERNATIONAL SANITARY CONFERENCES ON CHOLERA, 1851–1894". The Historical Journal. 49 (2): 453–476. doi:10.1017/S0018246X06005280. S2CID 162994263.
Jenson, Deborah; Szabo, Victoria (November 2011). "Cholera in Haiti and Other Caribbean Regions, 19th Century". Emerging Infectious Diseases. 17 (11): 2130–2135. doi:10.3201/eid1711.110958. PMC 3310590. PMID 22099117.
Kotar, S. L.; Gessler, J. E. (2014). Cholera: A Worldwide History. ISBN 978-0-7864-7242-0.
Kudlick, Catherine Jean (1996). Cholera in Post-Revolutionary Paris: A Cultural History. Berkeley: University of California Press.
Legros, Dominique (15 October 2018). "Global Cholera Epidemiology: Opportunities to Reduce the Burden of Cholera by 2030". The Journal of Infectious Diseases. 218 (suppl_3): S137–S140. doi:10.1093/infdis/jiy486. PMC 6207143. PMID 30184102.
Mukharji, Projit Bihari (2012). "The Cholera Cloud in the Nineteenth-Century British World: History of an Object-Without-an-Essence". Bulletin of the History of Medicine. 86 (3): 303–332. doi:10.1353/bhm.2012.0050. JSTOR 26305866. PMID 23241908. S2CID 207267413. INIST:26721136 Project MUSE 492086.
Rosenberg, Charles E. (1987). The Cholera Years: The United States in 1832, 1849, and 1866. University of Chicago Press. ISBN 978-0-226-72677-9.
Roth, Mitchel (1997). "Cholera, Community, and Public Health in Gold Rush Sacramento and San Francisco". Pacific Historical Review. 66 (4): 527–551. doi:10.2307/3642236. JSTOR 3642236.
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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Invasive hydatidiform mole and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Choriocarcinoma and can you explain it in depth? [/INST] Choriocarcinoma is a malignant, trophoblastic cancer, usually of the placenta. It is characterized by early hematogenous spread to the lungs. It belongs to the malignant end of the spectrum in gestational trophoblastic disease (GTD). It is also classified as a germ cell tumor and may arise in the testis or ovary.

Signs and symptoms
increased quantitative chorionic gonadotropin (the "pregnancy hormone") levels
vaginal bleeding
shortness of breath
hemoptysis (coughing up blood)
chest pain
chest X-ray shows multiple infiltrates of various shapes in both lungs
presents in males as a testicular cancer, sometimes with skin hyperpigmentation (from excess chorionic gonadotropin cross reacting with the alpha MSH receptor), gynecomastia, and weight loss (from excess chorionic gonadotropin cross reacting with the LH, FSH, and TSH receptor) in males
can present with decreased thyroid-stimulating hormone (TSH) due to hyperthyroidism.

Cause
Choriocarcinoma of the placenta during pregnancy is preceded by:

hydatidiform mole (50% of cases)
spontaneous abortion (20% of cases)
ectopic pregnancy (2% of cases)
normal term pregnancy (20–30% of cases)
hyperemesis gravidarumRarely, choriocarcinoma occurs in primary locations other than the placenta;  very rarely, it occurs in testicles. Although trophoblastic components are common components of mixed germ cell tumors, pure choriocarcinoma of the adult testis is rare. Pure choriocarcinoma of the testis represents the most aggressive pathologic variant of germ cell tumors in adults, characteristically with early hematogenous and lymphatic metastatic spread </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 Claudication and can you explain it in depth? [/INST] Claudication is a medical term usually referring to impairment in walking, or pain, discomfort, numbness, or tiredness in the legs that occurs during walking or standing and is relieved by rest.  The perceived level of pain from claudication can be mild to extremely severe.  Claudication is most common in the calves but it can also affect the feet, thighs, hips, buttocks, or arms. The word claudication comes from the Latin claudicare meaning to limp.
Claudication that appears after a short amount of walking may sometimes be described by US medical professionals by the number of typical city street blocks that the patient can walk before the onset of claudication. Thus, "one-block claudication" appears after walking one block, "two-block claudication" appears after walking two blocks, etc. The term block would be understood more exactly locally but is on the order of 100 metres.

Types
Intermittent vascular
Intermittent vascular (or arterial) claudication (Latin: claudicatio intermittens) most often refers to cramping pains in the buttock or leg muscles, especially the calves. It is caused by poor circulation of the blood to the affected area, called peripheral arterial disease. The poor blood flow is often a result of atherosclerotic blockages more proximal to the affected area; individuals with intermittent claudication may have diabetes — often undiagnosed. Another cause, or exacerbating factor, is excessive sitting (several hours), especially in the absence of reasonable breaks, along with a general lack of walking or other exercise that stimulates the legs.

Spinal or neurogenic
Spinal or neurogenic claudication is not due to lack of blood supply, but rather it is caused by nerve root compression or stenosis of the spinal canal, usually from a degenerative spine, most often at the "L4-L5" or "L5-S1" level.  This may result from many factors, including bulging disc, herniated disc or fragments from previously herniated discs (post-operative), scar tissue from previous surgeries, osteophytes (bone spurs that jut out from the edge of a vertebra into the foramen, the opening through which the nerve root passes).  In most cases neurogenic claudication is bilateral, i.e. symmetrical.

Jaw
Jaw claudication is pain in the jaw or ear while chewing.  This is caused by insufficiency of the arteries supplying the jaw muscles, associated with giant cell arteritis.

Diagnosis
Differential diagnosis
Vascular (or arterial) claudication typically occurs after activity or ambulation for a distance with resultant vascular insufficiency (lack of blood flow) where the muscular demands of oxygen outweighs the supply. Symptoms are lower extremity cramping. Resting from activity even in a standing position may help relieve the symptoms </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 Colic and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Common cold and can you explain it in depth? [/INST] The common cold, also known simply as a cold, is a viral infectious disease of the upper respiratory tract that primarily affects the respiratory mucosa of the nose, throat, sinuses, and larynx. Signs and symptoms may appear less than two days after exposure to the virus. These may include coughing, sore throat, runny nose, sneezing, headache, and fever. People usually recover in seven to ten days, but some symptoms may last up to three weeks. Occasionally, those with other health problems may develop pneumonia.Well over 200 virus strains are implicated in causing the common cold, with rhinoviruses, coronaviruses, adenoviruses and enteroviruses being the most common. They spread through the air during close contact with infected people or indirectly through contact with objects in the environment, followed by transfer to the mouth or nose. Risk factors include going to child care facilities, not sleeping well, and psychological stress. The symptoms are mostly due to the bodys immune response to the infection rather than to tissue destruction by the viruses themselves. The symptoms of influenza are similar to those of a cold, although usually more severe and less likely to include a runny nose.There is no vaccine for the common cold. The primary methods of prevention are hand washing; not touching the eyes, nose or mouth with unwashed hands; and staying away from sick people. Some evidence supports the use of face masks. There is also no cure, but the symptoms can be treated. Zinc may reduce the duration and severity of symptoms if started shortly after the onset of symptoms. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen may help with pain. Antibiotics, however, should not be used, as all colds are caused by viruses, and there is no good evidence that cough medicines are effective.The common cold is the most frequent infectious disease in humans. Under normal circumstances, the average adult gets two to three colds a year, while the average child may get six to eight. Infections occur more commonly during the winter. These infections have existed throughout human history.

Signs and symptoms
The typical symptoms of a cold include cough, runny nose, sneezing, nasal congestion, and a sore throat, sometimes accompanied by muscle ache, fatigue, headache, and loss of appetite. A sore throat is present in about 40% of cases, a cough in about 50%, and muscle ache likewise in about 50%. In adults, a fever is generally not present but it is common in infants and young children. The cough is usually mild compared to that accompanying influenza. While a cough and a fever indicate a higher likelihood of influenza in adults, a great deal of similarity exists between these two conditions. A number of the viruses that cause the common cold may also result in asymptomatic infections.The color of the mucus or nasal secretion may vary from clear to yellow to green and does not indicate the class of agent causing the infection.

Progression
A cold usually begins with fatigue, a feeling of being chilled, sneezing, and a headache, followed in a couple of days by a runny nose and cough. Symptoms may begin within sixteen hours of exposure and typically peak two to four days after onset. They usually resolve in seven to ten days, but some can last for up to three weeks. The average duration of cough is eighteen days and in some cases people develop a post-viral cough which can linger after the infection is gone. In children, the cough lasts for more than ten days in 35–40% of cases and continues for more than 25 days in 10%.

Causes
Viruses
The common cold is an infection of the upper respiratory tract which can be caused by many different viruses. The most commonly implicated is a rhinovirus (30–80%), a type of picornavirus with 99 known serotypes. Other commonly implicated viruses include human coronaviruses (≈ 15%), influenza viruses (10–15%), adenoviruses (5%), human respiratory syncytial virus (RSV), enteroviruses other than rhinoviruses, human parainfluenza viruses, and human metapneumovirus. Frequently more than one virus is present. In total, more than 200 viral types are associated with colds.

Transmission
The common cold virus is typically transmitted via airborne droplets (aerosols), direct contact with infected nasal secretions, or fomites (contaminated objects). Which of these routes is of primary importance has not been determined. The viruses may survive for prolonged periods in the environment (over 18 hours for rhinoviruses) and can be picked up by peoples hands and subsequently carried to their eyes or nose where infection occurs. Transmission from animals is considered highly unlikely; an outbreak documented at a British scientific base on Adelaide Island after seventeen weeks of isolation was thought to have been caused by transmission from a contaminated object or an asymptomatic human carrier, rather than from the husky dogs which were also present at the base.Transmission is common in daycare and at school due to the proximity of many children with little immunity and frequently poor hygiene. These infections are then brought home to other members of the family. There is no evidence that recirculated air during commercial flight is a method of transmission. People sitting in close proximity appear to be at greater risk of infection.Rhinovirus-caused colds are most infectious during the first three days of symptoms; they are much less infectious afterwards.

Weather
A common misconception is that one can "catch a cold" simply through prolonged exposure to cold weather. Although it is now known that colds are viral infections, the prevalence of many such viruses are indeed seasonal, occurring more frequently during cold weather. The reason for the seasonality has not been conclusively determined. Possible explanations may include cold temperature-induced changes in the respiratory system, decreased immune response, and low humidity causing an increase in viral transmission rates, perhaps due to dry air allowing small viral droplets to disperse farther and stay in the air longer.The apparent seasonality may also be due to social factors, such as people spending more time indoors, near infected people, and specifically children at school. Although normal exposure to cold does not increase ones risk of infection, severe exposure leading to significant reduction of body temperature (hypothermia) may put one at a greater risk for the common cold; although controversial, the majority of evidence suggests that it may increase susceptibility to infection.

Other
Herd immunity, generated from previous exposure to cold viruses, plays an important role in limiting viral spread, as seen with younger populations that have greater rates of respiratory infections. Poor immune function is a risk factor for disease. Insufficient sleep and malnutrition have been associated with a greater risk of developing infection following rhinovirus exposure; this is believed to be due to their effects on immune function. Breast feeding decreases the risk of acute otitis media and lower respiratory tract infections among other diseases, and it is recommended that breast feeding be continued when an infant has a cold. In the developed world breast feeding may not be protective against the common cold in and of itself.

Pathophysiology
The symptoms of the common cold are believed to be primarily related to the immune response to the virus. The mechanism of this immune response is virus specific. For example, the rhinovirus is typically acquired by direct contact; it binds to humans via ICAM-1 receptors and the CDHR3 receptor through unknown mechanisms to trigger the release of inflammatory mediators. These inflammatory mediators then produce the symptoms. It does not generally cause damage to the nasal epithelium. The respiratory syncytial virus (RSV), on the other hand, is contracted by direct contact and airborne droplets. It then replicates in the nose and throat before frequently spreading to the lower respiratory tract. RSV does cause epithelium damage. Human parainfluenza virus typically results in inflammation of the nose, throat, and bronchi. In young children when it affects the trachea it may produce the symptoms of croup due to the small size of their airways.

Diagnosis
The distinction between viral upper respiratory tract infections is loosely based on the location of symptoms, with the common cold affecting primarily the nose (rhinitis), throat (pharyngitis), and lungs (bronchitis). There can be significant overlap, and more than one area can be affected. Self-diagnosis is frequent. Isolation of the viral agent involved is rarely performed, and it is generally not possible to identify the virus type through symptoms.

Prevention
The only useful ways to reduce the spread of cold viruses are physical measures such as using correct hand washing technique and face masks; in the healthcare environment, gowns and disposable gloves are also used. Isolation or quarantine is not used as the disease is so widespread and symptoms are non-specific. There is no vaccine to protect against the common cold. Vaccination has proven difficult as there are many viruses involved and they mutate rapidly. Creation of a broadly effective vaccine is, therefore, highly improbable.Regular hand washing appears to be effective in reducing the transmission of cold viruses, especially among children. Whether the addition of antivirals or antibacterials to normal hand washing provides greater benefit is unknown. Wearing face masks when around people who are infected may be beneficial; however, there is insufficient evidence for maintaining a greater social distance.It is unclear if zinc supplements affect the likelihood of contracting a cold. Routine vitamin C supplements do not reduce the risk or severity of the common cold, though they may reduce its duration. Gargling with water was found useful in one small trial.

Management
Treatments of the common cold primarily involve medications and other therapies for symptomatic relief. Getting plenty of rest, drinking fluids to maintain hydration, and gargling with warm salt water are reasonable conservative measures. Much of the benefit from symptomatic treatment is, however, attributed to the placebo effect. As of 2010, no medications or herbal remedies had been conclusively demonstrated to shorten the duration of infection.

Symptomatic
Treatments that may help with symptoms include simple pain medication and medications for fevers such as ibuprofen and acetaminophen (paracetamol). It, however, is not clear if acetaminophen helps with symptoms. It is not known if over the counter cough medications are effective for treating an acute cough. Cough medicines are not recommended for use in children due to a lack of evidence supporting effectiveness and the potential for harm. In 2009, Canada restricted the use of over-the-counter cough and cold medication in children six years and under due to concerns regarding risks and unproven benefits. The misuse of dextromethorphan (an over-the-counter cough medicine) has led to its ban in a number of countries. Intranasal corticosteroids have not been found to be useful.In adults short term use of nasal decongestants may have a small benefit. Antihistamines may improve symptoms in the first day or two; however, there is no longer-term benefit and they have adverse effects such as drowsiness. Other decongestants such as pseudoephedrine appear effective in adults. Combined oral analgesics, antihistaminics and decongestants are generally effective for older children and adults. Ipratropium nasal spray may reduce the symptoms of a runny nose but has little effect on stuffiness. Ipratropium may also help with cough in adults. The safety and effectiveness of nasal decongestant use in children is unclear.Due to lack of studies, it is not known whether increased fluid intake improves symptoms or shortens respiratory illness. As of 2017 heated and humidified air, such as via RhinoTherm, is of unclear benefit. One study has found chest vapor rub to provide some relief of nocturnal cough, congestion, and sleep difficulty.Some advise to avoid physical exercise if there are symptoms such as fever, widespread muscle aches or fatigue. It is regarded as safe to perform moderate exercise if the symptoms are confined to the head, including runny nose, nasal congestion, sneezing, or a minor sore throat. There is a popular belief that having a hot drink can help with cold symptoms, but evidence to support this is very limited.

Antibiotics and antivirals
Antibiotics have no effect against viral infections, including the common cold. Due to their side effects, antibiotics cause overall harm but are still frequently prescribed. Some of the reasons that antibiotics are so commonly prescribed include peoples expectations for them, physicians desire to help, and the difficulty in excluding complications that may be amenable to antibiotics. There are no effective antiviral drugs for the common cold even though some preliminary research has shown benefits.

Zinc
Zinc supplements may shorten the duration of colds by up to 33% and reduce the severity of symptoms if supplementation begins within 24 hours of the onset of symptoms. Some zinc remedies directly applied to the inside of the nose have led to the loss of the sense of smell. A 2017 review did not recommend the use of zinc for the common cold for various reasons; whereas a 2017 and 2018 review both recommended the use of zinc, but also advocated further research on the topic.

Alternative medicine
While there are many alternative medicines and Chinese herbal medicines supposed to treat the common cold, there is insufficient scientific evidence to support their use. As of 2015, there is weak evidence to support nasal irrigation with saline. There is no firm evidence that Echinacea products or garlic provide any meaningful benefit in treating or preventing colds.

Vitamins C and D
Vitamin C supplementation does not affect the incidence of the common cold, but may reduce its duration. There is no conclusive evidence that vitamin D supplementation is efficacious in the prevention or treatment of respiratory tract infections.

Prognosis
The common cold is generally mild and self-limiting with most symptoms generally improving in a week. In children, half of cases go away in 10 days and 90% in 15 days. Severe complications, if they occur, are usually in the very old, the very young, or those who are immunosuppressed. Secondary bacterial infections may occur resulting in sinusitis, pharyngitis, or an ear infection. It is estimated that sinusitis occurs in 8% and ear infection in 30% of cases.

Epidemiology
The common cold is the most common human disease and affects people all over the globe. Adults typically have two to three infections annually, and children may have six to ten colds a year (and up to twelve colds a year for school children). Rates of symptomatic infections increase in the elderly due to declining immunity.Native Americans and Inuit are more likely to be infected with colds and develop complications such as otitis media than Caucasians. This may be explained as much by issues such as poverty and overcrowding as by ethnicity.

History
While the cause of the common cold was identified in the 1950s, the disease appears to have been with humanity since its early history. Its symptoms and treatment are described in the Egyptian Ebers papyrus, the oldest existing medical text, written before the 16th century BCE. The name "cold" came into use in the 16th century, due to the similarity between its symptoms and those of exposure to cold weather.In the United Kingdom, the Common Cold Unit (CCU) was set up by the Medical Research Council in 1946 and it was where the rhinovirus was discovered in 1956. In the 1970s, the CCU demonstrated that treatment with interferon during the incubation phase of rhinovirus infection protects somewhat against the disease, but no practical treatment could be developed. The unit was closed in 1989, two years after it completed research of zinc gluconate lozenges in the prevention and treatment of rhinovirus colds, the only successful treatment in the history of the unit.

Research directions
Antivirals have been tested for effectiveness in the common cold; as of 2009, none had been both found effective and licensed for use. There are ongoing trials of the anti-viral drug pleconaril which shows promise against picornaviruses as well as trials of BTA-798. The oral form of pleconaril had safety issues and an aerosol form is being studied. Double-stranded RNA activated caspase oligomerizer (DRACO), a broad-spectrum antiviral therapy, has shown preliminary effectiveness in treating rhinovirus, as well as other infectious viruses.The genomes of all known human rhinovirus strains have been sequenced.

Societal impact
The economic impact of the common cold is not well understood in much of the world. In the United States, the common cold leads to 75–100 million physician visits annually at a conservative cost estimate of $7.7 billion per year </s>