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Oseltamivir

ethyl (3 R ,4 R ,5 S )-5-amino-4-acetamido-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate CCC(CC)OC1C=C(CC(C1NC(=O)C)N)C(=O)OCC InChI=1S/C16H28N2O4/c1-5-12(6-2)22-14-9-11(16(20)21-7-3)8-13(17)15(14)18-10(4)19/h9,12-15H,5-8,17H2,1-4H3,(H,18,19)/t13-,14+,15+/m0/s1 Y Key:VSZGPKBBMSAYNT-RRFJBIMHSA-N Y Oseltamivir , sold under the brand name Tamiflu , is an antiviral medication used to treat and prevent influenza A and influenza B , viruses that cause the flu . Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection. They recommend it to prevent infection in those at high risk, but not the general population. The Centers for Disease Control and Prevention (CDC) recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection. It is taken by mouth, either as a pill or liquid. Recommendations regarding oseltamivir are controversial as are criticisms of the recommendations. A 2014 Cochrane Review concluded that oseltamivir does not reduce hospitalizations, and that there is no evidence of reduction in complications of influenza. Two meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks. They also found little evidence regarding whether treatment changes the risk of hospitalization or death in high risk populations. However, another meta-analysis found that oseltamivir was effective for prevention of influenza at the individual and household levels. Common side effects include vomiting , diarrhea , headache, and trouble sleeping. Other side effects may include psychiatric symptoms and seizures . In the United States it is recommended for influenza infection during pregnancy. It has been taken by a small number of pregnant women without signs of problems. Dose adjustment may be needed in those with kidney problems. Oseltamivir was approved for medical use in the US in 1999. It was the first neuraminidase inhibitor available by mouth. It is on the World Health Organization's List of Essential Medicines but was downgraded to "complementary" status in 2017. A generic version was approved in the US in 2016. In 2020, it was the 178th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Oseltamivir is used for the prevention and treatment of influenza caused by influenza A and B viruses. It is on the World Health Organization's List of Essential Medicines . The WHO supports its use for severe illness due to confirmed or suspected influenza virus infection in critically ill people who have been hospitalized. Oseltamivir's risk-benefit ratio is controversial. In 2017, it was moved from the core to the complementary list based on its lower cost-effectiveness. The Expert Committee did not recommend the deletion of oseltamivir from the EML and EMLc, recognizing that it is the only medicine included on the Model Lists for critically ill patients with influenza and for influenza pandemic preparedness. However, the Committee noted that, since the inclusion of oseltamivir on the Model List in 2009, new evidence in seasonal and pandemic influenza has lowered earlier estimates of the magnitude of effect of oseltamivir on relevant clinical outcomes. The Committee recommended that the listing of oseltamivir be amended, moving the medicine from the core to the Complementary List, and that its use be restricted to severe illness due to confirmed or suspected influenza virus infection in critically ill hospitalized patients. The Expert Committee noted that WHO guidelines for pharmacological management of pandemic and seasonal influenza would be updated in 2017: unless new information is provided to support the use of oseltamivir in seasonal and pandemic outbreaks, the next Expert Committee might consider oseltamivir for deletion. The US Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), Public Health England and the American Academy of Pediatrics (AAP) recommend the use of oseltamivir for people who have complications or are at high risk for complications. This includes those who are hospitalized, young children, those over the age of 65, people with other significant health problems, those who are pregnant, and Indigenous peoples of the Americas among others. The Infectious Disease Society of America takes the same position as the CDC. A systematic review of systematic reviews in PLoS One did not find evidence for benefits in people who are at risk, noting that "the trials were not designed or powered to give results regarding serious complications, hospitalization and mortality", as did a 2014 Cochrane Review. The Cochrane Review further recommended: "On the basis of the findings of this review, clinicians and healthcare policy-makers should urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza." That is not utilizing NIs for prevention or treatment "Based on these findings there appears to be no evidence for patients, clinicians or policy-makers to use these drugs to prevent serious outcomes, both in annual influenza and pandemic influenza outbreaks." The CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, and Roche (the originator) reject the conclusions of the Cochrane Review, arguing in part that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from people not infected with influenza. The EMA did not change its labeling of the drug in response to the Cochrane study. A 2014 review in the New England Journal of Medicine recommended that all people admitted to intensive care units during influenza outbreaks with a diagnosis of community-acquired pneumonia receive oseltamivir until the absence of influenza infection is established by PCR testing. A 2015 systematic review and meta-analysis found oseltamivir effective at treating the symptoms of influenza, reducing the length of hospitalization, and reducing the risk of otitis media . The same review found that oseltamivir did not significantly increase the risk of adverse events. A 2016 systematic review found that oseltamivir slightly reduced the time it takes for the symptoms of influenza to be alleviated, and that it also increased the risk of "nausea, vomiting, [and] psychiatric events in adults and vomiting in children." The decrease in duration of sickness was about 18 hours. In those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours. A German clinical practice guideline recommends against its use. Two 2013 meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks. When the analysis was restricted to people with confirmed infection, the same 2014 Cochrane Review (see above) found unclear evidence of change in the risk of complications such as pneumonia , while three other reviews found a decreased risk. Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1.0 day. Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting. The 2014 Cochrane Collaboration review concluded that oseltamivir did not affect the need for hospitalizations, and that there is no proof of reduction of complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection. The authors recommended that guidance should be revised to take account of the evidence of small benefit and increased risk of harms. The US Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), the Public Health England (PHE), the Infectious Disease Society of America (IDSA), the American Academy of Pediatrics (AAP), and Roche (the originator) rejected the recommendations of the 2014 Cochrane Review to urgently change treatment guidelines and drug labels. As of 2017 [ update ] , the CDC does not recommend to use oseltamivir generally for prevention due to concerns that widespread use will encourage resistance development. They recommend that it be considered in those at high risk, who have been exposed to influenza within 48 hours and have not received or only recently been vaccinated. They recommended it during outbreaks in long term care facilities and in those who are significantly immunosuppressed. As of 2011 [ update ] , reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease. A systematic review of systematic reviews found low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1 to 12% (a relative decrease of 64 to 92%). It recommended against its use in healthy, low-risk persons due to cost, the risk of resistance development, and side effects and concluded it might be useful for prevention in unvaccinated high risk persons. The US Centers for Disease Control and Prevention (CDC), European Centre for Disease Prevention and Control (ECDC), Public Health England and the American Academy of Pediatrics (AAP) recommend the use of oseltamivir for people who have complications or are at high risk for complications. This includes those who are hospitalized, young children, those over the age of 65, people with other significant health problems, those who are pregnant, and Indigenous peoples of the Americas among others. The Infectious Disease Society of America takes the same position as the CDC. A systematic review of systematic reviews in PLoS One did not find evidence for benefits in people who are at risk, noting that "the trials were not designed or powered to give results regarding serious complications, hospitalization and mortality", as did a 2014 Cochrane Review. The Cochrane Review further recommended: "On the basis of the findings of this review, clinicians and healthcare policy-makers should urgently revise current recommendations for use of the neuraminidase inhibitors (NIs) for individuals with influenza." That is not utilizing NIs for prevention or treatment "Based on these findings there appears to be no evidence for patients, clinicians or policy-makers to use these drugs to prevent serious outcomes, both in annual influenza and pandemic influenza outbreaks." The CDC, ECDC, Public Health England, Infectious Disease Society of America, the AAP, and Roche (the originator) reject the conclusions of the Cochrane Review, arguing in part that the analysis inappropriately forms conclusions about outcomes in people who are seriously ill based on results obtained primarily in healthy populations, and that the analysis inappropriately included results from people not infected with influenza. The EMA did not change its labeling of the drug in response to the Cochrane study. A 2014 review in the New England Journal of Medicine recommended that all people admitted to intensive care units during influenza outbreaks with a diagnosis of community-acquired pneumonia receive oseltamivir until the absence of influenza infection is established by PCR testing. A 2015 systematic review and meta-analysis found oseltamivir effective at treating the symptoms of influenza, reducing the length of hospitalization, and reducing the risk of otitis media . The same review found that oseltamivir did not significantly increase the risk of adverse events. A 2016 systematic review found that oseltamivir slightly reduced the time it takes for the symptoms of influenza to be alleviated, and that it also increased the risk of "nausea, vomiting, [and] psychiatric events in adults and vomiting in children." The decrease in duration of sickness was about 18 hours. In those who are otherwise healthy the CDC states that antivirals may be considered within the first 48 hours. A German clinical practice guideline recommends against its use. Two 2013 meta-analyses have concluded that benefits in those who are otherwise healthy do not outweigh its risks. When the analysis was restricted to people with confirmed infection, the same 2014 Cochrane Review (see above) found unclear evidence of change in the risk of complications such as pneumonia , while three other reviews found a decreased risk. Together, published studies suggest that oseltamivir reduces the duration of symptoms by 0.5–1.0 day. Any benefit of treatment must be balanced against side effects, which include psychiatric symptoms and increased rates of vomiting. The 2014 Cochrane Collaboration review concluded that oseltamivir did not affect the need for hospitalizations, and that there is no proof of reduction of complications of influenza (such as pneumonia) because of a lack of diagnostic definitions, or reduction of the spread of the virus. There was also evidence that suggested that oseltamivir prevented some people from producing sufficient numbers of their own antibodies to fight infection. The authors recommended that guidance should be revised to take account of the evidence of small benefit and increased risk of harms. The US Centers for Disease Control and Prevention (CDC), the European Centre for Disease Prevention and Control (ECDC), the Public Health England (PHE), the Infectious Disease Society of America (IDSA), the American Academy of Pediatrics (AAP), and Roche (the originator) rejected the recommendations of the 2014 Cochrane Review to urgently change treatment guidelines and drug labels. As of 2017 [ update ] , the CDC does not recommend to use oseltamivir generally for prevention due to concerns that widespread use will encourage resistance development. They recommend that it be considered in those at high risk, who have been exposed to influenza within 48 hours and have not received or only recently been vaccinated. They recommended it during outbreaks in long term care facilities and in those who are significantly immunosuppressed. As of 2011 [ update ] , reviews concluded that when oseltamivir is used preventatively it decreases the risk of exposed people developing symptomatic disease. A systematic review of systematic reviews found low to moderate evidence that it decreases the risk of getting symptomatic influenza by 1 to 12% (a relative decrease of 64 to 92%). It recommended against its use in healthy, low-risk persons due to cost, the risk of resistance development, and side effects and concluded it might be useful for prevention in unvaccinated high risk persons. Common adverse drug reactions (ADRs) associated with oseltamivir therapy (occurring in over 1 percent of people) include nausea and vomiting. In adults, oseltamivir increased the risk of nausea for which the number needed to harm was 28 and for vomiting was 22. So, for every 22 adult people on oseltamivir one experienced vomiting. In the treatment of children, oseltamivir also induced vomiting. The number needed to harm was 19. So, for every 19 children on oseltamivir one experienced vomiting. In prevention there were more headaches, kidney, and psychiatric events. Oseltamivir's effect on the heart is unclear: it may reduce cardiac symptoms, but may also induce serious arrhythmias. Postmarketing reports include liver inflammation and elevated liver enzymes, rash, allergic reactions including anaphylaxis , toxic epidermal necrolysis , abnormal heart rhythms , seizure, confusion, aggravation of diabetes, and haemorrhagic colitis and Stevens–Johnson syndrome . The US and EU package inserts for oseltamivir contain a warning of psychiatric effects observed in post-marketing surveillance. The frequency of these appears to be low and a causative role for oseltamivir has not been established. The 2014 Cochrane Review found a dose-response effect on psychiatric events. In trials of prevention in adults one person was harmed for every 94 treated. Neither of the two most cited published treatment trials of oseltamivir reported any drug-attributable serious adverse events. It is pregnancy category C in the United States and category B in Australia, meaning that it has been taken by a small number of women without signs of problems and in animal studies it looks safe. Dose adjustment may be needed in those with kidney problems. Oseltamivir is a neuraminidase inhibitor , a competitive inhibitor of influenza's neuraminidase enzyme. The enzyme cleaves the sialic acid which is found on glycoproteins on the surface of human cells that helps new virions to exit the cell, preventing new viral particles from being released. The vast majority of mutations conferring resistance are single amino acid residue substitutions (His274Tyr in N1) in the neuraminidase enzyme. A 2011 meta-analysis of 15 studies found a pooled incidence rate for oseltamivir resistance of 2.6%. Subgroup analyses detected higher rates among influenza A patients, especially the H1N1 subtype. It was found that a substantial number of patients might become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance might be significantly associated with pneumonia. In severely immunocompromised patients there were reports of prolonged shedding of oseltamivir- (or zanamivir )-resistant virus, even after oseltamivir treatment was stopped. As of December 15, 2010 [ update ] , the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide showed resistance to oseltamivir. The CDC found sporadic oseltamivir-resistant 2009 H1N1 virus infections had been identified, including with rare episodes of limited transmission, but the public health impact had been limited. Those sporadic cases of resistance were found in immunosuppressed patients during oseltamivir treatment and persons who developed illness while receiving oseltamivir chemoprophylaxis. During 2011, a new influenza A(H1N1)2009 variant with mildly reduced oseltamivir (and zanamivir) sensitivity was detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia. While there is concern that antiviral resistance may develop in people with haematologic malignancies due to their inability to reduce viral loads and several surveillance studies found oseltamivir-resistant pH1N1 after administration of oseltamivir in those people, as of November 2013 [ update ] , widespread transmission of oseltamivir-resistant pH1N1 has not occurred. During the 2007–08 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant. In the 2008–09 season, the proportion of resistant H1N1 increased to 99.4%, while no other seasonal strains (H3N2, B) showed resistance. From 2009 to 2014, oseltamivir resistance was very low in seasonal flu. In the 2010–11 flu season, 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B remained oseltamivir susceptible in the US. In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible. In the 2013–14 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir. Three studies have found resistance in 0%, 3.3%, and 18% of subjects. In the study with the 18% resistance rate, the subjects were children, many of whom had not been previously exposed to influenza virus and therefore had a weakened immune response; the results suggest that higher and earlier dosing may be necessary in such populations. In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals not treated with these drugs. The prevalence was 1.7%. According to the CDC, As of 2019 [ update ] , transmission of oseltamivir-resistant influenza B virus strains—from persons treated with the drug—is rare. As of 2013 [ update ] , H274Y and N294S mutations that confer resistance to oseltamivir have been identified in a few H5N1 isolates from infected patients treated with oseltamivir, and have emerged spontaneously in Egypt. As of 2013 [ update ] , two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation. As of December 15, 2010 [ update ] , the World Health Organization (WHO) reported 314 samples of the prevalent 2009 pandemic H1N1 flu tested worldwide showed resistance to oseltamivir. The CDC found sporadic oseltamivir-resistant 2009 H1N1 virus infections had been identified, including with rare episodes of limited transmission, but the public health impact had been limited. Those sporadic cases of resistance were found in immunosuppressed patients during oseltamivir treatment and persons who developed illness while receiving oseltamivir chemoprophylaxis. During 2011, a new influenza A(H1N1)2009 variant with mildly reduced oseltamivir (and zanamivir) sensitivity was detected in more than 10% of community specimens in Singapore and more than 30% of samples from northern Australia. While there is concern that antiviral resistance may develop in people with haematologic malignancies due to their inability to reduce viral loads and several surveillance studies found oseltamivir-resistant pH1N1 after administration of oseltamivir in those people, as of November 2013 [ update ] , widespread transmission of oseltamivir-resistant pH1N1 has not occurred. During the 2007–08 flu season, the US CDC found 10.9% of H1N1 samples (n=1,020) to be resistant. In the 2008–09 season, the proportion of resistant H1N1 increased to 99.4%, while no other seasonal strains (H3N2, B) showed resistance. From 2009 to 2014, oseltamivir resistance was very low in seasonal flu. In the 2010–11 flu season, 99.1% of H1N1, 99.8% of H3N, and 100% of Influenza B remained oseltamivir susceptible in the US. In January 2012, the US and European CDCs reported all seasonal flu samples tested since October 2011 to be oseltamivir susceptible. In the 2013–14 season only 1% of 2009 H1N1 viruses showed oseltamivir resistance. No other influenza viruses were resistant to oseltamivir. Three studies have found resistance in 0%, 3.3%, and 18% of subjects. In the study with the 18% resistance rate, the subjects were children, many of whom had not been previously exposed to influenza virus and therefore had a weakened immune response; the results suggest that higher and earlier dosing may be necessary in such populations. In 2007, Japanese investigators detected neuraminidase-resistant influenza B virus strains in individuals not treated with these drugs. The prevalence was 1.7%. According to the CDC, As of 2019 [ update ] , transmission of oseltamivir-resistant influenza B virus strains—from persons treated with the drug—is rare. As of 2013 [ update ] , H274Y and N294S mutations that confer resistance to oseltamivir have been identified in a few H5N1 isolates from infected patients treated with oseltamivir, and have emerged spontaneously in Egypt. As of 2013 [ update ] , two of 14 adults infected with A(H7N9) and treated with oseltamivir developed oseltamivir-resistant virus with the Arg292Lys mutation. Its oral bioavailability is over 80% and is extensively metabolised to its active form upon first-pass through the liver. It has a volume of distribution of 23–26 litres. Its half-life is about 1–3 hours and its active carboxylate metabolite has a half-life of 6–10 hours. More than 90% of the oral dose is eliminated in the urine as the active metabolite. Oseltamivir was discovered by scientists at Gilead Sciences using shikimic acid as a starting point for synthesis ; shikimic acid was originally available only as an extract of Chinese star anise ; but by 2006, 30% of the supply was manufactured recombinantly in E. coli. Gilead exclusively licensed their relevant patents to Roche in 1996. The drug's patent has not been protected in Thailand, the Philippines, Indonesia, and several other countries. In 1999, the FDA approved oseltamivir phosphate for the treatment of influenza in adults based on two double-blind, randomized, placebo-controlled clinical trials. In June 2002, the European Medicines Agency (EMA) approved oseltamivir phosphate for prophylaxis and treatment of influenza. In 2003, a pooled analysis of ten randomised clinical trials concluded that oseltamivir reduced the risk of lower respiratory tract infections resulting in antibiotic use and hospital admissions in adults. Oseltamivir (as Tamiflu) was widely used during the H5N1 avian influenza epidemic in Southeast Asia in 2005. [ medical citation needed ] In response to the epidemic, various governments – including those of the United Kingdom, Canada, Israel, United States, and Australia – stockpiled quantities of oseltamivir in preparation for a possible pandemic and there were worldwide shortages of the drug, driven by the high demand for stockpiling. In November 2005, US President George W. Bush requested that Congress fund US$1 billion for the production and stockpile of oseltamivir, after Congress had already approved $1.8 billion for military use of the drug. Defense Secretary Donald Rumsfeld, who was a past chairman of Gilead Sciences, recused himself from all government decisions regarding the drug. In 2006, a Cochrane Review (since withdrawn) raised controversy by concluding that oseltamivir should not be used during routine seasonal influenza because of its low effectiveness. In December 2008, the Indian drug company Cipla won a case in India's court system allowing it to manufacture a cheaper generic version of Tamiflu, called Antiflu. In May 2009, Cipla won approval from the World Health Organization (WHO) certifying that its drug Antiflu was as effective as Tamiflu, and Antiflu is included in the WHO list of prequalified medicinal products. In 2009, a new A/H1N1 influenza virus was discovered to be spreading in North America. In June 2009, the WHO declared the A/H1N1 influenza a pandemic. The National Institute for Health and Care Excellence (NICE), the CDC, the WHO, and the ECDC maintained their recommendation to use oseltamivir. From 2010 to 2012, Cochrane requested Roche's full clinical study reports of their trials, which they did not provide. In 2011, a freedom of information request to the European Medicines Agency (EMA) provided Cochrane with reports from 16 Roche oseltamivir trials. In 2012, the Cochrane team published an interim review based on those reports. In 2013, Roche released 74 full clinical study reports of oseltamivir trials after GSK released the data on zanamivir studies. In 2014, Cochrane published an updated review based solely on full clinical study reports and regulatory documents. In 2016, Roche's oseltamivir patents began to expire. There have been [ when? ] reports of oseltamivir reducing disease severity and hospitalization time in canine parvovirus infection. The drug may limit the ability of the virus to invade the crypt cells of the small intestine and decrease gastrointestinal bacterial colonization and toxin production. Oseltamivir has been deemed ineffective at treating COVID-19 , consistent with the SARS-CoV-2 virus lacking influenza's neuraminidase enzyme.

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influenza virus

https://api.wikimedia.org/core/v1/wikipedia/en/page/2020–2024_H5N1_outbreak/html

2020–2024 H5N1 outbreak

Since 2020, global cases of avian influenza subtype H5N1 have been rising, with cases reported from every continent as of February 2023 except for Australia and Antarctica . In late 2023, H5N1 was discovered in the Antarctic for the first time, raising fears of imminent spread throughout the region, potentially leading to a "catastrophic breeding failure" among animals that had not previously been exposed to avian influenza viruses. The virus involved in the outbreak is classified in H5 clade 2.3.4.4b. H5N6 and H5N8 viruses with the H5-2.3.4.4b hemagglutinin (HA) gene became prominent globally among poultry in 2018 – 2020. In 2020, reassortment (genetic "swapping") between these H5-2.3.4.4b poultry viruses and N1 wild bird viruses led to the emergence of a H5N1 with a H5-2.3.4.4b gene. The virus then spread across Europe, detected there in autumn , before spreading to Africa and Asia . It continues to swap genes with local flu viruses as it travels the globe. : (fig.1) In May 2021, H5N1 was detected in wild red foxes in the Netherlands . It was later detected in December in Estonia in wild foxes. In January 2022, an infection in an eighty-year-old man was reported, who raised ducks in England . Also in January, infections were reported from the United States in wild birds. In February, infections were reported from commercial poultry centres in the U.S., and Peru reported infections in sea lions . The virus continued to spread further, infecting additional species of mammals. In October, a mink farm in northwest Spain was affected. A human case of H5N1 was reported in the U.S. in April, "though this detection may have been the result of contamination of the nasal passages with the virus rather than actual infection." In September, Spain reported a human case; this was followed by a second case in November, in a person who worked at the same poultry farm as the first. Both were asymptomatic. In November, China reported a human case, infected due to contact with poultry. The case died from their infection. H5N1 was first detected in the islands of the Antarctic region in October 2023, via a brown skua on Bird Island, near South Georgia . Within several months, hundreds of elephant seals were found dead, as well as fur seals, kelp gulls and further brown skua. In December 2023, conservation officials confirmed that a polar bear had died of H5N1 near Alaska's northernmost city, Utqiagvik . In February 2023, Cambodia reported the death of a girl due to H5N1 infection after developing symptoms on 16 February. The girl's father also tested positive for the virus. The World Health Organization (WHO) described the situation as "worrying" and urged "heightened vigilance". Further sequencing determined that at least one of the two cases was from an older H5N1 clade, 2.3.2.1c, which had circulated as a common H5N1 strain in Cambodia for many years, rather than the more recent clade 2.3.4.4b, which had caused mass poultry deaths since 2020. This older clade had jumped to humans in the past yet hadn't previously resulted in any known human-to-human transmission. On March 1, 2023, as Taiwan raised its travel alert for Cambodia, the WHO and the U.S. Center for Disease and Control and Prevention (CDC) , in concert with Cambodian authorities, determined that both of the individuals had been infected through direct contact with poultry. In late February 2023, Argentina confirmed a case of H5N1 in industrial poultry, in the Rio Negro province. Avian product exports were suspended as a result. In March 2023, H5N1 was detected in black-necked swan populations in Carlos Anwandter Nature Sanctuary , Chile and Uruguay . In Uruguay the death of ten swans found in the locality of Estación Tapia was attributed to flu. Previously in Uruguay ten hens had died because of the flu in El Monarca, Montevideo . In late March 2023, Chile detected H5N1 in a 53 year-old man who had severe symptoms. The patient survived but had to stay on a ventilator. The virus was determined to be in the 2.3.4.4b lineage. In September 2023, Uruguay reported upwards of 400 seals and sea lions found dead of H5N1 on the nation's Atlantic coastline and along the River Plate . According to a 2024 paper, a large outbreak of H5N1 killed 70% of elephant seal pups born in the 2023 breeding season. In surveyed areas of Península Valdés , Argentina, seal mortality rates exceed 96%. A February 2024 article reports that the outbreak in South America has, since 2022, killed at least 600,000 wild birds and 50,000 mammals. On April 1 a domestic dog in Ottawa , Canada was tested positive for H5N1. On May 22, Brazil declared an 180-day "animal health emergency" in response to eight cases of H5N1 found in wild birds. Although Brazil's major poultry-producing regions are in the country's south and the infections were found in Espirito Santo state and Rio de Janeiro state, Brazil, as the world's largest exporter of chicken meat, created an emergency operations center to plan for and mitigate potential further spread of H5N1. A cluster of five human infections of H5N1 occurred in Cambodia in late January and early February. All patients had recent contact with sick poultry. One patient died. Sequencing of two of the patients indicate that they were infected by clade 2.3.2.1c, which is not the same same as the 2.3.4.4b clade virus that is causing global outbreaks in the US and beyond. A person in Vietnam died of H5N1 infection around the same time. It remains unreported which clade of H5 virus the patient in Vietnam was infected by. However, an April 2024 statement from the FAO reports that recent (~2023) reassortment in the Greater Mekong Subregion has produced viruses that carry internal genes from the new 2.3.4.4b virus but the H5 gene from the old 2.3.2.1c lineage. The FAO also states that the new type of virus is implicate in human cases, but it does not specify which. On April 5, the Philippines reported a H5N1 outbreak on a poultry farm in Leyte , which killed 4,475 birds. Earlier in the year, the Philippines Department of Agriculture temporarily banned poultry exports from several countries including Japan, Belgium, and France. On April 18, a H5N1 outbreak was detected in ducks in two parts in Alappuzha district , Kerala . The disease was confirmed in a lab for ducks reared in the area. The District Collector has decided to initiate the process of culling domestic birds within a 1 kilometre radius from the epicentre of the outbreak. The US CDC continues to report "widespread" occurrence in wild birds, "sporadic outbreaks" in poultry flocks, and "sporadic infections" as of March 2024. As of March 8, 2024, the United States Department of Agriculture's (USDA) Animal and Plant Health Inspection Service (APHIS) had recorded around 20 mammal species confirmed as being able to be infected by H5N1. Also in March 2024, H5N1 was confirmed to have infected farmed goats and cows in the USA. On April 2, a dairy worker in Texas became infected and strong indications of cow-to-cow spread were evident as cow herds in five different states became ill. A few days later on April 4, H5N1 was confirmed to have spread to several additional dairy herds in six US states including Texas, along with Idaho, Kansas, New Mexico, Ohio and Michigan. Scientists have deemed these to be either cow-to-cow transmission or spillover from wild birds . On April 11, H5N1 was found in dairy cattle herds in North Carolina and South Dakota. On April 10, researchers found several cases of HPAI H5N1 in animals in New York City, including three Canada geese, a red-tailed hawk, a peregrine falcon, and a chicken. H5N1 was detected in dead birds on the Antarctic mainland for the first time in February 2024. In February, scientists found H5N1 in 12 Antarctic skua seabirds carcasses on Beak Island . Additional cases have also been found at Hope Bay and on the Devil and Paulet islands . In March, scientists detected the virus in the nine Adélie penguins and one Antarctic cormorant . H5N6 and H5N8 viruses with the H5-2.3.4.4b hemagglutinin (HA) gene became prominent globally among poultry in 2018 – 2020. In 2020, reassortment (genetic "swapping") between these H5-2.3.4.4b poultry viruses and N1 wild bird viruses led to the emergence of a H5N1 with a H5-2.3.4.4b gene. The virus then spread across Europe, detected there in autumn , before spreading to Africa and Asia . It continues to swap genes with local flu viruses as it travels the globe. : (fig.1)In May 2021, H5N1 was detected in wild red foxes in the Netherlands . It was later detected in December in Estonia in wild foxes. In January 2022, an infection in an eighty-year-old man was reported, who raised ducks in England . Also in January, infections were reported from the United States in wild birds. In February, infections were reported from commercial poultry centres in the U.S., and Peru reported infections in sea lions . The virus continued to spread further, infecting additional species of mammals. In October, a mink farm in northwest Spain was affected. A human case of H5N1 was reported in the U.S. in April, "though this detection may have been the result of contamination of the nasal passages with the virus rather than actual infection." In September, Spain reported a human case; this was followed by a second case in November, in a person who worked at the same poultry farm as the first. Both were asymptomatic. In November, China reported a human case, infected due to contact with poultry. The case died from their infection. H5N1 was first detected in the islands of the Antarctic region in October 2023, via a brown skua on Bird Island, near South Georgia . Within several months, hundreds of elephant seals were found dead, as well as fur seals, kelp gulls and further brown skua. In December 2023, conservation officials confirmed that a polar bear had died of H5N1 near Alaska's northernmost city, Utqiagvik . In February 2023, Cambodia reported the death of a girl due to H5N1 infection after developing symptoms on 16 February. The girl's father also tested positive for the virus. The World Health Organization (WHO) described the situation as "worrying" and urged "heightened vigilance". Further sequencing determined that at least one of the two cases was from an older H5N1 clade, 2.3.2.1c, which had circulated as a common H5N1 strain in Cambodia for many years, rather than the more recent clade 2.3.4.4b, which had caused mass poultry deaths since 2020. This older clade had jumped to humans in the past yet hadn't previously resulted in any known human-to-human transmission. On March 1, 2023, as Taiwan raised its travel alert for Cambodia, the WHO and the U.S. Center for Disease and Control and Prevention (CDC) , in concert with Cambodian authorities, determined that both of the individuals had been infected through direct contact with poultry. In late February 2023, Argentina confirmed a case of H5N1 in industrial poultry, in the Rio Negro province. Avian product exports were suspended as a result. In March 2023, H5N1 was detected in black-necked swan populations in Carlos Anwandter Nature Sanctuary , Chile and Uruguay . In Uruguay the death of ten swans found in the locality of Estación Tapia was attributed to flu. Previously in Uruguay ten hens had died because of the flu in El Monarca, Montevideo . In late March 2023, Chile detected H5N1 in a 53 year-old man who had severe symptoms. The patient survived but had to stay on a ventilator. The virus was determined to be in the 2.3.4.4b lineage. In September 2023, Uruguay reported upwards of 400 seals and sea lions found dead of H5N1 on the nation's Atlantic coastline and along the River Plate . According to a 2024 paper, a large outbreak of H5N1 killed 70% of elephant seal pups born in the 2023 breeding season. In surveyed areas of Península Valdés , Argentina, seal mortality rates exceed 96%. A February 2024 article reports that the outbreak in South America has, since 2022, killed at least 600,000 wild birds and 50,000 mammals. On April 1 a domestic dog in Ottawa , Canada was tested positive for H5N1. On May 22, Brazil declared an 180-day "animal health emergency" in response to eight cases of H5N1 found in wild birds. Although Brazil's major poultry-producing regions are in the country's south and the infections were found in Espirito Santo state and Rio de Janeiro state, Brazil, as the world's largest exporter of chicken meat, created an emergency operations center to plan for and mitigate potential further spread of H5N1. H5N1 was first detected in the islands of the Antarctic region in October 2023, via a brown skua on Bird Island, near South Georgia . Within several months, hundreds of elephant seals were found dead, as well as fur seals, kelp gulls and further brown skua. In December 2023, conservation officials confirmed that a polar bear had died of H5N1 near Alaska's northernmost city, Utqiagvik . In February 2023, Cambodia reported the death of a girl due to H5N1 infection after developing symptoms on 16 February. The girl's father also tested positive for the virus. The World Health Organization (WHO) described the situation as "worrying" and urged "heightened vigilance". Further sequencing determined that at least one of the two cases was from an older H5N1 clade, 2.3.2.1c, which had circulated as a common H5N1 strain in Cambodia for many years, rather than the more recent clade 2.3.4.4b, which had caused mass poultry deaths since 2020. This older clade had jumped to humans in the past yet hadn't previously resulted in any known human-to-human transmission. On March 1, 2023, as Taiwan raised its travel alert for Cambodia, the WHO and the U.S. Center for Disease and Control and Prevention (CDC) , in concert with Cambodian authorities, determined that both of the individuals had been infected through direct contact with poultry. In late February 2023, Argentina confirmed a case of H5N1 in industrial poultry, in the Rio Negro province. Avian product exports were suspended as a result. In March 2023, H5N1 was detected in black-necked swan populations in Carlos Anwandter Nature Sanctuary , Chile and Uruguay . In Uruguay the death of ten swans found in the locality of Estación Tapia was attributed to flu. Previously in Uruguay ten hens had died because of the flu in El Monarca, Montevideo . In late March 2023, Chile detected H5N1 in a 53 year-old man who had severe symptoms. The patient survived but had to stay on a ventilator. The virus was determined to be in the 2.3.4.4b lineage. In September 2023, Uruguay reported upwards of 400 seals and sea lions found dead of H5N1 on the nation's Atlantic coastline and along the River Plate . According to a 2024 paper, a large outbreak of H5N1 killed 70% of elephant seal pups born in the 2023 breeding season. In surveyed areas of Península Valdés , Argentina, seal mortality rates exceed 96%. A February 2024 article reports that the outbreak in South America has, since 2022, killed at least 600,000 wild birds and 50,000 mammals. On April 1 a domestic dog in Ottawa , Canada was tested positive for H5N1. On May 22, Brazil declared an 180-day "animal health emergency" in response to eight cases of H5N1 found in wild birds. Although Brazil's major poultry-producing regions are in the country's south and the infections were found in Espirito Santo state and Rio de Janeiro state, Brazil, as the world's largest exporter of chicken meat, created an emergency operations center to plan for and mitigate potential further spread of H5N1. A cluster of five human infections of H5N1 occurred in Cambodia in late January and early February. All patients had recent contact with sick poultry. One patient died. Sequencing of two of the patients indicate that they were infected by clade 2.3.2.1c, which is not the same same as the 2.3.4.4b clade virus that is causing global outbreaks in the US and beyond. A person in Vietnam died of H5N1 infection around the same time. It remains unreported which clade of H5 virus the patient in Vietnam was infected by. However, an April 2024 statement from the FAO reports that recent (~2023) reassortment in the Greater Mekong Subregion has produced viruses that carry internal genes from the new 2.3.4.4b virus but the H5 gene from the old 2.3.2.1c lineage. The FAO also states that the new type of virus is implicate in human cases, but it does not specify which. On April 5, the Philippines reported a H5N1 outbreak on a poultry farm in Leyte , which killed 4,475 birds. Earlier in the year, the Philippines Department of Agriculture temporarily banned poultry exports from several countries including Japan, Belgium, and France. On April 18, a H5N1 outbreak was detected in ducks in two parts in Alappuzha district , Kerala . The disease was confirmed in a lab for ducks reared in the area. The District Collector has decided to initiate the process of culling domestic birds within a 1 kilometre radius from the epicentre of the outbreak. The US CDC continues to report "widespread" occurrence in wild birds, "sporadic outbreaks" in poultry flocks, and "sporadic infections" as of March 2024. As of March 8, 2024, the United States Department of Agriculture's (USDA) Animal and Plant Health Inspection Service (APHIS) had recorded around 20 mammal species confirmed as being able to be infected by H5N1. Also in March 2024, H5N1 was confirmed to have infected farmed goats and cows in the USA. On April 2, a dairy worker in Texas became infected and strong indications of cow-to-cow spread were evident as cow herds in five different states became ill. A few days later on April 4, H5N1 was confirmed to have spread to several additional dairy herds in six US states including Texas, along with Idaho, Kansas, New Mexico, Ohio and Michigan. Scientists have deemed these to be either cow-to-cow transmission or spillover from wild birds . On April 11, H5N1 was found in dairy cattle herds in North Carolina and South Dakota. On April 10, researchers found several cases of HPAI H5N1 in animals in New York City, including three Canada geese, a red-tailed hawk, a peregrine falcon, and a chicken. H5N1 was detected in dead birds on the Antarctic mainland for the first time in February 2024. In February, scientists found H5N1 in 12 Antarctic skua seabirds carcasses on Beak Island . Additional cases have also been found at Hope Bay and on the Devil and Paulet islands . In March, scientists detected the virus in the nine Adélie penguins and one Antarctic cormorant . A cluster of five human infections of H5N1 occurred in Cambodia in late January and early February. All patients had recent contact with sick poultry. One patient died. Sequencing of two of the patients indicate that they were infected by clade 2.3.2.1c, which is not the same same as the 2.3.4.4b clade virus that is causing global outbreaks in the US and beyond. A person in Vietnam died of H5N1 infection around the same time. It remains unreported which clade of H5 virus the patient in Vietnam was infected by. However, an April 2024 statement from the FAO reports that recent (~2023) reassortment in the Greater Mekong Subregion has produced viruses that carry internal genes from the new 2.3.4.4b virus but the H5 gene from the old 2.3.2.1c lineage. The FAO also states that the new type of virus is implicate in human cases, but it does not specify which. On April 5, the Philippines reported a H5N1 outbreak on a poultry farm in Leyte , which killed 4,475 birds. Earlier in the year, the Philippines Department of Agriculture temporarily banned poultry exports from several countries including Japan, Belgium, and France. On April 18, a H5N1 outbreak was detected in ducks in two parts in Alappuzha district , Kerala . The disease was confirmed in a lab for ducks reared in the area. The District Collector has decided to initiate the process of culling domestic birds within a 1 kilometre radius from the epicentre of the outbreak. The US CDC continues to report "widespread" occurrence in wild birds, "sporadic outbreaks" in poultry flocks, and "sporadic infections" as of March 2024. As of March 8, 2024, the United States Department of Agriculture's (USDA) Animal and Plant Health Inspection Service (APHIS) had recorded around 20 mammal species confirmed as being able to be infected by H5N1. Also in March 2024, H5N1 was confirmed to have infected farmed goats and cows in the USA. On April 2, a dairy worker in Texas became infected and strong indications of cow-to-cow spread were evident as cow herds in five different states became ill. A few days later on April 4, H5N1 was confirmed to have spread to several additional dairy herds in six US states including Texas, along with Idaho, Kansas, New Mexico, Ohio and Michigan. Scientists have deemed these to be either cow-to-cow transmission or spillover from wild birds . On April 11, H5N1 was found in dairy cattle herds in North Carolina and South Dakota. On April 10, researchers found several cases of HPAI H5N1 in animals in New York City, including three Canada geese, a red-tailed hawk, a peregrine falcon, and a chicken. H5N1 was detected in dead birds on the Antarctic mainland for the first time in February 2024. In February, scientists found H5N1 in 12 Antarctic skua seabirds carcasses on Beak Island . Additional cases have also been found at Hope Bay and on the Devil and Paulet islands . In March, scientists detected the virus in the nine Adélie penguins and one Antarctic cormorant . H5-2.3.4.4b can be prevented by vaccination in chickens. The H5-Re14 (2.3.4.4b) strain used in updated vaccines since 2022 is a reasonably good match for the new virus.

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influenza virus

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Influenza prevention

Influenza prevention involves taking steps that one can use to decrease their chances of contracting flu viruses, such as the Pandemic H1N1/09 virus , responsible for the 2009 flu pandemic .People who contract influenza are most infective between the second and third days after infection, and infectivity lasts for around ten days. Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection. The transmission of influenza can be modeled mathematically , which helps predict how the virus will spread in a population. Influenza can be spread in three main ways: The relative importance of these three modes of transmission is unclear, and they may all contribute to the spread of the virus. In the airborne route, the droplets that are small enough for people to inhale are 0.5 to 5 µm in diameter and inhaling just one droplet might be enough to cause an infection. Although a single sneeze releases up to 40,000 droplets, most of these droplets are quite large and will quickly settle out of the air. How long influenza survives in airborne droplets seems to be influenced by the levels of humidity and UV radiation : with low humidity and a lack of sunlight in winter probably aiding its survival. As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such as banknotes, doorknobs, light switches and other household items. The length of time the virus will persist on a surface varies, with the virus surviving for one to two days on hard, non-porous surfaces such as plastic or metal, for about fifteen minutes from dry paper tissues, and only five minutes on skin. However, if the virus is present in mucus, this can protect it for longer periods. Avian influenza viruses can survive indefinitely when frozen. They are inactivated by heating to 56 °C (133 °F) for a minimum of 60 minutes, as well as by acids (at pH <2). According to the World Health Organization (WHO), the "main route of transmission of the pandemic influenza virus seems to be similar to seasonal influenza , via droplets that are expelled by speaking, sneezing or coughing." One of WHO's recommendations is to "keep your distance from people who show symptoms of influenza-like illness, such as coughing and sneezing (trying to maintain a distance of about 1 metre if possible)." Other WHO recommendations are listed below. The American Centers for Disease Control and Prevention (CDC) agrees that the "spread of novel H1N1 virus is thought to occur in the same way that seasonal flu spreads. Flu viruses are spread mainly from person to person through coughing or sneezing by people with influenza." The CDC also says that a person may become infected if he or she touches something with flu viruses on it "and then touches his or her eyes, nose, or mouth." Researchers have demonstrated anti-bodies against H1N1 variant influenza in 10 to 7 percent of workers and residents of swine farms in Jiangsu Province, China. Residents of a nearby city did not have detectable anti-bodies to H1N1 variant influenza. According to the World Health Organization (WHO), the "main route of transmission of the pandemic influenza virus seems to be similar to seasonal influenza , via droplets that are expelled by speaking, sneezing or coughing." One of WHO's recommendations is to "keep your distance from people who show symptoms of influenza-like illness, such as coughing and sneezing (trying to maintain a distance of about 1 metre if possible)." Other WHO recommendations are listed below. The American Centers for Disease Control and Prevention (CDC) agrees that the "spread of novel H1N1 virus is thought to occur in the same way that seasonal flu spreads. Flu viruses are spread mainly from person to person through coughing or sneezing by people with influenza." The CDC also says that a person may become infected if he or she touches something with flu viruses on it "and then touches his or her eyes, nose, or mouth." Researchers have demonstrated anti-bodies against H1N1 variant influenza in 10 to 7 percent of workers and residents of swine farms in Jiangsu Province, China. Residents of a nearby city did not have detectable anti-bodies to H1N1 variant influenza. Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits such as: not touching your eyes, nose or mouth; frequent hand washing (with soap and water, or with alcohol-based hand rubs); covering coughs and sneezes; avoiding close contact with sick people; and staying home yourself if you are sick. Avoiding spitting is also recommended. Although face masks might help prevent transmission when caring for the sick, there is mixed evidence on beneficial effects in the community. Smoking raises the risk of contracting influenza, as well as producing more severe disease symptoms. Thus, according to the laws of mathematical modelling of infectious diseases , smokers raise the exponential growth rates of influenza epidemics and may indirectly be responsible for a large percentage of influenza cases. [ citation needed ] Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may help prevent some infections. Alcohol is an effective sanitizer against influenza viruses, while quaternary ammonium compounds can be used with alcohol so that the sanitizing effect lasts for longer. In hospitals, quaternary ammonium compounds and bleach are used to sanitize rooms or equipment that have been occupied by patients with influenza symptoms. At home, this can be done effectively with a diluted chlorine bleach. Social distancing strategies used during past pandemics, such as closing schools, churches and theaters, slowed the spread of the virus but did not have a large effect on the overall death rate. It is uncertain if reducing public gatherings, by for example closing schools and workplaces, will reduce transmission since people with influenza may just be moved from one area to another; such measures would also be difficult to enforce and might be unpopular. When small numbers of people are infected, isolating the sick might reduce the risk of transmission. According to studies conducted in Australia and Japan, screening individuals for influenza symptoms at airports during the 2009 H1N1 outbreak was not an effective method of infection control. The Centers for Disease Control and Prevention (CDCP) recommends that businesses promote and administer annual flu vaccination within the workplace. Additional measures include reducing potential for exposure through increasing awareness of flu symptoms, using good cough and sneeze etiquette, staying home when ill, and frequent hand washing. The Occupational Health and Safety Administration (OSHA) recommends these controls to employers to decrease transmission of influenza in the workplace: Promotion, administration, and easy access to the flu vaccine Encourage sick workers to stay home Hand hygiene and cough etiquette Use airborne infection isolation rooms, when appropriate Ensure properly functioning heating, ventilation, and air conditioning (HVAC) systems Limit transport of infected patients Limit the number of staff who come in contact with flu patients Provide personal protective equipment (PPE) such as gloves, gowns, masks, to health care staff as well as disposal facilities Specific occupations with increased risk of influenza infection include health care, education and child care, air line industry, and agricultural workers. According to the WHO, you can decrease your chance of contracting the flu virus by taking the following steps: Get yourself (or family members age 6 months and older) vaccinated against current strains of influenza, if possible. Keep your distance from people who show symptoms of influenza-like illness, such as coughing and sneezing (trying to maintain a distance of about 1 metre if possible); Clean your hands thoroughly with soap and water, or cleanse them with an alcohol-based hand rub on a regular basis (especially if touching surfaces that are potentially contaminated); Avoid touching your mouth, nose and eyes as much as possible; Reduce the time spent in crowded settings if possible; Improve airflow in your living space by opening windows; Practice good health habits (including adequate sleep, eating nutritious food, and keeping physically active) The CDCP lists these as important ways to lower the risk of transmission: Cover the nose and mouth with a tissue when coughing or sneezing. Throw tissues in the trash after use; Wash hands often with soap and water, especially after coughing or sneezing. Alcohol-based hand cleaners are also effective; Avoid touching the eyes, nose, or mouth. Germs spread this way; Try to avoid close contact with sick people; Those sick with flu-like illness are recommended to stay home for at least 24 hours after their fever is gone, except to get medical care or for other necessities. (The fever should be gone without the use of a fever-reducing medicine.) The sickened are advised to keep away from others as much as possible to avoid making others sick.The Centers for Disease Control and Prevention (CDCP) recommends that businesses promote and administer annual flu vaccination within the workplace. Additional measures include reducing potential for exposure through increasing awareness of flu symptoms, using good cough and sneeze etiquette, staying home when ill, and frequent hand washing. The Occupational Health and Safety Administration (OSHA) recommends these controls to employers to decrease transmission of influenza in the workplace: Promotion, administration, and easy access to the flu vaccine Encourage sick workers to stay home Hand hygiene and cough etiquette Use airborne infection isolation rooms, when appropriate Ensure properly functioning heating, ventilation, and air conditioning (HVAC) systems Limit transport of infected patients Limit the number of staff who come in contact with flu patients Provide personal protective equipment (PPE) such as gloves, gowns, masks, to health care staff as well as disposal facilities Specific occupations with increased risk of influenza infection include health care, education and child care, air line industry, and agricultural workers.According to the WHO, you can decrease your chance of contracting the flu virus by taking the following steps: Get yourself (or family members age 6 months and older) vaccinated against current strains of influenza, if possible. Keep your distance from people who show symptoms of influenza-like illness, such as coughing and sneezing (trying to maintain a distance of about 1 metre if possible); Clean your hands thoroughly with soap and water, or cleanse them with an alcohol-based hand rub on a regular basis (especially if touching surfaces that are potentially contaminated); Avoid touching your mouth, nose and eyes as much as possible; Reduce the time spent in crowded settings if possible; Improve airflow in your living space by opening windows; Practice good health habits (including adequate sleep, eating nutritious food, and keeping physically active) The CDCP lists these as important ways to lower the risk of transmission: Cover the nose and mouth with a tissue when coughing or sneezing. Throw tissues in the trash after use; Wash hands often with soap and water, especially after coughing or sneezing. Alcohol-based hand cleaners are also effective; Avoid touching the eyes, nose, or mouth. Germs spread this way; Try to avoid close contact with sick people; Those sick with flu-like illness are recommended to stay home for at least 24 hours after their fever is gone, except to get medical care or for other necessities. (The fever should be gone without the use of a fever-reducing medicine.) The sickened are advised to keep away from others as much as possible to avoid making others sick.Watch for emergency warning signs that need urgent medical attention. These warning signs include: [ citation needed ] Fast breathing or trouble breathing Bluish or gray skin color Not drinking enough fluids Not urinating or no tears when crying Severe or persistent vomiting Not waking up or not interacting Being so irritable that the child does not want to be held Pain or pressure in the chest or abdomen Sudden dizziness Confusion Flu-like symptoms improve but then return with fever and worse cough In the 2009 pandemic, the initial demand for vaccine greatly outstripped the supply. As the 2009 pandemic got underway, the first vaccine to become available in the United States by mid-October 2009 was about 2.2 million doses of the weakened live-virus nasal spray formulation . This form was not then recommended for some of the people who were at highest risk of complications from flu, including pregnant women and people with asthma. [ citation needed ] The attenuated live virus was instead suggested to be used to allow some priority groups like health care workers and healthy children 2 or older, to allow them to be vaccinated immediately. Those to whom the weakened virus might pose a heightened risk were recommended to wait for the release of killed-virus vaccines, which followed weeks to months later. [ citation needed ] Vaccine uptake by the public was very low in the UK, but predicted by greater belief in the vaccine's efficacy and safety and a greater perceived risk of the disease. A survey of Americans done in late June 2009 by the Harvard School of Public Health found that roughly 90% said they would be willing to avoid shopping malls, movie theaters, public transportation, and worship services for more than two weeks if health officials told them to. It also found that parents were worried about closures of schools or day care centers, with 43% saying they would lose pay or have money problems if they had to stay home a week or more because they were sick or had to care for someone. In the UK, the government established a National Pandemic Flu Service with a hotline and website, enabling persons with symptoms to get advice or obtain drugs without first getting a prescription from a doctor. Individuals with increased exposure to animals, especially birds and swine, are at increased risk of variant influenza infection. This includes agricultural workers, as well as residents of farms, individuals who keep swine and/or birds as pets, and animal exhibitors. Variant influenza viruses do not normally infect humans, but when they do cause human infection, the virus can be passed from animals to humans directly, or between humans. Due to human to human transmission, family and close contacts of agricultural workers are at increased risk of influenza as well. Unfortunately, there is also decreased access to health care in agricultural communities which makes prevention and response to influenza outbreaks more difficult. During the 2009 H1N1 pandemic, multiple factors were identified as increasing the vulnerability of agricultural workers and their communities. These factors included substandard housing, immigration status, scape-goating, economic barriers, communication and cultural barriers, and discrimination. Steege et al., found that 75% of agricultural workers were uninsured, making them less likely to receive the flu vaccine and less likely to seek care when ill. Public health recommendations for agricultural communities: surveillance of agricultural workers Inclusion of agricultural workers in prevention efforts and planning Separating ICE from emergency services Increased access to influenza vaccination Risk reduction training (cough etiquette, etc.) PPE use Workplace Sanitation Recommendations for agricultural workers and exhibitors: Influenza vaccination Limit time swine are kept on the fairgrounds to no more than 72 hours Wash hands with soap and water when leaving the barn Restrict food and drink in animal area Do not sleep in animal areas Additional recommendations for visitors to agricultural exhibits: High Risk: Defined as people younger than 5 years, older than 65 years, pregnant women, and people with chronic illnesses. Avoid pigs and swine barns Low Risk: Don't eat, drink, or apply anything to your mouth in pig areas Don't take toys, pacifiers, cups, baby bottles, strollers, or similar items into pig areas Avoid close contact with pigs that look or act ill Use gloves, protective clothing, masks if contact with ill pigs Wash your hands often with soap and running water before and after exposure to pigs. If soap and water are not available, use an alcohol-based hand rub. Watch your pig(s) for signs of illness. Call a veterinarian if you suspect illness. Avoid contact with pigs if you have flu symptoms. Wait until you have been fever-free for 7 days or until you have been without fever for 24 hours without taking temperature-reducing medications; whichever is longer If you become ill, contact a health care provider. Let them know you are higher risk and about any recent exposure to pigs or swine barns. The same medications that are used for seasonal flu can be used for variant virus infection. Defined as people younger than 5 years, older than 65 years, pregnant women, and people with chronic illnesses. Avoid pigs and swine barns Don't eat, drink, or apply anything to your mouth in pig areas Don't take toys, pacifiers, cups, baby bottles, strollers, or similar items into pig areas Avoid close contact with pigs that look or act ill Use gloves, protective clothing, masks if contact with ill pigs Wash your hands often with soap and running water before and after exposure to pigs. If soap and water are not available, use an alcohol-based hand rub. Watch your pig(s) for signs of illness. Call a veterinarian if you suspect illness. Avoid contact with pigs if you have flu symptoms. Wait until you have been fever-free for 7 days or until you have been without fever for 24 hours without taking temperature-reducing medications; whichever is longer If you become ill, contact a health care provider. Let them know you are higher risk and about any recent exposure to pigs or swine barns. The same medications that are used for seasonal flu can be used for variant virus infection.

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influenza virus

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Antigenic variation

Antigenic variation or antigenic alteration refers to the mechanism by which an infectious agent such as a protozoan , bacterium or virus alters the proteins or carbohydrates on its surface and thus avoids a host immune response , making it one of the mechanisms of antigenic escape . It is related to phase variation . Antigenic variation not only enables the pathogen to avoid the immune response in its current host, but also allows re-infection of previously infected hosts. Immunity to re-infection is based on recognition of the antigens carried by the pathogen, which are "remembered" by the acquired immune response . If the pathogen's dominant antigen can be altered, the pathogen can then evade the host's acquired immune system. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates . Antigenic variation can result from gene conversion , site-specific DNA inversions, hypermutation , or recombination of sequence cassettes. The result is that even a clonal population of pathogens expresses a heterogeneous phenotype . Many of the proteins known to show antigenic or phase variation are related to virulence . Antigenic variation in bacteria is best demonstrated by species of the genus Neisseria (most notably, Neisseria meningitidis and Neisseria gonorrhoeae , the gonococcus); species of the genus Streptococcus and the Mycoplasma . The Neisseria species vary their pili (protein polymers made up of subunits called pilin which play a critical role in bacterial adhesion , and stimulate a vigorous host immune response) and the Streptococci vary their M-protein. In the bacterium Borrelia burgdorferi , the cause of Lyme disease , the surface lipoprotein VlsE can undergo recombination which results in antigenic diversity. The bacterium carries a plasmid that contains fifteen silent vls cassettes and one functional copy of vlsE . Segments of the silent cassettes recombine with the vlsE gene, generating variants of the surface lipoprotein antigen. Antigenic variation is employed by a number of different protozoan parasites. Trypanosoma brucei and Plasmodium falciparum are some of the best studied examples. Trypanosoma brucei , the organism that causes sleeping sickness , replicates extracellularly in the bloodstream of infected mammals and is subjected to numerous host defense mechanisms including the complement system , and the innate and adaptive immune systems. To protect itself, the parasite decorates itself with a dense, homogeneous coat (~10^7 molecules) of the variant surface glycoprotein (VSG). In the early stages of invasion, the VSG coat is sufficient to protect the parasite from immune detection. The host eventually identifies the VSG as a foreign antigen and mounts an attack against the microbe. However, the parasite's genome has over 1,000 genes that code for different variants of the VSG protein, located on the subtelomeric portion of large chromosomes , or on intermediate chromosomes. These VSG genes become activated by gene conversion in a hierarchical order: telomeric VSGs are activated first, followed by array VSGs, and finally pseudogene VSGs. Only one VSG is expressed at any given time. Each new gene is switched in turn into a VSG expression site (ES). This process is partially dependent on homologous recombination of DNA, which is mediated in part by the interaction of the T. brucei BRCA2 gene with RAD51 (however, this is not the only possible mechanism, as BRCA2 variants still display some VSG switching). In addition to homologous recombination, transcriptional regulation is also important in antigen switching, since T. brucei has multiple potential expression sites. A new VSG can either be selected by transcriptional activation of a previously silent ES, or by recombination of a VSG sequence into the active ES (see figure, "Mechanisms of VSG Switching in T. brucei "). Although the biological triggers that result in VSG switching are not fully known, mathematical modeling suggests that the ordered appearance of different VSG variants is controlled by at least two key parasite-derived factors: differential activation rates of parasite VSG and density-dependent parasite differentiation. Plasmodium falciparum , the major etiologic agent of human malaria, has a very complex life cycle that occurs in both humans and mosquitoes. While in the human host, the parasite spends most of its life cycle within hepatic cells and erythrocytes (in contrast to T. brucei which remains extracellular). As a result of its mainly intracellular niche, parasitized host cells which display parasite proteins must be modified to prevent destruction by the host immune defenses. In the case of Plasmodium , this is accomplished via the dual purpose Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is encoded by the diverse family of genes known as the var family of genes (approximately 60 genes in all). The diversity of the gene family is further increased via a number of different mechanisms including exchange of genetic information at telomeric loci, as well as meiotic recombination. The PfEMP1 protein serves to sequester infected erythrocytes from splenic destruction via adhesion to the endothelium . Moreover, the parasite is able to evade host defense mechanisms by changing which var allele is used to code the PfEMP1 protein. Like T. brucei , each parasite expresses multiple copies of one identical protein. However, unlike T. brucei , the mechanism by which var switching occurs in P. falciparum is thought to be purely transcriptional. Var switching has been shown to take place soon after invasion of an erythrocyte by a P. falciparum parasite. Fluorescent in situ hybridization analysis has shown that activation of var alleles is linked to altered positioning of the genetic material to distinct "transcriptionally permissive" areas. Trypanosoma brucei , the organism that causes sleeping sickness , replicates extracellularly in the bloodstream of infected mammals and is subjected to numerous host defense mechanisms including the complement system , and the innate and adaptive immune systems. To protect itself, the parasite decorates itself with a dense, homogeneous coat (~10^7 molecules) of the variant surface glycoprotein (VSG). In the early stages of invasion, the VSG coat is sufficient to protect the parasite from immune detection. The host eventually identifies the VSG as a foreign antigen and mounts an attack against the microbe. However, the parasite's genome has over 1,000 genes that code for different variants of the VSG protein, located on the subtelomeric portion of large chromosomes , or on intermediate chromosomes. These VSG genes become activated by gene conversion in a hierarchical order: telomeric VSGs are activated first, followed by array VSGs, and finally pseudogene VSGs. Only one VSG is expressed at any given time. Each new gene is switched in turn into a VSG expression site (ES). This process is partially dependent on homologous recombination of DNA, which is mediated in part by the interaction of the T. brucei BRCA2 gene with RAD51 (however, this is not the only possible mechanism, as BRCA2 variants still display some VSG switching). In addition to homologous recombination, transcriptional regulation is also important in antigen switching, since T. brucei has multiple potential expression sites. A new VSG can either be selected by transcriptional activation of a previously silent ES, or by recombination of a VSG sequence into the active ES (see figure, "Mechanisms of VSG Switching in T. brucei "). Although the biological triggers that result in VSG switching are not fully known, mathematical modeling suggests that the ordered appearance of different VSG variants is controlled by at least two key parasite-derived factors: differential activation rates of parasite VSG and density-dependent parasite differentiation. Plasmodium falciparum , the major etiologic agent of human malaria, has a very complex life cycle that occurs in both humans and mosquitoes. While in the human host, the parasite spends most of its life cycle within hepatic cells and erythrocytes (in contrast to T. brucei which remains extracellular). As a result of its mainly intracellular niche, parasitized host cells which display parasite proteins must be modified to prevent destruction by the host immune defenses. In the case of Plasmodium , this is accomplished via the dual purpose Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is encoded by the diverse family of genes known as the var family of genes (approximately 60 genes in all). The diversity of the gene family is further increased via a number of different mechanisms including exchange of genetic information at telomeric loci, as well as meiotic recombination. The PfEMP1 protein serves to sequester infected erythrocytes from splenic destruction via adhesion to the endothelium . Moreover, the parasite is able to evade host defense mechanisms by changing which var allele is used to code the PfEMP1 protein. Like T. brucei , each parasite expresses multiple copies of one identical protein. However, unlike T. brucei , the mechanism by which var switching occurs in P. falciparum is thought to be purely transcriptional. Var switching has been shown to take place soon after invasion of an erythrocyte by a P. falciparum parasite. Fluorescent in situ hybridization analysis has shown that activation of var alleles is linked to altered positioning of the genetic material to distinct "transcriptionally permissive" areas. Different virus families have different levels of ability to alter their genomes and trick the immune system into not recognizing. Some viruses have relatively unchanging genomes like paramyxoviruses while others like influenza have rapidly changing genomes that inhibit our ability to create long lasting vaccines against the disease. Viruses in general have much faster rate of mutation of their genomes than human or bacterial cells. In general viruses with shorter genomes have faster rates of mutation than longer genomes since they have a faster rate of replication . It was classically thought that viruses with an RNA genome always had a faster rate of antigenic variation than those with a DNA genome because RNA polymerase lacks a mechanism for checking for mistakes in translation but recent work by Duffy et al. shows that some DNA viruses have the same high rates of antigenic variation as their RNA counterparts. Antigenic variation within viruses can be categorized into 6 different categories called antigenic drift , shift , rift, lift, sift, and gift [ citation needed ] The antigenic properties of influenza viruses are determined by both hemagglutinin and neuraminidase . Specific host proteases cleave the single peptide HA into two subunits HA1 and HA2. The virus becomes highly virulent if the amino acids at the cleavage sites are lipophilic. Selection pressure in the environment selects for antigenic changes in the antigen determinants of HA, that includes places undergoing adaptive evolution and in antigenic locations undergoing substitutions, which ultimately results in changes in the antigenicity of the virus. Glycosylation of HA does not correlate with either the antigenicity or the selection pressure. Antigenic variation may be classified into two types, antigenic drift that results from a change in few amino acids and antigenic shift which is the outcome of acquiring new structural proteins. A new vaccine is required every year because influenza virus has the ability to undergo antigenic drift. Antigenic shift occurs periodically when the genes for structural proteins are acquired from other animal hosts resulting in a sudden dramatic change in viral genome. Recombination between segments that encode for hemagglutinin and neuraminidase of avian and human influenza virus segments have resulted in worldwide influenza epidemics called pandemics such as the Asian flu of 1957 when 3 genes from Eurasian avian viruses were acquired and underwent reassortment with 5 gene segments of the circulating human strains. Another example comes from the 1968 Hong Kong flu which acquired 2 genes by reassortment from Eurasian avian viruses with the 6 gene segments from circulating human strains. After vaccination, IgG+ antibody-secreting plasma cells (ASCs) increase rapidly and reaches a maximum level at day 7 before returning to a minimum level at day 14. The influenza-specific memory B-cells reach their maxima at day 14–21. The secreted antibodies are specific to the vaccine virus. Further, most of the monoclonal antibodies isolated have binding affinities against HA and the remaining demonstrate affinity against NA, nucleoprotein (NP) and other antigens. These high affinity human monoclonal antibodies can be produced within a month after vaccination and because of their human origin, they will have very little, if any, antibody-related side-effects in humans. They can potentially be used to develop passive antibody therapy against influenza virus transmission. The ability of an antiviral antibody to inhibit hemagglutination can be measured and used to generate a two-dimensional map using a process called antigenic cartography so that antigenic evolution can be visualized. These maps can show how changes in amino acids can alter the binding of an antibody to virus particle and help to analyze the pattern of genetic and antigenic evolution. Recent findings show that as a result of antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site, a compensatory mutation in NA can result leading to NA antigenic variation. As a consequence, drug resistance develops to NA inhibitors. Such a phenomenon can mask the evolution of NA evolution in nature because the resistance to NA inhibitors could be due to antibody-driven, HA escape. The major challenge in controlling HIV-1 infection in the long term is immune escape. The extent and frequency to which an epitope will be targeted by a particular HLA allele differs from person-to-person. Moreover, as a consequence of immunodominance, an individual's CTL response is limited to a few epitopes of a specific HLA allele although six HLA class 1 alleles are expressed. Although the CTL response in the acute phase is directed against limited number of epitopes, the epitopic repertoire increases with time due to viral escape. Additionally amino acid co-evolution is a challenging issue that needs to be addressed. For example, a substitution in a particular site results in a secondary or compensatory mutation in another site. An invaluable discovery was that when a selective pressure is applied, the pattern of HIV-1 evolution can be predicted. In individuals who express a protective HLA B*27 allele, the first mutation that occurs in the Gag epitope KK10 is at position 6 from an L to an M and after several years there is a change in position 2 from a R to a K. Therefore, the knowledge of the predictability of the escape pathways can be utilized to design immunogens. The region gp120 of HIV-1 Env which contacts CD4 , its primary receptor, is functionally conserved and vulnerable to neutralizing antibodies such as monoclonal antibody b12. Recent findings show that resistance to neutralization by b12 was an outcome of substitutions that resided in the region proximal to CD4 contact surface. In this way the virus evades neutralization by b12 without affecting its binding to CD4. Flaviviridae is a family of viruses that encompasses well known viruses such as West Nile virus and Dengue virus . The genus Flavivirus has a prototypical envelope protein (E-protein) on its surface which serves as the target for virus neutralizing antibodies. E protein plays a role in binding to receptor and could play a role in evading the host immune system. It has three major antigenic domains namely A, B and C that correspond to the three structural domains II, III and I. Structural domain III is a putative receptor binding domain and antibodies against it neutralize the infectivity of flaviviruses. Mutations that lead to antigenic differences can be traced to the biochemical nature of the amino acid substitutions as well as the location of the mutation in the domain III. For example, substitutions at different amino acids results in varying levels of neutralization by antibodies. If mutation in a critical amino acid can dramatically alter neutralization by antibodies then WNV vaccines and diagnostic assays becomes difficult to rely on. Other flaviviruses that cause dengue, louping ill and yellow fever escape antibody neutralization via mutations in the domain III of the E protein. The antigenic properties of influenza viruses are determined by both hemagglutinin and neuraminidase . Specific host proteases cleave the single peptide HA into two subunits HA1 and HA2. The virus becomes highly virulent if the amino acids at the cleavage sites are lipophilic. Selection pressure in the environment selects for antigenic changes in the antigen determinants of HA, that includes places undergoing adaptive evolution and in antigenic locations undergoing substitutions, which ultimately results in changes in the antigenicity of the virus. Glycosylation of HA does not correlate with either the antigenicity or the selection pressure. Antigenic variation may be classified into two types, antigenic drift that results from a change in few amino acids and antigenic shift which is the outcome of acquiring new structural proteins. A new vaccine is required every year because influenza virus has the ability to undergo antigenic drift. Antigenic shift occurs periodically when the genes for structural proteins are acquired from other animal hosts resulting in a sudden dramatic change in viral genome. Recombination between segments that encode for hemagglutinin and neuraminidase of avian and human influenza virus segments have resulted in worldwide influenza epidemics called pandemics such as the Asian flu of 1957 when 3 genes from Eurasian avian viruses were acquired and underwent reassortment with 5 gene segments of the circulating human strains. Another example comes from the 1968 Hong Kong flu which acquired 2 genes by reassortment from Eurasian avian viruses with the 6 gene segments from circulating human strains. After vaccination, IgG+ antibody-secreting plasma cells (ASCs) increase rapidly and reaches a maximum level at day 7 before returning to a minimum level at day 14. The influenza-specific memory B-cells reach their maxima at day 14–21. The secreted antibodies are specific to the vaccine virus. Further, most of the monoclonal antibodies isolated have binding affinities against HA and the remaining demonstrate affinity against NA, nucleoprotein (NP) and other antigens. These high affinity human monoclonal antibodies can be produced within a month after vaccination and because of their human origin, they will have very little, if any, antibody-related side-effects in humans. They can potentially be used to develop passive antibody therapy against influenza virus transmission. The ability of an antiviral antibody to inhibit hemagglutination can be measured and used to generate a two-dimensional map using a process called antigenic cartography so that antigenic evolution can be visualized. These maps can show how changes in amino acids can alter the binding of an antibody to virus particle and help to analyze the pattern of genetic and antigenic evolution. Recent findings show that as a result of antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site, a compensatory mutation in NA can result leading to NA antigenic variation. As a consequence, drug resistance develops to NA inhibitors. Such a phenomenon can mask the evolution of NA evolution in nature because the resistance to NA inhibitors could be due to antibody-driven, HA escape. After vaccination, IgG+ antibody-secreting plasma cells (ASCs) increase rapidly and reaches a maximum level at day 7 before returning to a minimum level at day 14. The influenza-specific memory B-cells reach their maxima at day 14–21. The secreted antibodies are specific to the vaccine virus. Further, most of the monoclonal antibodies isolated have binding affinities against HA and the remaining demonstrate affinity against NA, nucleoprotein (NP) and other antigens. These high affinity human monoclonal antibodies can be produced within a month after vaccination and because of their human origin, they will have very little, if any, antibody-related side-effects in humans. They can potentially be used to develop passive antibody therapy against influenza virus transmission.The ability of an antiviral antibody to inhibit hemagglutination can be measured and used to generate a two-dimensional map using a process called antigenic cartography so that antigenic evolution can be visualized. These maps can show how changes in amino acids can alter the binding of an antibody to virus particle and help to analyze the pattern of genetic and antigenic evolution. Recent findings show that as a result of antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site, a compensatory mutation in NA can result leading to NA antigenic variation. As a consequence, drug resistance develops to NA inhibitors. Such a phenomenon can mask the evolution of NA evolution in nature because the resistance to NA inhibitors could be due to antibody-driven, HA escape. The major challenge in controlling HIV-1 infection in the long term is immune escape. The extent and frequency to which an epitope will be targeted by a particular HLA allele differs from person-to-person. Moreover, as a consequence of immunodominance, an individual's CTL response is limited to a few epitopes of a specific HLA allele although six HLA class 1 alleles are expressed. Although the CTL response in the acute phase is directed against limited number of epitopes, the epitopic repertoire increases with time due to viral escape. Additionally amino acid co-evolution is a challenging issue that needs to be addressed. For example, a substitution in a particular site results in a secondary or compensatory mutation in another site. An invaluable discovery was that when a selective pressure is applied, the pattern of HIV-1 evolution can be predicted. In individuals who express a protective HLA B*27 allele, the first mutation that occurs in the Gag epitope KK10 is at position 6 from an L to an M and after several years there is a change in position 2 from a R to a K. Therefore, the knowledge of the predictability of the escape pathways can be utilized to design immunogens. The region gp120 of HIV-1 Env which contacts CD4 , its primary receptor, is functionally conserved and vulnerable to neutralizing antibodies such as monoclonal antibody b12. Recent findings show that resistance to neutralization by b12 was an outcome of substitutions that resided in the region proximal to CD4 contact surface. In this way the virus evades neutralization by b12 without affecting its binding to CD4. Flaviviridae is a family of viruses that encompasses well known viruses such as West Nile virus and Dengue virus . The genus Flavivirus has a prototypical envelope protein (E-protein) on its surface which serves as the target for virus neutralizing antibodies. E protein plays a role in binding to receptor and could play a role in evading the host immune system. It has three major antigenic domains namely A, B and C that correspond to the three structural domains II, III and I. Structural domain III is a putative receptor binding domain and antibodies against it neutralize the infectivity of flaviviruses. Mutations that lead to antigenic differences can be traced to the biochemical nature of the amino acid substitutions as well as the location of the mutation in the domain III. For example, substitutions at different amino acids results in varying levels of neutralization by antibodies. If mutation in a critical amino acid can dramatically alter neutralization by antibodies then WNV vaccines and diagnostic assays becomes difficult to rely on. Other flaviviruses that cause dengue, louping ill and yellow fever escape antibody neutralization via mutations in the domain III of the E protein.

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influenza virus

https://api.wikimedia.org/core/v1/wikipedia/en/page/Influenza_virus_nucleoprotein/html

Influenza virus nucleoprotein

Influenza virus nucleoprotein (NP) is a structural protein which encapsidates the negative strand viral RNA . NP is one of the main determinants of species specificity. The question of how far the NP gene can cross the species barrier by reassortment and become adapted by mutation to the new host has been discussed.

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influenza virus

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List of seasonal influenza vaccines

Seasonal influenza vaccine brands include Fluzone/Fluzone Quadrivalent and Vaxigrip/VaxigripTetra, Influvac and Optaflu.Fluenz, FluMist and their quadrivalent formulations are nasal attenuated vaccines by AstraZeneca .Fluarix, Flulaval and their quadrivalent formulations are split virus inactivated vaccines by GlaxoSmithKline . Fluarix Flulaval Fluarix Tetra Influvac and its quadrivalent formulation are surface antigen subunit vaccines marketed by Mylan . Influvac Influvac Tetra They contain inactivated purified surface fragments (subunits) from the three different strains of the influenza virus ( A/H1N1 , A/H3N2 , and Influenza B virus ) that are selected and distributed by the World Health Organization , on the basis of their latest recommendations. Previously, they were produced and marketed by Abbott Laboratories In February 2010, Abbott acquired the vaccines subunit from Solvay Pharmaceuticals included in its $6.2 billion purchase and the subunit influenza vaccine — Influvac has been commercially available on the market since the early nineteen-eighties. With the acquisition of Solvay, Abbott retained access to the Eastern European, Middle Eastern & Latin American markets. Approximately $850 million of sales revenue from vaccines was reported by Solvay Pharmaceuticals in 2009. In February 2015, Mylan Laboratories completed the deal with Abbott to purchase Abbott's generic drugs business in developed markets, which includes Influvac. Optaflu is a trivalent surface antigen inactivated vaccine prepared in cell cultures manufactured by Novartis . On April 27, 2007, Novartis received a positive opinion supporting European Union approval of Optaflu. It is the first influenza vaccine made in a mammalian cell line, rather than chicken eggs. The plan was to manufacture the vaccine in Holly Springs, North Carolina . The United States government provided $500 million in construction costs and guaranteed vaccine purchases. Novartis' flu vaccine unit was sold to CSL Limited in 2014, and was placed under CSL subsidiary, bioCSL (Seqirus). bioCSL as marketing authorization holder decided to discontinue the usage of Optaflu brand in 2017 due to commercial reasons Vaxigrip Tetra and Fluquadri are quadrivalent split virus inactivated vaccines by Sanofi-Aventis .Sanofi Pasteur produces the following vaccines: Fluzone and its quadrivalent formulation are split virus inactivated vaccines distributed by Sanofi Pasteur mainly in the United States. Fluzone is typically administered in a single dose by intramuscular injection; an intradermal injection is also available. It is presented as a 0.25 ml syringe for pediatric use, as a 0.5 ml syringe for adults and children, as a 0.5 ml vial for adults and children, and as a 5 ml vial for adults and children. Fluzone must be refrigerated under temperatures from 2 to 8 °C (36 to 46 °F) and is inactivated by freezing. Fluzone was initially approved in 1980 by the FDA. The following adverse effects have been reported: A high-dose vaccine (Fluzone High-Dose) four times the strength of standard flu vaccine was approved by the FDA in 2009. This vaccine is intended for people 65 and over, who typically have weakened immune response due to normal aging. The vaccine produces a greater immune response than standard vaccine. According to the CDC, "a study published in the New England Journal of Medicine [in August, 2014] indicated that the high-dose vaccine was 24.2% more effective in preventing flu in adults 65 years of age and older relative to a standard-dose vaccine." The CDC recommends the high-dose vaccine for people 65 and over but expresses no preference between it and standard vaccine. Further studies were underway as of 2014 [ update ] . [ citation needed ] Vaxigrip and its quadrivalent formulation Vaxigrip Tetra are split virus inactivated vaccines made by Sanofi Pasteur in Europe. Vaxigrip provides immune responses to three influenza strains and VaxigripTetra adds another B strain. VaxigripTetra was approved in Europe in 2016 except for infants younger than three years old. Flublok and its quadrivalent formulation are recombinant subunit vaccines prepared in cell cultures . Recombinant influenza vaccines are produced using recombinant virus technology. This method does not require an egg-grown vaccine virus and does not use chicken eggs in the production process. The DNA for the hemagglutinin antigen of influenza virus is added to a baculovirus . This recombinant virus is then used to infect cultured insect cells (of the moth Spodoptera frugiperda ), which subsequently produce the hemagglutinin protein. The protein is harvested and purified. This is done for four different types of influenza hemagglutinin to create the Flublok Quadrivalent vaccine. Fluzone and its quadrivalent formulation are split virus inactivated vaccines distributed by Sanofi Pasteur mainly in the United States. Fluzone is typically administered in a single dose by intramuscular injection; an intradermal injection is also available. It is presented as a 0.25 ml syringe for pediatric use, as a 0.5 ml syringe for adults and children, as a 0.5 ml vial for adults and children, and as a 5 ml vial for adults and children. Fluzone must be refrigerated under temperatures from 2 to 8 °C (36 to 46 °F) and is inactivated by freezing. Fluzone was initially approved in 1980 by the FDA. The following adverse effects have been reported: A high-dose vaccine (Fluzone High-Dose) four times the strength of standard flu vaccine was approved by the FDA in 2009. This vaccine is intended for people 65 and over, who typically have weakened immune response due to normal aging. The vaccine produces a greater immune response than standard vaccine. According to the CDC, "a study published in the New England Journal of Medicine [in August, 2014] indicated that the high-dose vaccine was 24.2% more effective in preventing flu in adults 65 years of age and older relative to a standard-dose vaccine." The CDC recommends the high-dose vaccine for people 65 and over but expresses no preference between it and standard vaccine. Further studies were underway as of 2014 [ update ] . [ citation needed ]Fluzone is typically administered in a single dose by intramuscular injection; an intradermal injection is also available. It is presented as a 0.25 ml syringe for pediatric use, as a 0.5 ml syringe for adults and children, as a 0.5 ml vial for adults and children, and as a 5 ml vial for adults and children. Fluzone must be refrigerated under temperatures from 2 to 8 °C (36 to 46 °F) and is inactivated by freezing. Fluzone was initially approved in 1980 by the FDA. The following adverse effects have been reported: A high-dose vaccine (Fluzone High-Dose) four times the strength of standard flu vaccine was approved by the FDA in 2009. This vaccine is intended for people 65 and over, who typically have weakened immune response due to normal aging. The vaccine produces a greater immune response than standard vaccine. According to the CDC, "a study published in the New England Journal of Medicine [in August, 2014] indicated that the high-dose vaccine was 24.2% more effective in preventing flu in adults 65 years of age and older relative to a standard-dose vaccine." The CDC recommends the high-dose vaccine for people 65 and over but expresses no preference between it and standard vaccine. Further studies were underway as of 2014 [ update ] . [ citation needed ]Vaxigrip and its quadrivalent formulation Vaxigrip Tetra are split virus inactivated vaccines made by Sanofi Pasteur in Europe. Vaxigrip provides immune responses to three influenza strains and VaxigripTetra adds another B strain. VaxigripTetra was approved in Europe in 2016 except for infants younger than three years old. Flublok and its quadrivalent formulation are recombinant subunit vaccines prepared in cell cultures . Recombinant influenza vaccines are produced using recombinant virus technology. This method does not require an egg-grown vaccine virus and does not use chicken eggs in the production process. The DNA for the hemagglutinin antigen of influenza virus is added to a baculovirus . This recombinant virus is then used to infect cultured insect cells (of the moth Spodoptera frugiperda ), which subsequently produce the hemagglutinin protein. The protein is harvested and purified. This is done for four different types of influenza hemagglutinin to create the Flublok Quadrivalent vaccine. Afluria and its quadrivalent formulation are a split virus inactivated vaccines . Fluad and its quadrivalent formulations are adjuvanted surface antigen inactivated vaccines. Flucelvax and its quadrivalent formulations are surface antigen inactivated vaccines prepared in cell cultures . Novartis developed the first influenza vaccine, which did not need to be grown in chicken eggs, a cell-based vaccine . In 2014, CSL Limited obtained Novartis' flu vaccine unit, and transferred it to CSL Subsidiary, bioCSL, named Seqirus. The following are list of bioCSL flu vaccine brands:

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influenza virus

https://api.wikimedia.org/core/v1/wikipedia/en/page/The_Great_Influenza/html

The Great Influenza

The Great Influenza: The Story of the Deadliest Plague in History (originally subtitled The Epic Story of the Deadliest Pandemic in History ) is a 2004 nonfiction book by John M. Barry that examines the Spanish flu , a 1918-1920 flu pandemic and one of the worst pandemics in history. Barry focuses on what was occurring in the United States at the time and attempts to place it against the background of American history and within the context of the history of medicine. The book describes how the flu started in Haskell County, Kansas , USA, and spread to the U.S. Army training camp Camp Funston , Kansas, USA, and around the world through troop movements during World War I .The 1918 influenza pandemic has been declared, according to Barry's text, as the 'deadliest plague in history'. The extensiveness of this declaration can be supported through the following statements: "the greatest medical holocaust in history" and "the pandemic ranks with the plague of Justinian and the Black Death as one of the three most destructive human epidemics". Although the origin site for the pandemic has been widely debated, Barry follows the research findings of epidemiologist Edwin O. Jordan to claim that the disease originated from Haskell County, Kansas and was spread to army camps, across the US and then to Europe. The influenza strain of the 1918 pandemic infected approximately 500 million people and during the First World War, this viral infection reported more deaths than military engagement. Moreover, the disease caused the fatalities of more than 50 million people worldwide. During the development of this disease, the influenza strain, colloquially, became known as the 'Spanish flu' due to the fact that Spain was the first country to publicly report on the disease. Barry's book reviews details of the events preceding, during and following the 1918 influenza pandemic. Part 1 of the text includes accounts of various scientists and intellectuals throughout history, and describes their theories, and methodologies. He identifies and critiques the progression of science throughout history and the evolution of medicine to be performed as a science-based occupation. Specifically, the first part of Barry's text contextualises the US medical field in comparison to Europe, highlighting the inhibitors of progress in the US. Barry introduces William H. Welch as a key influential figure in US medicine due to him being an acclaimed 'inspiration' to many graduates from The Johns Hopkins University School of Medicine who went on to make vital discoveries in science. Moreover, this part of the text details the lack of advancement of other US medical schools compared to the Hopkins institution due to the Flexner Report that was introduced in 1919, specifically that 80% of medical schools were categorised as 'poor quality' and in need of closing. Moreover, Barry discusses Welch founding the Johns Hopkins Bloomberg School of Public Health in 1916, in which Welch was the first Dean. Part 2 of the text identifies Haskell County, Kansas to be the origin site of the influenza strain based on epidemiological evidence derived from a local doctor to the site, Loring Miner and details the distribution across the US through army camps. Furthermore, Barry addresses the difficulty of explaining the origin of viruses, even in modern-day science and references this as an ' enigma '. He defines what a virus is, specifically their function and the process of replication of viruses to produce iterations of original virus. Also, Barry narrates Influenza A virus subtype H1N1 originating from wild birds and discusses how the structure of the virus makes it suitable for attacking respiratory systems, hence also the reasoning for its rapid spread from host to host. Barry goes through the function of the immune system in recognising and fighting viruses, as well as the presence of mutations to impede the immune system's functionality. Part 3 of the text examines the potential reasonings the US joined the First World War and their preparatory process, including creating a National Research Council (United States) that incorporated scientifically qualified men identified in the first part of the text to prevent this influenza spread.  This council was created after an outbreak of measles spread severely within the US army troops and majority of the cases leading to pneumonia. Although a vaccine for pneumonia was eventually developed, a board was created for its specific consideration within the army. Barry discusses the shortage of medical professionals among civilians and President Woodrow Wilson 's drastic measures, to gather troops for the First World War, as key factors for the spread of the 1918 influenza virus. Part 4, 5 and 6 of the text discusses the casualties due to the pandemic specifically in the second half of 1918, as well as comparing the first and second wave statistics. These parts include different forms of evidence that portray accounts of the public's fear and uncertainty of the pandemic and the contributing influences to these emotions, specifically the misinformation or lack of information distributed by the media during this time period. Part 7 of the text details the accounts of scientists and their attempts to generate an effective vaccine to prevent the spread of the influenza strain. Barry narrates that the scientists at the time were tasked to understand the epidemiology of the influenza virus and identify the pathogen that was causing this disease. Although, the disease was identified as airborne, scientists were not successful in enforcing social distancing or lockdown to prevent the viral spread. Moreover, due to the inability to control this pandemic, Barry narrates that scientists rushed their methodology and processes of identifying the pathogen causing the virus. Most scientists followed the assumption that the causing pathogen was B influenzae. However, Barry states that when Welch has the virus, the scientist Oswald Avery maintained scientifical protocol and process of experiment in the hopes of identifying the correct pathogen that was causing this virus. Part 8 and 9 describes the conclusion of the pandemic, specifically detailing the scientific realisations, viral mutations and emotional aftermath caused by the pandemic. Barry narrates President Wilson's unwillingness to follow scientists' warnings and continued to send men to war which ultimately increased the spread of influenza in the tightly packed ships. Barry reports that the public health system was overwhelmed and that the only way the influenza outbreak could be mitigated was through quarantines, however they were not established by authority. Parts 8 and 9 outline the desperation of citizens to relieve symptoms and addresses individual concoctions to heal and untested vaccines being used, despite the knowledge that isolation was the only valid method of prevention of viral distribution. Barry details the consequence of numerous orphans due to the virus targeting young adults, as well as the public opinion distrusting their leaders and science. Finally, the last part of the text follows scientist Oswald Avery's continual researching of the pneumonia pathogen subsequent to the pandemic, and details his findings. Avery spent over a decade researching this and Barry states that his findings revolutionised the world of biology as he was the first scientist to prove that DNA carries genetic information. Barry concludes his narration of the events of the 1918 influenza pandemic with reference to scientists, Paul A. Lewis and Richard Shope , finally detecting the pathogen responsible for the pandemic, however not until 1931. The geographical origins of the 1918 influenza virus is a familiar point of contention due to the various evidence-based claims. Although the origin site for the pandemic has been widely debated, Barry follows the research findings of epidemiologist Edwin O. Jordan to claim that the disease originated from Haskell County, Kansas and was spread to army camps, across the US and then to Europe. Nevertheless, the general consensus is more indistinct than Barry's claim; the acknowledgement being that the disease originated from the Midwest of the United States of America. The location in which the H1N1 influenza A virus originated is a point of contention and has been acknowledged to be in China, the United States of America or Europe. Olson and colleagues critique the widely held viewpoint that the virus emerged from Kansas, USA; stating that this dominant belief "has become widely accepted without rigorous re-evaluation of the original evidence". They suggest the idea of the virus originating in Europe and spreading to New York due to troop movements in the First World War. Moreover, this idea was initiated in 1919 by Dr William Hallock Park , a bacteriologist and the director of the New York City Health Department, in which he states that "observations in France and England indicated a filterable virus was present in at least one of the cases". Moreover, it has been suggested by Langford that there might have been a mild outbreak of influenza in 1917 that travelled to England and France "via the personnel of the Chinese Labour Corps, then mutated to a more virulent form when the Chinese workers returned home in 1918". However, this suggestion cannot be confirmed due to bacteriological and clinical data being too insubstantial and irregular. Barry's theory regarding the geographical site of origin for the 1918 influenza virus is also problematic due to the 'herald wave' that was evident during the beginning months of 1918 in not only New York, USA, but also in military camps throughout Norway during the same time period. Although Barry's discussion of the virus first emerging in Kansas, USA is widely accepted, it is evident that it is a point of contention in the word of science.John M. Barry, author of 'The Great Influenza', has been considered alongside Alfred W. Crosby , author of the 'America's Forgotten Pandemic' to be 'ground breaking' historiographical work on the 1918 influenza pandemic. Crosby's text, first published in 1976, is considered a dominant historical text unpacking the events of the 1918 influenza virus and significantly discusses the significant presence of the First World War to 'shadow' details of the pandemic into obscurity. This is relevant as Barry's text was originally published in 2004 which was 28 years after Crosby's 'America's Forgotten Pandemic'. Hence, although it has been stated that Barry 'echoes' Crosby's historical research in 'The Great Influenza', he has a stronger emphasis on the biology. Also, Barry's had the opportunity to collate 28 years of further research and commentary to better inform his text's historical, and biological narrative of the 1918 influenza.Stephen C. Schoenbaum comments on John Barry's non-fiction text through his 2004 review by critically stating that the text "includes lots of interesting tidbits, some relevant, some not, some accurate, and some not". Furthermore, Schoenbaum identifies 'telling stories' as a strong component of the text, however its historical overview should not be considered 'definitive'. Nevertheless, Barry's text is declared as a "rewarding experience" with other scholarly authors not presenting the "same combination of interests as Mr Barry". Andrew Noymer recognises the broad audience regarding accessibility of Barry's non-fiction text and its focus on specific historical, and medical matters. This is evident through his statement, "… the book is written for a general audience as well as for academic experts". Moreover, Noymer indicates the questionable reliability of Barry's anecdotes as "not all anecdotes… [were] documented by sources in the endnotes". Hence, suggesting there to be an issue when evaluating the book as "a piece of historical research" Joseph Topinka, Daniel Molnar, Brandon Gardner and Rosemary Wosky extensively evaluate the quality of John Barry's text The Great Influenza: The Epic Story of the Deadliest Plague in History in their 2015 review. The review recognises the historical framework Barry provides for understanding the social environment, as well as the political issues of the influenza pandemic. The review declares "Barry's description of the spreading of the influenza and the reaction to it by the local and national governments all provide lessons from which we can learn". Hence, Topinka et al. indicate their perspective of the didactic nature of the text, specifically regarding decision-making or lack thereof, as well as advocation for public education and alteration of legal frameworks under public health law. They agree with Barry's discussion of the historical spread of this disease, specifically that "we must learn from the influenza pandemic of 1918". A 2004 Journal of Clinical Investigation review said that the book was "well conceived, well researched, and extremely well written" targeting a broad audience-physicians, scientists, medical students, and history buffs. Barry Gewen of The New York Times praised it saying "He is a good teacher, in part because he assumes that his readers don't know anything. He explains the technical stuff clearly, with nice, homey analogies". In the summer of 2005, then-President George W. Bush read the book while on vacation at his ranch in Crawford. His study would later set forth plans for the federal government to prepare for future pandemics in a November 2005 speech. In 2020, the book experienced a surge in popularity as a result of the COVID-19 pandemic .

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influenza virus

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Negative-strand RNA virus

See text Negative-strand RNA viruses ( −ssRNA viruses ) are a group of related viruses that have negative-sense , single-stranded genomes made of ribonucleic acid (RNA). They have genomes that act as complementary strands from which messenger RNA (mRNA) is synthesized by the viral enzyme RNA-dependent RNA polymerase (RdRp). During replication of the viral genome, RdRp synthesizes a positive-sense antigenome that it uses as a template to create genomic negative-sense RNA. Negative-strand RNA viruses also share a number of other characteristics: most contain a viral envelope that surrounds the capsid, which encases the viral genome, −ssRNA virus genomes are usually linear, and it is common for their genome to be segmented. Negative-strand RNA viruses constitute the phylum Negarnaviricota , in the kingdom Orthornavirae and realm Riboviria . They are descended from a common ancestor that was a double-stranded RNA (dsRNA) virus , and they are considered to be a sister clade of reoviruses , which are dsRNA viruses. Within the phylum, there are two major branches that form two subphyla: Haploviricotina , whose members are mostly non-segmented and which encode an RdRp that synthesizes caps on mRNA, and Polyploviricotina , whose members are segmented and which encode an RdRp that snatches caps from host mRNAs. A total of six classes in the phylum are recognized. Negative-strand RNA viruses are closely associated with arthropods and can be informally divided between those that are reliant on arthropods for transmission and those that are descended from arthropod viruses but can now replicate in vertebrates without the aid of arthropods. Prominent arthropod-borne −ssRNA viruses include the Rift Valley fever virus and the tomato spotted wilt virus . Notable vertebrate −ssRNA viruses include the Ebola virus , hantaviruses , influenza viruses , the Lassa fever virus , and the rabies virus .Negarnaviricota takes the first part of its name from Latin nega , meaning negative, the middle part rna refers to RNA, and the final part, - viricota , is the suffix used for virus phyla. The subphylum Haploviricotina takes the first part of its name, Haplo , from Ancient Greek ἁπλός, meaning simple, and - viricotina is the suffix used for virus subphyla. The subphylum Polyploviricotina follows the same pattern, Polyplo being taken from Ancient Greek πολύπλοκος, meaning complex. All viruses in Negarnaviricota are negative-sense, single-stranded RNA (−ssRNA) viruses. They have genomes made of RNA, which are single instead of double-stranded. Their genomes are negative sense, meaning that messenger RNA (mRNA) can be synthesized directly from the genome by the viral enzyme RNA-dependent RNA polymerase (RdRp), also called RNA replicase, which is encoded by all −ssRNA viruses. Excluding viruses in the genus Tenuivirus and some in the family Chuviridae , all −ssRNA viruses have linear rather than circular genomes, and the genomes may be segmented or non-segmented. All −ssRNA genomes contain terminal inverted repeats , which are palindromic nucleotide sequences at each end of the genome. Replication of −ssRNA genomes is executed by RdRp, which initiates replication by binding to a leader sequence on the 3'-end (usually pronounced "three prime end") of the genome. RdRp then uses the negative sense genome as a template to synthesize a positive-sense antigenome. When replicating the antigenome, RdRp first binds to the trailer sequence on the 3'-end of the antigenome. Thereafter, RdRp ignores all transcription signals on the antigenome and synthesizes a copy of the genome while using the antigenome as a template. Replication is executed while the genome is inside the nucleocapsid, and RdRp unveils the capsid and translocates along the genome during replication. As new nucleotide sequences are synthesized by RdRp, capsid proteins are assembled and encapsidate the newly replicate viral RNA. Transcribing mRNA from the genome follows the same directional pattern as producing the antigenome. At the leader sequence, RdRp synthesizes a 5-'end (usually pronounced "five prime end") triphosphate-leader RNA and either, in the case of the subphylum Haploviricotina , caps the 5'-end or, in the case of the subphylum Polyploviricotina , snatches a cap from a host mRNA and attaches it to the viral mRNA so that the mRNA can be translated by the host cell's ribosomes . After capping the mRNA, RdRp initiates transcription at a gene start signal and later terminates transcription upon reaching a gene end signal. At the end of transcription, RdRp synthesizes a polyadenylated tail (poly (A) tail) consisting of hundreds of adenines in the mRNA's 3-end, which may be done by stuttering on a sequence of uracils . After the poly (A) tail is constructed, the mRNA is released by RdRp. In genomes that encode more than one transcribable portion, RdRp can continue scanning to the next start sequence to continue with transcription. Some −ssRNA viruses are ambisense , meaning that both the negative genomic strand and positive antigenome separately encode different proteins. In order to transcribe ambisense viruses, two rounds of transcription are performed: first, mRNA is produced directly from the genome; second, mRNA is created from the antigenome. All ambisense viruses contain a hairpin loop structure to stop transcription after the protein's mRNA has been transcribed. Negative-strand RNA viruses contain a ribonucleoprotein complex composed of the genome and an RdRp attached to each segment of the genome surrounded by a capsid. The capsid is composed of proteins whose folded structure contains five alpha-helices in the N-terminal lobe (5-H motif) and three alpha-helices in the C-terminal lobe (3-H motif). Inside the capsid, the genome is sandwiched between these two motifs. Excluding the family Aspiviridae , −ssRNA viruses contain an outer viral envelope , a type of a lipid membrane that surrounds the capsid. The shape of the virus particle, called a virion, of −ssRNA viruses varies and may be filamentous, pleomorphic, spherical, or tubular. Genome segmentation is a prominent trait among many −ssRNA viruses, and −ssRNA viruses range from having genomes with one segment, typical for members of the order Mononegavirales , to genomes with ten segments, as is the case for Tilapia tilapinevirus . There is no clear trend over time that determines the number of segments, and genome segmentation among −ssRNA viruses appears to be a flexible trait since it has evolved independently on multiple occasions. Most members of the subphylum Haploviricotina are nonsegmented, whereas segmentation is universal in Polyploviricotina . All viruses in Negarnaviricota are negative-sense, single-stranded RNA (−ssRNA) viruses. They have genomes made of RNA, which are single instead of double-stranded. Their genomes are negative sense, meaning that messenger RNA (mRNA) can be synthesized directly from the genome by the viral enzyme RNA-dependent RNA polymerase (RdRp), also called RNA replicase, which is encoded by all −ssRNA viruses. Excluding viruses in the genus Tenuivirus and some in the family Chuviridae , all −ssRNA viruses have linear rather than circular genomes, and the genomes may be segmented or non-segmented. All −ssRNA genomes contain terminal inverted repeats , which are palindromic nucleotide sequences at each end of the genome. Replication of −ssRNA genomes is executed by RdRp, which initiates replication by binding to a leader sequence on the 3'-end (usually pronounced "three prime end") of the genome. RdRp then uses the negative sense genome as a template to synthesize a positive-sense antigenome. When replicating the antigenome, RdRp first binds to the trailer sequence on the 3'-end of the antigenome. Thereafter, RdRp ignores all transcription signals on the antigenome and synthesizes a copy of the genome while using the antigenome as a template. Replication is executed while the genome is inside the nucleocapsid, and RdRp unveils the capsid and translocates along the genome during replication. As new nucleotide sequences are synthesized by RdRp, capsid proteins are assembled and encapsidate the newly replicate viral RNA. Transcribing mRNA from the genome follows the same directional pattern as producing the antigenome. At the leader sequence, RdRp synthesizes a 5-'end (usually pronounced "five prime end") triphosphate-leader RNA and either, in the case of the subphylum Haploviricotina , caps the 5'-end or, in the case of the subphylum Polyploviricotina , snatches a cap from a host mRNA and attaches it to the viral mRNA so that the mRNA can be translated by the host cell's ribosomes . After capping the mRNA, RdRp initiates transcription at a gene start signal and later terminates transcription upon reaching a gene end signal. At the end of transcription, RdRp synthesizes a polyadenylated tail (poly (A) tail) consisting of hundreds of adenines in the mRNA's 3-end, which may be done by stuttering on a sequence of uracils . After the poly (A) tail is constructed, the mRNA is released by RdRp. In genomes that encode more than one transcribable portion, RdRp can continue scanning to the next start sequence to continue with transcription. Some −ssRNA viruses are ambisense , meaning that both the negative genomic strand and positive antigenome separately encode different proteins. In order to transcribe ambisense viruses, two rounds of transcription are performed: first, mRNA is produced directly from the genome; second, mRNA is created from the antigenome. All ambisense viruses contain a hairpin loop structure to stop transcription after the protein's mRNA has been transcribed. Negative-strand RNA viruses contain a ribonucleoprotein complex composed of the genome and an RdRp attached to each segment of the genome surrounded by a capsid. The capsid is composed of proteins whose folded structure contains five alpha-helices in the N-terminal lobe (5-H motif) and three alpha-helices in the C-terminal lobe (3-H motif). Inside the capsid, the genome is sandwiched between these two motifs. Excluding the family Aspiviridae , −ssRNA viruses contain an outer viral envelope , a type of a lipid membrane that surrounds the capsid. The shape of the virus particle, called a virion, of −ssRNA viruses varies and may be filamentous, pleomorphic, spherical, or tubular. Genome segmentation is a prominent trait among many −ssRNA viruses, and −ssRNA viruses range from having genomes with one segment, typical for members of the order Mononegavirales , to genomes with ten segments, as is the case for Tilapia tilapinevirus . There is no clear trend over time that determines the number of segments, and genome segmentation among −ssRNA viruses appears to be a flexible trait since it has evolved independently on multiple occasions. Most members of the subphylum Haploviricotina are nonsegmented, whereas segmentation is universal in Polyploviricotina . Phylogenetic analysis based on RdRp shows that −ssRNA viruses are descended from a common ancestor and that they are likely a sister clade of reoviruses , which are dsRNA viruses. Within the phylum, there are two clear branches, assigned to two subphyla, based on whether RdRp synthesizes a cap on viral mRNA or snatches a cap from host mRNA and attaches that cap to viral mRNA. Within the phylum, −ssRNA viruses that infect arthropods appear to be basal and the ancestors of all other −ssRNA viruses. Arthropods frequently live together in large groups, which allows for viruses to be transmitted easily. Over time, this has led to arthropod −ssRNA viruses gaining a high level of diversity. While arthropods host large quantities of viruses, there is disagreement about the degree to which cross-species transmission of arthropod −ssRNA viruses occurs among arthropods. Plant and vertebrate −ssRNA viruses tend to be genetically related to arthropod-infected viruses. Furthermore, most −ssRNA viruses outside of arthropods are found in species that interact with arthropods. Arthropods therefore serve as both key hosts and vectors of transmission of −ssRNA viruses. In terms of transmission, non-arthropod −ssRNA viruses can be distinguished between those that are reliant on arthropods for transmission and those that can circulate among vertebrates without the aid of arthropods. The latter group is likely to have originated from the former, adapting to vertebrate-only transmission. Negarnaviricota belongs to the kingdom Orthornavirae , which encompasses all RNA viruses that encode RdRp, and the realm Riboviria , which includes Orthornavirae as well as all viruses that encode reverse transcriptase in the kingdom Pararnavirae . Negarnaviricota contains two subphyla, which contain a combined six classes, five of which are monotypic down to lower taxa: Subphylum: Haploviricotina , which contains −ssRNA viruses that encode an RdRp that synthesizes a cap structure on viral mRNA and which usually have nonsegmented genomes Class: Chunquiviricetes Order: Muvirales Family: Qinviridae Genus: Yingvirus Class: Milneviricetes Order: Serpentovirales Family: Aspviridae Genus: Ophiovirus Class: Monjiviricetes Class: Yunchangviricetes Order: Goujianvirales Family: Yueviridae Genus: Yuyuevirus Subphylum: Polyploviricotina , which contains −ssRNA viruses that encode an RdRp that takes a cap from host mRNA to use as the cap on viral mRNA and which have segmented genomes Class: Ellioviricetes Order: Bunyavirales Class: Insthoviricetes Order: Articulavirales Class: Chunquiviricetes Order: Muvirales Family: Qinviridae Genus: Yingvirus Class: Milneviricetes Order: Serpentovirales Family: Aspviridae Genus: Ophiovirus Class: Monjiviricetes Class: Yunchangviricetes Order: Goujianvirales Family: Yueviridae Genus: Yuyuevirus Order: Muvirales Family: Qinviridae Genus: Yingvirus Family: Qinviridae Genus: Yingvirus Order: Serpentovirales Family: Aspviridae Genus: Ophiovirus Family: Aspviridae Genus: Ophiovirus Order: Goujianvirales Family: Yueviridae Genus: Yuyuevirus Family: Yueviridae Genus: Yuyuevirus Class: Ellioviricetes Order: Bunyavirales Class: Insthoviricetes Order: Articulavirales Negative-strand RNA viruses are classified as Group V in the Baltimore classification system, which groups viruses together based on their manner of mRNA production and which is often used alongside standard virus taxonomy, which is based on evolutionary history. Therefore, Group V and Negarnaviricota are synonymous. Negative-strand RNA viruses caused many widely known diseases. Many of these are transmitted by arthropods, including the Rift Valley fever virus and the tomato spotted wilt virus . Among vertebrates, bats and rodents are common vectors for many viruses, including the Ebola virus and the rabies virus , transmitted by bats and other vertebrates, and the Lassa fever virus and hantaviruses , transmitted by rodents. Influenza viruses are common among birds and mammals. Human-specific −ssRNA viruses include the measles virus and the mumps virus . Many diseases caused by −ssRNA viruses have been known throughout history, including hantavirus infection, measles, and rabies. In modern history, some such as Ebola and influenza have caused deadly disease outbreaks. The vesicular stomatitis virus , first isolated in 1925 and one of the first animal viruses to be studied because it could be studied well in cell cultures , was identified as an −ssRNA virus, which was unique at the time because other RNA viruses that had been discovered were positive sense. In the early 21st century, the bovine disease rinderpest , caused by −ssRNA rinderpest virus, became the second disease to be eradicated, after smallpox , caused by a DNA virus. In the 21st century, viral metagenomics has become common to identify viruses in the environment. For −ssRNA viruses, this allowed for a large number of invertebrate, and especially arthropod, viruses to be identified, which helped to provide insight into the evolutionary history of −ssRNA viruses. Based on phylogenetic analysis of RdRp showing that −ssRNA viruses were descended from a common ancestor, Negarnaviricota and its two subphyla were established in 2018, and it was placed into the then newly established realm Riboviria .

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influenza virus

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Spike protein

In virology , a spike protein or peplomer protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an enveloped virus . : 29–33 The proteins are usually glycoproteins that form dimers or trimers . : 29–33 The term "peplomer" refers to an individual spike from the viral surface; collectively the layer of material at the outer surface of the virion has been referred to as the "peplos". The term is derived from the Greek peplos , "a loose outer garment", "robe or cloak", or "woman['s] mantle". Early systems of viral taxonomy , such as the Lwoff – Horne – Tournier system proposed in the 1960s, used the appearance and morphology of the "peplos" and peplomers as important characteristics for classification. More recently, the term "peplos" is considered a synonym for viral envelope . : 362Spikes or peplomers are usually rod- or club-shaped projections from the viral surface. Spike proteins are membrane proteins with typically large external ectodomains , a single transmembrane domain that anchors the protein in the viral envelope , and a short tail in the interior of the virion . They may also form protein–protein interactions with other viral proteins, such as those forming the nucleocapsid . : 51–2 They are usually glycoproteins , more commonly via N -linked than O -linked glycosylation . : 33Spikes typically have a role in viral entry . They may interact with cell-surface receptors located on the host cell and may have hemagglutinizing activity as a result, or in other cases they may be enzymes . : 362 For example, influenza virus has two surface proteins with these two functions, hemagglutinin and neuraminidase . : 329 The binding site for the cell-surface receptor is usually located at the tip of the spike. : 33 Many spike proteins are membrane fusion proteins . Being exposed on the surface of the virion, spike proteins can be antigens . : 362Spikes or peplomers can be visible in electron micrograph images of enveloped viruses such as orthomyxoviruses , paramyxoviruses , rhabdoviruses , filoviruses , coronaviruses , bunyaviruses , arenaviruses , and retroviruses . : 33 Coronaviruses exhibit coronavirus spike protein , also known as the S protein, on their surfaces; S is a class I fusion protein and is responsible for mediating viral entry as the first step in viral infection. It is highly antigenic and accounts for most antibodies produced by the immune system in response to infection. For this reason the spike protein has been the focus of development for COVID-19 vaccines in response to the COVID-19 pandemic caused by the virus SARS-CoV-2 . A subgenus of the betacoronaviruses , known as embecoviruses (not including SARS-like coronaviruses), have an additional shorter surface protein known as hemagglutinin esterase . The COVID-19 pandemic necessitated identification of viral particles in electron micrographs of patient tissue samples. A number of reports misidentified normal subcellular structures as coronaviruses due to their superficial resemblance to coronavirus morphology, and because the distinctive spikes of coronaviruses are apparent by negative stain but much less visible in thin section . Most influenza virus subgroups have two surface proteins described as peplomers, neuraminidase (an enzyme ) and hemagglutinin (also a class I fusion protein). Some instead have a single hemagglutinin esterase protein with both functions. : 356–9 Retroviruses such as the human immunodeficiency virus (HIV) have surface peplomers. : 318–25 These are protein complexes formed by two proteins, gp41 and gp120 , both expressed from the env gene, collectively forming a spike protein complex that mediates viral entry. Coronaviruses exhibit coronavirus spike protein , also known as the S protein, on their surfaces; S is a class I fusion protein and is responsible for mediating viral entry as the first step in viral infection. It is highly antigenic and accounts for most antibodies produced by the immune system in response to infection. For this reason the spike protein has been the focus of development for COVID-19 vaccines in response to the COVID-19 pandemic caused by the virus SARS-CoV-2 . A subgenus of the betacoronaviruses , known as embecoviruses (not including SARS-like coronaviruses), have an additional shorter surface protein known as hemagglutinin esterase . The COVID-19 pandemic necessitated identification of viral particles in electron micrographs of patient tissue samples. A number of reports misidentified normal subcellular structures as coronaviruses due to their superficial resemblance to coronavirus morphology, and because the distinctive spikes of coronaviruses are apparent by negative stain but much less visible in thin section . Most influenza virus subgroups have two surface proteins described as peplomers, neuraminidase (an enzyme ) and hemagglutinin (also a class I fusion protein). Some instead have a single hemagglutinin esterase protein with both functions. : 356–9Retroviruses such as the human immunodeficiency virus (HIV) have surface peplomers. : 318–25 These are protein complexes formed by two proteins, gp41 and gp120 , both expressed from the env gene, collectively forming a spike protein complex that mediates viral entry.

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influenza virus

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Global spread of H5N1

The global spread of H5N1 influenza in birds is considered a significant pandemic threat. While other H5N1 influenza strains are known, they are significantly different on a genetic level from a recent, highly pathogenic, emergent strain of H5N1, which was able to achieve hitherto unprecedented global spread in 2008. The H5N1 strain is a fast-mutating , highly pathogenic avian influenza virus (HPAI) found in multiple bird species. It is both epizootic (an epidemic in non-humans) and panzootic (a disease affecting animals of many species especially over a wide area). Unless otherwise indicated, "H5N1" in this timeline refers to the recent highly pathogenic strain of H5N1. Notes: Tens of millions of birds have died of H5N1 influenza and hundreds of millions of birds have been slaughtered and disposed of, to limit the spread of H5N1. Countries that have reported one or more major highly pathogenic H5N1 outbreaks in birds (causing at least thousands but in some cases millions of dead birds) are (in order of first outbreak occurrence): South Korea , Vietnam , Japan , Thailand , Cambodia , Laos , Indonesia , China , Malaysia , Russia , Kazakhstan , Mongolia , Turkey , Romania , Croatia , Ukraine , Cyprus , Iraq , Nigeria , Egypt , India , France , Niger , Bosnia , Azerbaijan , Albania , Cameroon , Myanmar , Afghanistan , Israel , Pakistan , Jordan , Burkina Faso , Germany , Sudan , Ivory Coast , Djibouti , Hungary , United Kingdom , Kuwait , Bangladesh , Saudi Arabia , Ghana , Czech Republic , Togo , Nepal , Bhutan , the Philippines , and Chile . Highly pathogenic H5N1 has been found in birds in the wild in numerous other countries: Austria , Bulgaria , Denmark , Greece , Iran , Italy , Poland , Serbia and Montenegro , Slovakia , Slovenia , Spain , Sweden , Switzerland , and Uruguay . Surveillance of H5N1 in humans, poultry, wild birds, cats and other animals remains very weak in many parts of Asia and Africa. Much remains unknown about the exact extent of its spread. H5N1 has low pathogenic varieties endemic in birds in North America. H5N1 has a highly pathogenic variety that is endemic in dozens of species of birds throughout south Asia and parts of Africa . So far, it is very difficult for humans to become infected with H5N1. The presence of highly pathogenic (deadly) H5N1 around the world in both birds in the wild ( swans , magpies , ducks , geese , pigeons , eagles , etc.) and in chickens and turkeys on farms has been demonstrated in millions of cases with the virus isolate actually sequenced in hundreds of cases yielding definitive proof of the evolution of this strain of this subtype of the species Influenzavirus A (bird flu virus). According to Robert G. Webster : The epicenters of both the Asian influenza pandemic of 1957 and the Hong Kong influenza pandemic of 1968 were in Southeast Asia, and it is in this region that multiple clades of H5N1 influenza virus have already emerged. The Asian H5N1 virus was first detected in Guangdong Province , China, in 1996, when it killed some geese, but it received little attention until it spread through live-poultry markets in Hong Kong to humans in May 1997, killing 6 of 18 infected people. [...] From 1997 to May 2005, H5N1 viruses were largely confined to Southeast Asia, but after they had infected wild birds in Qinghai Lake, China, they rapidly spread westward. [...] The intermittent spread to humans will continue, and the virus will continue to evolve. Map On July 25, 2008, the Food and Agriculture Organization (FAO) released an Avian Influenza Disease Emergency Situation Update, reporting that H5N1 pathogenicity was continuing to gradually rise in endemic areas but the avian influenza disease situation in farmed birds was being held in check by vaccination. Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006 and 55 in June 2007. In January 2004 a major new outbreak of H5N1 surfaced in Vietnam and Thailand 's poultry industry, and within weeks spread to ten countries and regions in Asia , including Indonesia , South Korea , Japan and China . In October 2004 researchers discovered H5N1 is far more dangerous than previously believed because waterfowl , especially ducks , were directly spreading the highly pathogenic strain of H5N1 to chickens , crows , pigeons , and other birds and that it was increasing its ability to infect mammals as well. From this point on, avian influenza experts increasingly refer to containment as a strategy that can delay but not prevent a future avian flu pandemic. In January 2005 an outbreak of avian influenza affected thirty three out of sixty four cities and provinces in Vietnam , leading to the forced killing of nearly 1.2 million poultry. Up to 140 million birds are believed to have died or been killed because of the outbreak. In April 2005 there begins an unprecedented die-off of over 6,000 migratory birds at Qinghai Lake in central China over three months. This strain of H5N1 is the same strain as is spread west by migratory birds over at least the next ten months. In August 2005 H5N1 spread to Kazakhstan , Mongolia and Russia . On September 29, 2005, David Nabarro , the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill 5 to 150 million people. David Nabarro later stated that as the virus had spread to migratory birds, an outbreak could start in Africa or the Middle East . Later in 2005 H5N1 spread to Turkey , Romania , Croatia and Kuwait . In January, Japan , Hungary , Russia , and the United Kingdom joined the list of nations seeing a resurgence of bird deaths due to H5N1. In February, Pakistan , Turkey , Afghanistan , and Myanmar joined the list and Kuwait saw its first major outbreak of H5N1 avian influenza . In March Bangladesh and Saudi Arabia each saw their first major outbreak of H5N1 avian influenza and Ghana in May. As H5N1 continued killing many birds and a few people throughout the spring in countries where it is now endemic, in June Malaysia and Germany saw a resurgence of bird deaths due to H5N1, while the Czech Republic and Togo experienced their first major outbreak of H5N1 avian influenza . In July France and India also saw a resurgence of bird deaths due to H5N1. As of the July 25, 2008 FAO Avian Influenza Disease Emergency Situation Update, H5N1 pathogenicity is continuing to gradually rise in wild birds in endemic areas but the avian influenza disease situation in farmed birds is being held in check by vaccination. Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006 and 55 in June 2007. The "global HPAI situation can be said to have improved markedly in the first half of 2008 [but] cases of HPAI are still underestimated and underreported in many countries because of limitations in country disease surveillance systems". In January 2004 a major new outbreak of H5N1 surfaced in Vietnam and Thailand 's poultry industry, and within weeks spread to ten countries and regions in Asia , including Indonesia , South Korea , Japan and China . In October 2004 researchers discovered H5N1 is far more dangerous than previously believed because waterfowl , especially ducks , were directly spreading the highly pathogenic strain of H5N1 to chickens , crows , pigeons , and other birds and that it was increasing its ability to infect mammals as well. From this point on, avian influenza experts increasingly refer to containment as a strategy that can delay but not prevent a future avian flu pandemic.In January 2005 an outbreak of avian influenza affected thirty three out of sixty four cities and provinces in Vietnam , leading to the forced killing of nearly 1.2 million poultry. Up to 140 million birds are believed to have died or been killed because of the outbreak. In April 2005 there begins an unprecedented die-off of over 6,000 migratory birds at Qinghai Lake in central China over three months. This strain of H5N1 is the same strain as is spread west by migratory birds over at least the next ten months. In August 2005 H5N1 spread to Kazakhstan , Mongolia and Russia . On September 29, 2005, David Nabarro , the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill 5 to 150 million people. David Nabarro later stated that as the virus had spread to migratory birds, an outbreak could start in Africa or the Middle East . Later in 2005 H5N1 spread to Turkey , Romania , Croatia and Kuwait .In January, Japan , Hungary , Russia , and the United Kingdom joined the list of nations seeing a resurgence of bird deaths due to H5N1. In February, Pakistan , Turkey , Afghanistan , and Myanmar joined the list and Kuwait saw its first major outbreak of H5N1 avian influenza . In March Bangladesh and Saudi Arabia each saw their first major outbreak of H5N1 avian influenza and Ghana in May. As H5N1 continued killing many birds and a few people throughout the spring in countries where it is now endemic, in June Malaysia and Germany saw a resurgence of bird deaths due to H5N1, while the Czech Republic and Togo experienced their first major outbreak of H5N1 avian influenza . In July France and India also saw a resurgence of bird deaths due to H5N1.As of the July 25, 2008 FAO Avian Influenza Disease Emergency Situation Update, H5N1 pathogenicity is continuing to gradually rise in wild birds in endemic areas but the avian influenza disease situation in farmed birds is being held in check by vaccination. Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006 and 55 in June 2007. The "global HPAI situation can be said to have improved markedly in the first half of 2008 [but] cases of HPAI are still underestimated and underreported in many countries because of limitations in country disease surveillance systems". As of the July 25, 2008 FAO Avian Influenza Disease Emergency Situation Update, H5N1 pathogenicity is continuing to gradually rise in wild birds in endemic areas but the avian influenza disease situation in farmed birds is being held in check by vaccination. Eleven outbreaks of H5N1 were reported worldwide in June 2008 in five countries (China, Egypt, Indonesia, Pakistan and Vietnam) compared to 65 outbreaks in June 2006 and 55 in June 2007. The "global HPAI situation can be said to have improved markedly in the first half of 2008 [but] cases of HPAI are still underestimated and underreported in many countries because of limitations in country disease surveillance systems". Avian influenza virus H3N2 is endemic in pigs (" swine flu ") in China and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. Health experts say pigs can carry human influenza viruses, which can combine (i.e. exchange homologous genome sub-units by genetic reassortment ) with H5N1 , passing genes and mutating into a form which can pass easily among humans. H3N2 evolved from H2N2 by antigenic shift and caused the Hong Kong Flu pandemic of 1968 and 1969 that killed up to 750,000 humans. The dominant strain of annual flu in humans in January 2006 is H3N2 . Measured resistance to the standard antiviral drugs amantadine and rimantadine in H3N2 in humans has increased to 91% in 2005. A combination of these two subtypes of the species known as the avian influenza virus in a country like China is a worst-case scenario. In August 2004, researchers in China found H5N1 in pigs. In 2005, it was discovered that H5N1 "could be infecting up to half of the pig population in some areas of Indonesia , but without causing symptoms [...] Chairul Nidom, a virologist at Airlangga University 's tropical disease center in Surabaya , Java, was conducting independent research earlier this year. He tested the blood of 10 apparently healthy pigs housed near poultry farms in western Java where avian flu had broken out, Nature reported. Five of the pig samples contained the H5N1 virus. The Indonesian government has since found similar results in the same region, Nature reported. Additional tests of 150 pigs outside the area were negative." In Bangkok, Thailand , all the cats in one household are known to have died of H5N1 in 2004. Tigers and leopards in Thai zoos also died, while in 2007 two cats near an outbreak in poultry and people in Iraq were confirmed to have died of H5N1, as were three German cats that ate wild birds. In Austria , cats were infected but remained healthy. Cats in Indonesia were also found to have been infected with H5N1. The spread to species and populations of birds, and the ability of felids (cats) to catch H5N1 from eating this natural prey, means the creation of a reservoir for H5N1 in cats where the virus can adapt to mammals is one of the many possible pathways to a pandemic . Variants have been found in a number of domestic cats, leopards , and tigers in Thailand , with high lethality. "The Thailand Zoo tiger outbreak killed more than 140 tigers, causing health officials to make the decision to cull all the sick tigers in an effort to stop the zoo from becoming a reservoir for H5N1 influenza. A study of domestic cats showed H5N1 virus infection by ingestion of infected poultry and also by contact with other infected cats (Kuiken et al., 2004)." The initial OIE report reads: "the clinical manifestations began on 11 October 2004 with weakness, lethargy, respiratory distress, and high fever (about 41-42 degrees Celsius). There was no response to any antibiotic treatment. Death occurred within three days following the onset of clinical signs with severe pulmonary lesions." A dead cat infected with the H5N1 bird flu virus was found in Germany . Hans Seitinger, the top agriculture official in the southern state of Styria , Austria announced that several still living cats in Styria have tested positive for H5N1: It was announced in the August 2006 CDC EID journal that while literature describing HPAI H5N1 infection in cats had been limited to a subset of clade I viruses; a Qinghai-like virus (they are genetically distinct from other clade II viruses) killed up to five cats and 51 chickens from February 3 to 5, 2006 in Grd Jotyar (~10 km north of Erbil City , Iraq). Two of the cats were available for examination. "Chairul Anwar Nidom of Airlangga University in Surabaya, Indonesia , told journalists last week that he had taken blood samples from 500 stray cats near poultry markets in four areas of Java , including the capital, Jakarta , and one area in Sumatra , all of which have recently had outbreaks of H5N1 in poultry and people. Of these cats, 20% carried antibodies to H5N1. This does not mean that they were still carrying the virus, only that they had been infected - probably through eating birds that had H5N1. Many other cats that were infected are likely to have died from the resulting illness, so many more than 20% of the original cat populations may have acquired H5N1." On 20 and 21 June in Poland multiple reports of cats dying from unknown causes with neurological and respiratory symptoms that matched H5N1 to some degree. Some viral alerts have risen, mostly posted on Facebook by veterinary clinics alerting their clients. At that time most of the data was anecdotal. On 26 June it was confirmed by Polands Chief Veterinary Officer Paweł Niemczuk, who stated that in 9 of 11 tested cases it is indeed H5N1: "The results of subsequently tested samples taken from cats from Lublin and Poznań are available. Until June 26 at 11:00 11 samples were tested at the National Veterinary Institute in Puławy, of which 9 gave a positive result for H5N1 influenza. Positive samples come from Poznań, Tri-City, and Lublin. Further detailed studies of the genetic material of viruses are underway. Preliminary research excludes the origin of the influenza virus that has been causing gulls to become ill in recent weeks. Today, a sanitary and epizootic meeting was held, where a plan for further action was discussed." Variants have been found in a number of domestic cats, leopards , and tigers in Thailand , with high lethality. "The Thailand Zoo tiger outbreak killed more than 140 tigers, causing health officials to make the decision to cull all the sick tigers in an effort to stop the zoo from becoming a reservoir for H5N1 influenza. A study of domestic cats showed H5N1 virus infection by ingestion of infected poultry and also by contact with other infected cats (Kuiken et al., 2004)." The initial OIE report reads: "the clinical manifestations began on 11 October 2004 with weakness, lethargy, respiratory distress, and high fever (about 41-42 degrees Celsius). There was no response to any antibiotic treatment. Death occurred within three days following the onset of clinical signs with severe pulmonary lesions." A dead cat infected with the H5N1 bird flu virus was found in Germany . Hans Seitinger, the top agriculture official in the southern state of Styria , Austria announced that several still living cats in Styria have tested positive for H5N1: It was announced in the August 2006 CDC EID journal that while literature describing HPAI H5N1 infection in cats had been limited to a subset of clade I viruses; a Qinghai-like virus (they are genetically distinct from other clade II viruses) killed up to five cats and 51 chickens from February 3 to 5, 2006 in Grd Jotyar (~10 km north of Erbil City , Iraq). Two of the cats were available for examination."Chairul Anwar Nidom of Airlangga University in Surabaya, Indonesia , told journalists last week that he had taken blood samples from 500 stray cats near poultry markets in four areas of Java , including the capital, Jakarta , and one area in Sumatra , all of which have recently had outbreaks of H5N1 in poultry and people. Of these cats, 20% carried antibodies to H5N1. This does not mean that they were still carrying the virus, only that they had been infected - probably through eating birds that had H5N1. Many other cats that were infected are likely to have died from the resulting illness, so many more than 20% of the original cat populations may have acquired H5N1." On 20 and 21 June in Poland multiple reports of cats dying from unknown causes with neurological and respiratory symptoms that matched H5N1 to some degree. Some viral alerts have risen, mostly posted on Facebook by veterinary clinics alerting their clients. At that time most of the data was anecdotal. On 26 June it was confirmed by Polands Chief Veterinary Officer Paweł Niemczuk, who stated that in 9 of 11 tested cases it is indeed H5N1: "The results of subsequently tested samples taken from cats from Lublin and Poznań are available. Until June 26 at 11:00 11 samples were tested at the National Veterinary Institute in Puławy, of which 9 gave a positive result for H5N1 influenza. Positive samples come from Poznań, Tri-City, and Lublin. Further detailed studies of the genetic material of viruses are underway. Preliminary research excludes the origin of the influenza virus that has been causing gulls to become ill in recent weeks. Today, a sanitary and epizootic meeting was held, where a plan for further action was discussed." H5N1 has been transmitted in laboratories to many species including mice and ferrets to study its effects. A purposely mutated strain in ferrets has engendered a notable international policy debate regarding the openness of scientific research, the mandates of public health, and the potential for bioterrorism. H5N1 was transmitted in the wild to three civet cats in Vietnam in August 2005 and a stone marten in Germany in March 2006. The BBC reported that a stray dog in Azerbaijan died from the disease on March 15, 2006. People living in areas where the A(H5N1) virus has infected birds are advised to keep their cats indoors. "Cats can be infected through the respiratory tract. Cats can also be infected when they ingest the virus, which is a novel route for influenza transmission in mammals. But cats excrete only one-thousandth the amount of virus that chickens do [...] The concern is that if large numbers of felines and other carnivores become infected, the virus might mutate in a series of events that could lead to an epidemic among humans. Dogs, foxes, seals, and other carnivores may be vulnerable to A(H5N1) virus infection, Dr. Osterhaus said. Tests in Thailand have shown that the virus has infected dogs without causing apparent symptoms." H5N1 has the potential to infect cattle . Asymptomatic shedding of H5N1 by infected calves and subsequent seroconversion is possible. Bird-to-calf transmission resulting in seroconversion is probable. While the incidence of clinical infections of cattle with H5N1 in H5N1 endemic regions should be low, "serum from bovine species would be a valuable source of additional information about transmission events, especially in regions like Asia and Egypt, where HPAIV (H5N1) is endemic and probability of contact between poultry and cattle is high."

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influenza virus

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H5N1 vaccine

A H5N1 vaccine is an influenza vaccine intended to provide immunization to influenza A virus subtype H5N1 . Vaccines have been formulated against several of the avian H5N1 influenza varieties. Vaccination of poultry against the H5N1 epizootic is widespread in certain countries. Some vaccines also exist for use in humans, and others are in testing, but none have been made available to civilian populations, however production could be scaled up to quantities sufficient to protect much of the Earth's population in the event of an H5N1 pandemic . In January 2020, the U.S. Food and Drug Administration (FDA) approved Audenz , an adjuvanted influenza A (H5N1) monovalent vaccine. Audenz is a vaccine indicated for active immunization for the prevention of disease caused by the influenza A virus H5N1 subtype contained in the vaccine. Audenz is approved for use in persons six months of age and older at increased risk of exposure to the influenza A virus H5N1 subtype contained in the vaccine. Some older, egg-based H5N1 vaccines for humans that have been licensed are: Other licensed H5N1 vaccines include: In November 2013, the U.S. Food and Drug Administration (FDA) approved an experimental H5N1 bird flu vaccine to be held in stockpiles. In a clinical trial including 3,400 adults, 91% of people age 18-64 and 74% of people age 65 or older formed an immune response sufficient to provide protection. Reported adverse effects were generally mild, with pain at the injection site being the most common adverse effect. H5N1 continually mutates, meaning vaccines based on current samples of avian H5N1 cannot be depended upon to work in the case of a future pandemic of H5N1. While there can be some cross-protection against related flu strains, the best protection would be from a vaccine specifically produced for any future pandemic flu virus strain. Daniel R. Lucey , co-director of the Biohazardous Threats and Emerging Diseases graduate program at Georgetown University, has made this point, "There is no H5N1 pandemic so there can be no pandemic vaccine ." However, "pre-pandemic vaccines" have been created; are being refined and tested; and do have some promise both in furthering research and preparedness for the next pandemic. Vaccine manufacturing companies are being encouraged to increase capacity so that if a pandemic vaccine is needed, facilities will be available for rapid production of large amounts of a vaccine specific to a new pandemic strain. [ medical citation needed ] Problems with H5N1 vaccine production include: [ medical citation needed ] lack of overall production capacity lack of surge production capacity (it is impractical to develop a system that depends on hundreds of millions of 11-day-old specialized eggs on a standby basis) the pandemic H5N1 might be lethal to chickens Cell culture (cell-based) manufacturing technology can be applied to influenza vaccines as they are with most viral vaccines and thereby solve the problems associated with creating flu vaccines using chicken eggs. According to the United States Department of Health and Human Services : Current U.S.-licensed vaccines stimulate an immune response based on the quantity of HA ( hemagglutinin ) antigen included in the dose. Methods to stimulate a strong immune response using less HA antigen are being studied in H5N1 and H9N2 vaccine trials. These include changing the mode of delivery from intramuscular to intradermal and the addition of immune-enhancing adjuvant to the vaccine formulation. Additionally, HHS is soliciting contract proposals from manufacturers of vaccines , adjuvants , and medical devices for the development and licensure of influenza vaccines that will provide dose-sparing alternative strategies. Chiron Corporation is now [ when? ] recertified and under contract with the National Institutes of Health to produce 8,000–10,000 investigational doses of Avian Flu (H5N1) vaccine . MedImmune and Aventis Pasteur are under similar contracts. The United States government hopes to obtain enough vaccine in 2006 to treat 4 million people. However, it is unclear whether this vaccine would be effective against a hypothetical mutated strain that would be easily transmitted through human populations, and the shelf life of stockpiled doses has yet to be determined. The New England Journal of Medicine reported on March 30, 2006, on one of dozens of vaccine studies being conducted. The Treanor et al. study was on vaccine produced from the human isolate (A/Vietnam/1203/2004 H5N1 ) of a virulent clade 1 influenza A (H5N1) virus with the use of a plasmid rescue system, with only the hemagglutinin and neuraminidase genes expressed and administered without adjuvant. "The rest of the genes were derived from an avirulent egg-adapted influenza A/PR/8/34 strain. The hemagglutinin gene was further modified to replace six basic amino acids associated with high pathogenicity in birds at the cleavage site between hemagglutinin 1 and hemagglutinin 2. Immunogenicity was assessed by microneutralization and hemagglutination-inhibition assays with the use of the vaccine virus, although a subgroup of samples were tested with the use of the wild-type influenza A/Vietnam/1203/2004 (H5N1) virus." The results of this study combined with others scheduled to be completed by spring 2007 is hoped will provide a highly immunogenic vaccine that is cross-protective against heterologous influenza strains. On August 18, 2006. the World Health Organization (WHO) changed the H5N1 strains recommended for candidate vaccines for the first time since 2004. "The WHO's new prototype strains, prepared by reverse genetics, include three new H5N1 subclades. The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam , Thailand , and Cambodia and bird isolates from Laos and Malaysia . Clade 2 viruses were first identified in bird isolates from China , Indonesia , Japan , and South Korea before spreading westward to the Middle East , Europe , and Africa . The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Subclade 1, Indonesia Subclade 2, Middle East, Europe, and Africa Subclade 3, China On the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains: An A/Indonesia/2/2005-like virus An A/Bar headed goose/Quinghai/1A/2005-like virus An A/Anhui/1/2005-like virus [...] Until now, [ when? ] researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, [ when? ] the first clinical trial of a U.S. vaccine for H5N1 showed modest results. In May, [ when? ] French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant. Vaccine experts aren't sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades." As of November 2006 [ update ] , the United States Department of Health and Human Services (HHS) had enough H5N1 pre-pandemic vaccine to treat about 3 million people (5.9 million full-potency doses) in spite of 0.2 million doses used for research and 1.4 million doses that have begun to lose potency (from the original 7.5 million full-potency doses purchased from Sanofi Pasteur and Chiron Corp. ). The expected shelf life of seasonal flu vaccine is about a year so the fact that most of the H5N1 pre-pandemic stockpile is still good after about two years is considered encouraging. Current U.S.-licensed vaccines stimulate an immune response based on the quantity of HA ( hemagglutinin ) antigen included in the dose. Methods to stimulate a strong immune response using less HA antigen are being studied in H5N1 and H9N2 vaccine trials. These include changing the mode of delivery from intramuscular to intradermal and the addition of immune-enhancing adjuvant to the vaccine formulation. Additionally, HHS is soliciting contract proposals from manufacturers of vaccines , adjuvants , and medical devices for the development and licensure of influenza vaccines that will provide dose-sparing alternative strategies. Chiron Corporation is now [ when? ] recertified and under contract with the National Institutes of Health to produce 8,000–10,000 investigational doses of Avian Flu (H5N1) vaccine . MedImmune and Aventis Pasteur are under similar contracts. The United States government hopes to obtain enough vaccine in 2006 to treat 4 million people. However, it is unclear whether this vaccine would be effective against a hypothetical mutated strain that would be easily transmitted through human populations, and the shelf life of stockpiled doses has yet to be determined. The New England Journal of Medicine reported on March 30, 2006, on one of dozens of vaccine studies being conducted. The Treanor et al. study was on vaccine produced from the human isolate (A/Vietnam/1203/2004 H5N1 ) of a virulent clade 1 influenza A (H5N1) virus with the use of a plasmid rescue system, with only the hemagglutinin and neuraminidase genes expressed and administered without adjuvant. "The rest of the genes were derived from an avirulent egg-adapted influenza A/PR/8/34 strain. The hemagglutinin gene was further modified to replace six basic amino acids associated with high pathogenicity in birds at the cleavage site between hemagglutinin 1 and hemagglutinin 2. Immunogenicity was assessed by microneutralization and hemagglutination-inhibition assays with the use of the vaccine virus, although a subgroup of samples were tested with the use of the wild-type influenza A/Vietnam/1203/2004 (H5N1) virus." The results of this study combined with others scheduled to be completed by spring 2007 is hoped will provide a highly immunogenic vaccine that is cross-protective against heterologous influenza strains. On August 18, 2006. the World Health Organization (WHO) changed the H5N1 strains recommended for candidate vaccines for the first time since 2004. "The WHO's new prototype strains, prepared by reverse genetics, include three new H5N1 subclades. The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam , Thailand , and Cambodia and bird isolates from Laos and Malaysia . Clade 2 viruses were first identified in bird isolates from China , Indonesia , Japan , and South Korea before spreading westward to the Middle East , Europe , and Africa . The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Subclade 1, Indonesia Subclade 2, Middle East, Europe, and Africa Subclade 3, China On the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains: An A/Indonesia/2/2005-like virus An A/Bar headed goose/Quinghai/1A/2005-like virus An A/Anhui/1/2005-like virus [...] Until now, [ when? ] researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, [ when? ] the first clinical trial of a U.S. vaccine for H5N1 showed modest results. In May, [ when? ] French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant. Vaccine experts aren't sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades." As of November 2006 [ update ] , the United States Department of Health and Human Services (HHS) had enough H5N1 pre-pandemic vaccine to treat about 3 million people (5.9 million full-potency doses) in spite of 0.2 million doses used for research and 1.4 million doses that have begun to lose potency (from the original 7.5 million full-potency doses purchased from Sanofi Pasteur and Chiron Corp. ). The expected shelf life of seasonal flu vaccine is about a year so the fact that most of the H5N1 pre-pandemic stockpile is still good after about two years is considered encouraging. H5N1 clinical trials are clinical trials concerning H5N1 vaccines. They are intended to discover pharmacological effects and identify any adverse reactions the vaccines may achieve in humans.

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influenza virus

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Human metapneumovirus

Human metapneumovirus ( HMPV or hMPV ) is a negative-sense single-stranded RNA virus of the family Pneumoviridae and is closely related to the Avian metapneumovirus (AMPV) subgroup C. It was isolated for the first time in 2001 in the Netherlands by using the RAP-PCR (RNA arbitrarily primed PCR ) technique for identification of unknown viruses growing in cultured cells. As of 2016, it was the second most common cause (after respiratory syncytial virus (RSV)) of acute respiratory tract illness in otherwise-healthy children under the age of 5 in a large US outpatient clinic . The peak age of hospitalization for infants with HMPV occurs between 6–12 months of age, slightly older than the peak of RSV, which is around 2–3 months. The clinical features and severity of HMPV are similar to those of RSV. HMPV is also an important cause of disease in older adults.Human metapneumovirus was first discovered in 2001 in the Netherlands by Bernadette G. van den Hoogen and her colleagues. hMPV was first detected in the respiratory secretions of 28 young children in the Netherlands and had initially stood out from other common respiratory viruses because the testing methods van den Hoogen et al. had tried using (immunological assays using virus-specific antibodies and PCR-based methods using virus genome-specific primers) were only able to test for known respiratory viruses and, therefore, were unable to identify the novel virus. It was not until researchers began applying molecular biology techniques that the genetic characteristics and portions of the genomic sequences of the virus could be identified; these techniques included the randomly primed PCR technique which obtained the limited sequence data needed to reveal a clear relationship between this new virus and the avian pneumovirus. It was this close relationship to AMPV that gave rise to this new virus being named human metapneumovirus to reflect both its identity as a metapneumovirus and its use of humans as a host organism.HMPV was responsible for 12% of cases of acute respiratory tract illness in otherwise-healthy children in a US outpatient clinic and 15% and 8% of cases (respectively) of community-acquired pneumonia requiring hospitalization in children under and over the age of 5 in the United States. The virus is distributed worldwide and, in temperate regions, has a seasonal distribution generally following that of RSV and influenza virus during late winter and spring. Serologic studies have shown that by the age of five, virtually all children worldwide have been exposed to the virus. Despite near universal infection during early life, reinfections are common in older children and adults. Human metapneumovirus may cause mild upper respiratory tract infection (the common cold ). However, premature infants, immunocompromised persons, and older adults >65 years are at risk for severe disease and hospitalization. In some studies of hospitalizations and emergency room visits, HMPV is nearly as common and as severe as influenza in older adults. HMPV is associated with more severe disease in people with asthma and adults with chronic obstructive pulmonary disease ( COPD ). Numerous outbreaks of HMPV have been reported in long-term care facilities for children and adults, causing fatalities. The genomic organisation of HMPV is similar to RSV ; however, HMPV lacks the non-structural genes , NS1 and NS2, and the HMPV antisense RNA genome contains eight open reading frames in slightly different gene order than RSV (viz. 3'-N-P-M-F-M2-SH-G-L-5'). HMPV is genetically similar to the avian metapneumoviruses A, B and in particular type C. Phylogenetic analysis of HMPV has demonstrated the existence of two main genetic lineages termed subtype A and B containing within them the subgroups A1/A2 and B1/B2 respectively. Genotyping based on sequences of the F and G genes showed that subtype B was associated with increased cough duration and increased general respiratory systems compared to HMPV-A. hMPV is estimated to have a 3–6 day incubation period and is often most active during the later winter and spring seasons in temperate climates, overlapping with the RSV and influenza seasons and possibly allowing for repeated infection. But because it is still a relatively new virus and has not yet been researched very heavily, hMPV and its replication cycle still have a lot of mystery surrounding them. However, researchers have been able to elucidate some principal steps of hMPV's replication cycle, basing their approach and experimentation on the current knowledge we have of the viral life cycles and reproductive measures of the rest of the Paramyxoviridae family. With that being said, it has been determined that the first step of the hMPV replication cycle is attachment to the host cell, specifically the epithelial cells of the respiratory tract, using the G protein. This G protein contains a hydrophobic region that acts as an uncleaved signal peptide and a membrane anchor to facilitate its binding; however, because recombinant viruses that lack the G protein have still been able to replicate in vitro and in vivo , it seems that attachment via the G protein is not required for rest of the replication cycle. Next in the cycle is the fusion of the viral and host membranes which is likely mediated by the F protein. Though the fusion mechanism is very similar to that of other Paramyxoviridae family members and involves conformational changes of the F protein, the mechanism for hMPV does not depend on the G protein for fusion like its family members, showing consistency with the previously mentioned idea that the G protein is not necessary for subsequent steps of the hMPV replication cycle. Moreover, the fusion function of the F protein has been proven by its ability to bind to host cells via integrin αvβ1 using an Arginine-Glycine-Aspartate (RGD) motif , which is speculated to be the trigger for membrane fusion events. One main difference between hMPV and other Paramyxoviridae viruses' fusion mechanisms though is that hMPV's fusion events occur at acidic pH levels while other viruses' fusion events occur at neutral pH levels; however, more research needs to be conducted in this area to get a better understanding of what is different about the hMPV fusion mechanism and why. Although its specific function is uncertain, it is important to note the presence of the SH glycoprotein which seemingly does not have any effects on replication kinetics, cytopathic effects, or plaque formation of hMPV. After fusion, the viral ribonucleoprotein (RNP) containing negative-sense viral RNA (vRNA) genome is released into the cytoplasm and acts as a template for mRNA and antigenomic cRNA synthesis. From here, most of our knowledge about hMPV transcription is derived from what we already know about RSV and other Paramyxoviridae viruses, including that leader and trailer sequences in the genome are partially complementary and act as promoters for transcription. We see that proteins N, P, and L dissociate from the vRNA and bind to each other to form the polymerase complex so that the genomic RNA can act as a matrix for viral transcription and replication in the cytoplasm. The final step in the replication process of hMPV that is relatively certain is the journeying of the envelope glycoproteins (F, G, and SH) to zones of membranous accumulation via the Golgi apparatus to be exposed at the surface of infected cells. This allows infected cells to merge with adjacent cells through the action of viral fusion proteins on the surface, effectively spreading the virus's genome. The rest of the replication cycle following RNA and viral protein synthesis are unclear and require further research. HMPV infects airway epithelial cells in the nose and lung. HMPV is thought to attach to the target cell via the glycoprotein (G) protein interactions with heparan sulfate and other glycosaminoglycans. The HMPV fusion (F) protein encodes an RGD (Arg-Gly-Asp) motif that engages RGD-binding integrins as cellular receptors, then mediates fusion of the cell membrane and viral envelope in a pH-independent fashion, likely within endosomes . HMPV then induces the response of chemokines and cytokines such as IL-6, IFN-alpha, TNF-alpha, IL-2, and macrophage inflammatory proteins, which in turn leads to peribronchiolar and perivascular infiltration and inflammation. The identification of HMPV has predominantly relied on reverse-transcriptase polymerase chain reaction ( RT-PCR ) technology to amplify directly from RNA extracted from respiratory specimens. Alternative more cost-effective approaches to the detection of HMPV by nucleic acid -based approaches have been employed and these include:Though hMPV was first discovered and identified in 2001, serological studies showed that hMPV, or a close relative of it, had already been circulating for at least 50 years. From this information, it is clear that the virus had not just "jumped" from birds, or some other animal reservoir, to humans shortly before its discovery. So far, peak infection from hMPV in the northern hemisphere is in late winter and early spring, but it can be found globally across all continents and its distribution is very complex and dynamic. Researchers have found that hMPV is mostly localized and can differ significantly from community to community, allowing for the possibility of the strain in one location one year to be most similar to the strain in a different location the next year. This phenomenon has actually been recorded with the virus strains in Australia in 2001; in France in 2000 and 2002; in Canada in 1999, 2000, 2001, and 2002; in Israel in 2002; and in the Netherlands in 2001 all being very closely related based on their F gene sequences. There are at least two major genotypes of hMPV (A and B) that circulate during community outbreaks and each genotype has two of its own, but as of now, it seems that no one strain is dominant over the others and none of them are known to cause varying levels of severity. hMPV is most likely spread from infected individuals to others through 1. secretions from coughing and sneezing, 2. close personal contact (ex. touching, shaking hands, etc), and 3. touching objects with viruses on them then touching your mouth, nose, or eyes. Development of a reliable antiviral therapy treatment or vaccine to prevent the spread of hMPV has yet to occur, but there does seem to be promising developments in that area. In some vaccine trials, researchers have observed how a live recombinant human parainfluenza virus that contains the hMPV F gene can induce hMPV-specific antibodies and can protect experimental animals from hMPV. Another similar study demonstrated how a chimeric bovine /human parainfluenza virus 3 expressing the hMPV F gene allows for neutralizing antibodies against both parainfluenza and hMPV. However promising these results and trials may seem, it is important to note that these experiments have limitations including their small-population animal models. Overall, while vaccines and antiviral therapy treatments are in the works, the biggest difficulty that researchers face at the moment is the limited data available about the development of hMPV in the natural host. There are no conclusive studies to date; however, it is likely that transmission occurs by contact with contaminated secretions, via droplet, aerosol, or fomite vectors. Hospital-acquired infections with human metapneumovirus have been reported. HMPV has been shown to circulate during fall and winter months with alternating predominance of a single subtype each year. No treatment is yet known, but ribavirin has shown effectiveness in an animal model. American pharmaceutical corporation Moderna has conducted a clinical trial for a candidate modRNA vaccine against metapneumovirus. As of October 2019, the vaccine candidate has passed through phase I , with reports that the vaccine is well-tolerated at all dose levels at two months, and provokes an immune response which boosts the production of neutralising antibodies . Human metapneumovirus was first reported in 2001 and avian metapneumovirus in the 1970s. There are at least four lineages of human metapneumovirus—A1, A2, B1 and B2. Avian metapneumovirus has been divided into four subgroups—A, B, C and D. Bayesian estimates suggest that human metapneumovirus emerged 119–133 years ago and diverged from avian metapneumovirus around 1800.

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Hemagglutination assay

The hemagglutination assay or haemagglutination assay ( HA ) and the hemagglutination inhibition assay ( HI or HAI ) were developed in 1941–42 by American virologist George Hirst as methods for quantifying the relative concentration of viruses , bacteria , or antibodies. HA and HAI apply the process of hemagglutination , in which sialic acid receptors on the surface of red blood cells (RBCs) bind to the hemagglutinin glycoprotein found on the surface of influenza virus (and several other viruses) and create a network, or lattice structure, of interconnected RBCs and virus particles. The agglutinated lattice maintains the RBCs in a suspended distribution, typically viewed as a diffuse reddish solution. The formation of the lattice depends on the concentrations of the virus and RBCs, and when the relative virus concentration is too low, the RBCs are not constrained by the lattice and settle to the bottom of the well. Hemagglutination is observed in the presence of staphylococci, vibrios, and other bacterial species, similar to the mechanism viruses use to cause agglutination of erythrocytes. The RBCs used in HA and HI assays are typically from chickens, turkeys, horses, guinea pigs, or humans depending on the selectivity of the targeted virus or bacterium and the associated surface receptors on the RBC.A general procedure for HA is as follows, a serial dilution of virus is prepared across the rows in a U or V- bottom shaped 96-well microtiter plate. The most concentrated sample in the first well is often diluted to be 1/5x of the stock, and subsequent wells are typically two-fold dilutions (1/10, 1/20, 1/40, etc.).The final well serves as a negative control with no virus. Each row of the plate typically has a different virus and the same pattern of dilutions. After serial dilutions, a standardized concentration of RBCs is added to each well and mixed gently. The plate is incubated for 30 minutes at room temperature. Following the incubation period, the assay can be analyzed to distinguish between agglutinated and non-agglutinated wells. The images across a row will typically progress from agglutinated wells with high virus concentration and a diffuse reddish appearance to a series of wells with low virus concentrations containing a dark red pellet, or button, in the center of the well. The low concentration wells appear nearly identical to the no-virus negative control well. The button appearance occurs because the RBCs are not held in the agglutinated lattice structure and settle into the low point of the U or V-bottom well. The transition from agglutinated to non-agglutinated wells occurs distinctively, within 1 to 2 wells. The relative concentration, or titer, of the virus sample is based on the well with the last agglutinated appearance, immediately before a pellet is observed. Relative to the initial viral stock concentration, the virus concentration in this well will be some dilution of the stock, for example, 1/40-fold. The titer value of that sample is the inverse of the dilution, i.e., 40. In some cases, the virus is initially so dilute that agglutinated wells are never observed. In that case, the titer of these samples is commonly assigned as 5, indicating the highest possible concentration, but the accuracy of that value is clearly low. Alternatively, if the relative concentration of the virus is extremely high and the wells never transition to a button appearance. The titer value is then commonly assigned to be the highest dilution, such as 5120. HI is closely related to the HA assay, but includes anti-viral antibodies as "inhibitors" to interfere with the virus-RBC interaction. The goal is to characterize the concentration of antibodies in the antiserum or other samples containing antibodies. The HI assay is generally performed by creating a dilution series of antiserum across the rows of a 96-well microtiter plate. Each row would usually be a different sample. A standardized amount of virus or bacteria is added to each well, and the mixture is allowed to incubate at room temperature for 30 minutes. The last well in each row would be a negative control with no virus added. During the incubation, antibodies bind to the viral particles, and if the concentration and binding affinity of the antibodies are high enough, the viral particles are effectively blocked from causing hemagglutination. Next, a standardized amount of RBCs is added to each well and allowed to incubate at room temperature for an additional 30 minutes. The resulting HI plate images usually progress from non-agglutinated, "button" wells with high antibody concentration to agglutinated, red diffuse wells with low antibody concentration. The HI titer value is the inverse of the last dilution of serum that completely inhibited hemagglutination. The preceding descriptions of the HA and HI processes are generalized, and specific details can vary depending on the operator and laboratory. For example, serial dilutions across the rows is described, but some laboratories use an alternate orientation and perform dilutions down the columns instead. Similarly, the starting dilution, serial dilution factor, incubation times, and choice of U or V-bottom plate can depend on the specific laboratory.HA and HI have the advantages that the assays are simple, use relatively inexpensive and available instruments and supplies, and provide results within a few hours. The assays are also well established in many laboratories around the world, allowing some measure of credibility, comparison, and standardization. Optimal and reliable results require controlling several variables, such as incubation times, red blood cell concentration, and type of red blood cell. Non-specific factors in the sample can lead to interference and incorrect titer values. For example, molecules in the sample other than virus-specific antibodies can inhibit agglutination between virus and RBCs, as well as potentially blocking antibody from binding to virus. Receptor-destroying enzymes (RDE) are commonly used to treat samples prior to analysis to prevent non-specific inhibition. Analysis of the HA or HI results relies on a qualified individual to read the plate and determine the titer values. The manual interpretation method introduces more opportunities for discrepancies in the assay because results can be subjective and the agreement between human readers is inconsistent. Also, there is no digital record of the plate or titer determinations so the initial interpretation is tedious and commonly done in replicates. The range of potential variables and differences between expert readers can make comparing inter-laboratory results difficult.

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Influenza Genome Sequencing Project

The Influenza Genome Sequencing Project ( IGSP ), initiated in early 2004, seeks to investigate influenza evolution by providing a public data set of complete influenza genome sequences from collections of isolates representing diverse species distributions. The project is funded by the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH), and has been operating out of the NIAID Microbial Sequencing Center at The Institute for Genomic Research (TIGR, which in 2006 became The Venter Institute). Sequence information generated by the project has been continually placed into the public domain through GenBank .In late 2003, David Lipman , Lone Simonsen , Steven Salzberg , and a consortium of other scientists wrote a proposal to begin sequencing large numbers of influenza viruses at The Institute for Genomic Research (TIGR). Prior to this project, only a handful of flu genomes were publicly available. [ citation needed ] Their proposal was approved by the National Institutes of Health (NIH), and would later become the IGSP. New technology development led by Elodie Ghedin began at TIGR later that year, and the first publication describing > 100 influenza genomes appeared in 2005 in the journal Nature The project makes all sequence data publicly available through GenBank , an international, NIH-funded, searchable online database. This research helps to provide international researchers with the information needed to develop new vaccines , therapies and diagnostics, as well as improve understanding of the overall molecular evolution of Influenza and other genetic factors that determine their virulence. [ citation needed ] Such knowledge could not only help mitigate the impact of annual influenza epidemics , but could also improve scientific knowledge of the emergence of pandemic influenza viruses .The project completed its first genomes in March 2005 and has rapidly accelerated since. By mid-2008, over 3000 isolates had been completely sequenced from influenza viruses that are endemic in human ("human flu") avian ("bird flu") and swine ("swine flu") populations, including many strains of H3N2 (human), H1N1 (human), and H5N1 (avian). The project is funded by the National Institute of Allergy and Infectious Diseases (NIAID) which is a component of the NIH, which is an agency of the United States Department of Health and Human Services . The IGSP has expanded to include a growing list of collaborators, who have contributed both expertise and valuable collections of influenza isolates. Key early contributors included Peter Palese of the Mount Sinai School of Medicine in New York, Jill Taylor of the Wadsworth Center at the New York State Department of Health , Lance Jennings of Canterbury Health Laboratories (New Zealand), Jeff Taubenberger of the Armed Forces Institute of Pathology (who later moved to NIH), Richard Slemons of Ohio State University and Rob Webster of St. Jude's Children's Hospital in Memphis, Tennessee. In 2006 the project was joined by Ilaria Capua of the Istituto Zooprofilattico Sperimentale delle Venezie (in Italy), who contributed a valuable collection of avian flu isolates (including multiple H5N1 strains). Some of these avian isolates were described in a publication in Emerging Infectious Diseases in 2007. Nancy Cox from the Centers for Disease Control and Prevention (CDC) and Robert Couch from Baylor College of Medicine also joined the project in 2006, contributing over 150 influenza B isolates. The project began prospective studies of the 2007 influenza season with collaborators Florence Bourgeois and Kenneth Mandl of Children's Hospital Boston and the Harvard School of Public Health and Laurel Edelman of Surveillance Data Inc. [ citation needed ]

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Neuraminidase

Exo-α-sialidase ( EC 3.2.1.18 , sialidase, neuraminidase ; systematic name acetylneuraminyl hydrolase ) is a glycoside hydrolase that cleaves the glycosidic linkages of neuraminic acids : Neuraminidase enzymes are a large family, found in a range of organisms. The best-known neuraminidase is the viral neuraminidase , a drug target for the prevention of the spread of influenza infection. Viral neuraminidase was the first neuraminidase to be identified. It was discovered in 1957 by Alfred Gottschalk at the Walter and Eliza Hall Institute in Melbourne . The viral neuraminidases are frequently used as antigenic determinants found on the surface of the influenza virus. Some variants of the influenza neuraminidase confer more virulence to the virus than others. Other homologues are found in mammalian cells, which have a range of functions. At least four mammalian sialidase homologues have been described in the human genome (see NEU1 , NEU2 , NEU3 , NEU4 ). Sialidases may act as pathogenic factors in microbial infections. There are two major classes of Neuraminidase that cleave exo or endo poly-sialic acids:Sialidases, also called neuraminidases, catalyze the hydrolysis of terminal sialic acid residues from the newly formed virions and from the host cell receptors. Sialidase activities include assistance in the mobility of virus particles through the respiratory tract mucus and in the elution of virion progeny from the infected cell. Swiss-Prot lists 137 types of neuraminidase from various species as of October 18, 2006. Nine subtypes of influenza neuraminidase are known; many occur only in various species of duck and chicken. Subtypes N1 and N2 have been positively linked to epidemics in humans, and strains with N3 or N7 subtypes have been identified in a number of isolated deaths. [ citation needed ] CAZy defines a total of 85 glycosyl hydrolase families, of which families GH34 (viral), GH33 (cellular organisms), GH58 (viral and bacterial), GH83 (viral) are major families that contain this enzyme. GH58 is the only endo-acting family. The following is a list of major classes of neuraminidase enzymes: [ citation needed ]Influenza neuraminidase is a mushroom-shaped projection on the surface of the influenza virus. It has a head consisting of four co-planar and roughly spherical subunits, and a hydrophobic region that is embedded within the interior of the virus' membrane. It comprises a single polypeptide chain that is oriented in the opposite direction to the hemagglutinin antigen. The composition of the polypeptide is a single chain of six conserved polar amino acids, followed by hydrophilic, variable amino acids. β-Sheets predominate as the secondary level of protein conformation. [ citation needed ] The structure of trans-sialidase includes a catalytic β-propeller domain, a N -terminal lectin -like domain and an irregular beta-stranded domain inserted into the catalytic domain. Recent emergence of oseltamivir and zanamivir resistant human influenza A( H1N1 ) H274Y has emphasized the need for suitable expression systems to obtain large quantities of highly pure and stable, recombinant neuraminidase through two separate artificial tetramerization domains that facilitate the formation of catalytically active neuraminidase homotetramers from yeast and Staphylothermus marinus , which allow for secretion of FLAG-tagged proteins and further purification. The enzymatic mechanism of influenza virus sialidase has been studied by Taylor et al., shown in Figure 1. The enzyme catalysis process has four steps. The first step involves the distortion of the α-sialoside from a 2 C 5 chair conformation (the lowest-energy form in solution) to a pseudoboat conformation when the sialoside binds to the sialidase. The second step leads to an oxocarbocation intermediate, the sialosyl cation. The third step is the formation of Neu5Ac initially as the α-anomer, and then mutarotation and release as the more thermodynamically stable β-Neu5Ac. Neuraminidase inhibitors are useful for combating influenza infection: zanamivir , administered by inhalation; oseltamivir , administered orally; peramivir administered parenterally , that is through intravenous or intramuscular injection; and laninamivir which is in phase III clinical trials. [ citation needed ] There are two major proteins on the surface of influenza virus particles. One is the lectin haemagglutinin protein with three relatively shallow sialic acid-binding sites and the other is enzyme sialidase with the active site in a pocket. Because of the relative deep active site in which low-molecular-weight inhibitors can make multiple favorable interactions and approachable methods of designing transition-state analogues in the hydrolysis of sialosides, the sialidase becomes more attractive anti-influenza drug target than the haemagglutinin. After the X-ray crystal structures of several influenza virus sialidases were available, the structure-based inhibitor design was applied to discover potent inhibitors of this enzyme. The unsaturated sialic acid ( N -acetylneuraminic acid [Neu5ac]) derivative 2-deoxy-2, 3-didehydro- D - N -acetylneuraminic acid (Neu5Ac2en), a sialosyl cation transition-state (Figure 2) analogue, is believed the most potent inhibitor core template. Structurally modified Neu5Ac2en derivatives may give more effective inhibitors. Many Neu5Ac2en-based compounds have been synthesized and tested for their influenza virus sialidase inhibitory potential. For example: The 4-substituted Neu5Ac2en derivatives (Figure 3), 4-amino-Neu5Ac2en (Compound 1), which showed two orders of magnitude better inhibition of influenza virus sialidase than Neu5Ac2en5 and 4-guanidino-Neu5Ac2en (Compound 2), known as Zanamivir, which is now marketed for treatment of influenza virus as a drug, have been designed by von Itzstein and coworkers. A series of amide-linked C9 modified Neu5Ac2en have been reported by Megesh and colleagues as NEU1 inhibitors.

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Avian influenza in cats

Cats with avian influenza exhibit symptoms that can result in death. They are one of the few species that can get avian influenza . The specific virus that they get is H5N1, which is a subtype of avian influenza. In order to get the virus, cats need to be in contact with waterfowl, poultry, or uncooked poultry that are infected. Two of the main organs that the virus affects are the lungs and liver. The H5N1 virus has been found in China, Thailand, Vietnam, Indonesia, Iraq, Austria, Germany, and Poland. Besides being found in domestic cats, the virus has infected a variety of wild cats such as the Asiatic golden cat , the clouded leopard , tigers , and leopards . H5N1 was first discovered in domestic and wild cats in Asia, specifically in 2003 in the Thai zoo where two tigers and two leopards died. In 2004, the Thai zoo had 147 tigers that died or were euthanized. This was then followed by an outbreak in Germany in 2006, where three stray cats were found to be either dying or dead during the peak time of the virus outbreak. Currently, as of June 2023, there is an ongoing outbreak in Poland with at least 9 confirmed cases and multiple deaths. Because the virus infects the lungs of cats, it is one of the preferred model animals to study the effects of H5N1 in humans. The most common way a cat can obtain H5N1 is by consuming an infected bird. This has been studied in the 2006 and 2007 cases in Germany and Austria where the strains between the cat and the infected birds were not different between the species. A cat is able to then transfer the virus via the respiratory tract and the digestive tract to other cats. However, studies suggest that a cat cannot transfer the virus to a dog, and vice versa, while sharing a food bowl. Though there is no concrete evidence, there is a potential link between the transfer of the virus between poultry, wild birds, and humans. Once the cat is infected, after an incubation period of 2 to 3 days, the virus can be found in the respiratory tissues, attached to the type II pneumocytes and alveolar macrophages , as well as the intestinal tissues. There have also been some cases where the virus has been found in the brain and other systems in the body. As of right now the H5N1 virus has not adapted to transfer in between mammals, but there is a fear that this can occur. One epidemiological study that was performed in Germany and Austria on 171 cats found that less than 1.8% of this population had H5N1. In this same sample population of cats, less than 2.6% had antibodies to H5N1. Even though Germany and Austria are among the countries that have had naturally occurring cases, this study shows that very few cats have contracted the disease. There have also been studies looking at the T cells , specifically CD4 and CD8, in the cat after viral infection. Though the mechanism is not fully known, there seems to be an inverse relationship with the amount of T cells present and the amount of infected cells. Another study to test whether the ALVAC recombinant canarypox virus could prime the immune system in cats was performed. This vaccine has the same hemagglutinin as the H5N1 virus, and therefore worked on preventing death from two different strains of the virus, HPAIV A/Vietnam/1194/2004 and HPAIV A/Indonesia/05/2005. However, some of the cats that were vaccinated did exhibit hyperthermia and weight loss, and all of the cats did have some disease change (assuming lesions) in their lungs. All of the cats, except one, still excreted the virus even after being vaccinated. One epidemiological study that was performed in Germany and Austria on 171 cats found that less than 1.8% of this population had H5N1. In this same sample population of cats, less than 2.6% had antibodies to H5N1. Even though Germany and Austria are among the countries that have had naturally occurring cases, this study shows that very few cats have contracted the disease. There have also been studies looking at the T cells , specifically CD4 and CD8, in the cat after viral infection. Though the mechanism is not fully known, there seems to be an inverse relationship with the amount of T cells present and the amount of infected cells. Another study to test whether the ALVAC recombinant canarypox virus could prime the immune system in cats was performed. This vaccine has the same hemagglutinin as the H5N1 virus, and therefore worked on preventing death from two different strains of the virus, HPAIV A/Vietnam/1194/2004 and HPAIV A/Indonesia/05/2005. However, some of the cats that were vaccinated did exhibit hyperthermia and weight loss, and all of the cats did have some disease change (assuming lesions) in their lungs. All of the cats, except one, still excreted the virus even after being vaccinated. A cat that is infected with a high dose of the virus can show signs of fever , lethargy , and dyspnea . There have even been recorded cases where a cat has neurological symptoms such as circling or ataxia . In a case in February 2004, a 2-year-old male cat was panting and convulsing on top of having a fever two days prior to death. This cat also had lesions that were identified as renal congestion, pulmonary congestion, edema , and pneumonia . Upon inspection, the cat also had cerebral congestion, conjunctivitis , and hemorrhaging in the serosae of the intestines . However, a cat that is infected with a low dose of the virus may not necessarily show symptoms. Though they may be asymptomatic, they can still transfer small amounts of the virus. Cats can be protected from H5N1 if they are given a vaccination, as mentioned above. However, it was also found that cats can still shed some of the virus but in low numbers. If a cat is exhibiting symptoms, they should be put into isolation and kept indoors. Then they should be taken to a vet to get tested for the presence of H5N1. If there is a possibility that the cat has Avian Influenza, then there should be extra care when handling the cat. Some of the precautions include avoiding all direct contact with the cat by wearing gloves, masks, and goggles. Whatever surfaces the cat comes in contact with should be disinfected with standard household cleaners. Researchers have given tigers an antiviral treatment of Oseltamivir with a dose of 75 mg/60 kg two times a day. The specific dosage was extrapolated from human data, but there hasn't been any data to suggest protection. As with many antiviral treatments, the dosage depends on the species.

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Emergent virus

An emergent virus (or emerging virus ) is a virus that is either newly appeared , notably increasing in incidence / geographic range or has the potential to increase in the near future. Emergent viruses are a leading cause of emerging infectious diseases and raise public health challenges globally, given their potential to cause outbreaks of disease which can lead to epidemics and pandemics . As well as causing disease , emergent viruses can also have severe economic implications. Recent examples include the SARS-related coronaviruses , which have caused the 2002–2004 outbreak of SARS ( SARS-CoV-1 ) and the 2019–2023 pandemic of COVID-19 ( SARS-CoV-2 ). Other examples include the human immunodeficiency virus , which causes HIV/AIDS ; the viruses responsible for Ebola ; the H5N1 influenza virus responsible for avian influenza ; and H1N1/09 , which caused the 2009 swine flu pandemic (an earlier emergent strain of H1N1 caused the 1918 Spanish flu pandemic). Viral emergence in humans is often a consequence of zoonosis , which involves a cross-species jump of a viral disease into humans from other animals. As zoonotic viruses exist in animal reservoirs , they are much more difficult to eradicate and can therefore establish persistent infections in human populations. Emergent viruses should not be confused with re-emerging viruses or newly detected viruses. A re-emerging virus is generally considered to be a previously appeared virus that is experiencing a resurgence, for example measles . A newly detected virus is a previously unrecognized virus that had been circulating in the species as endemic or epidemic infections. Newly detected viruses may have escaped classification because they left no distinctive clues and/or could not be isolated or propagated in cell culture . Examples include human rhinovirus (a leading cause of common colds which was first identified in 1956), hepatitis C (eventually identified in 1989), and human metapneumovirus (first described in 2001, but thought to have been circulating since the 19th century). As the detection of such viruses is technology driven, the number reported is likely to expand.Given the rarity of spontaneous development of new virus species, the most frequent cause of emergent viruses in humans is zoonosis . This phenomenon is estimated to account for 73% of all emerging or re-emerging pathogens , with viruses playing a disproportionately large role. RNA viruses are particularly frequent, accounting for 37% of emerging and re-emerging pathogens. A broad range of animals — including wild birds, rodents, and bats — are associated with zoonotic viruses. It is not possible to predict specific zoonotic events that may be associated with a particular animal reservoir at any given time. Zoonotic spillover can either result in self-limited 'dead-end' infections, in which no further human-to-human transmission occurs (as with the rabies virus ), or in infectious cases, in which the zoonotic pathogen is able to sustain human-to-human transmission (as with the Ebola virus ). If the zoonotic virus is able to maintain successful human-to-human transmission, an outbreak may occur. Some spillover events can also result in the virus adapting exclusively for human infection (as occurred with the HIV virus ), in which case humans become a new reservoir for the pathogen. A successful zoonotic 'jump' depends on human contact with an animal harboring a virus variant that is able to infect humans. In order to overcome host-range restrictions and sustain efficient human-to-human transmission, viruses originating from an animal reservoir will normally undergo mutation , genetic recombination , and reassortment . Due to their rapid replication and high mutation rates, RNA viruses are more likely to successfully adapt for invasion of a new host population. While bats are essential members of many ecosystems, they are also frequently implicated as frequent sources of emerging virus infections. Their immune systems have evolved in such a way as to suppress any inflammatory response to viral infections, thereby allowing them to become tolerant hosts for evolving viruses, and consequently provide major reservoirs of zoonotic viruses. They are associated with more zoonotic viruses per host species than any other mammal, and molecular studies have demonstrated that they are the natural hosts for several high-profile zoonotic viruses, including severe acute respiratory syndrome – related coronaviruses and Ebola / Marburg hemorrhagic fever filoviruses. In terms of their potential for spillover events, bats have taken over the leading role previously assigned to rodents. Viruses can be transmitted from bats via several mechanisms, including bites, aerosolization of saliva (e.g., during echolocation ), and feces/urine. Due to their distinct ecology /behavior, bats are naturally more susceptible to viral infection and transmission. Several bat species (e.g., brown bats) aggregate in crowded roosts, which promotes intra- and interspecies viral transmission. Moreover, as bats are widespread in urban areas, humans occasionally encroach on their habitats which are contaminated with guano and urine. Their ability to fly and migration patterns also means that bats are able to spread disease over a large geographic area, while also acquiring new viruses. Additionally, bats experience persistent viral infections which, together with their extreme longevity (some bat species have lifespans of 35 years), helps to maintain viruses and transmit them to other species. Other bat characteristics which contribute to their potency as viral hosts include: their food choices, torpor / hibernation habits, and susceptibility to reinfection. While bats are essential members of many ecosystems, they are also frequently implicated as frequent sources of emerging virus infections. Their immune systems have evolved in such a way as to suppress any inflammatory response to viral infections, thereby allowing them to become tolerant hosts for evolving viruses, and consequently provide major reservoirs of zoonotic viruses. They are associated with more zoonotic viruses per host species than any other mammal, and molecular studies have demonstrated that they are the natural hosts for several high-profile zoonotic viruses, including severe acute respiratory syndrome – related coronaviruses and Ebola / Marburg hemorrhagic fever filoviruses. In terms of their potential for spillover events, bats have taken over the leading role previously assigned to rodents. Viruses can be transmitted from bats via several mechanisms, including bites, aerosolization of saliva (e.g., during echolocation ), and feces/urine. Due to their distinct ecology /behavior, bats are naturally more susceptible to viral infection and transmission. Several bat species (e.g., brown bats) aggregate in crowded roosts, which promotes intra- and interspecies viral transmission. Moreover, as bats are widespread in urban areas, humans occasionally encroach on their habitats which are contaminated with guano and urine. Their ability to fly and migration patterns also means that bats are able to spread disease over a large geographic area, while also acquiring new viruses. Additionally, bats experience persistent viral infections which, together with their extreme longevity (some bat species have lifespans of 35 years), helps to maintain viruses and transmit them to other species. Other bat characteristics which contribute to their potency as viral hosts include: their food choices, torpor / hibernation habits, and susceptibility to reinfection. While bats are essential members of many ecosystems, they are also frequently implicated as frequent sources of emerging virus infections. Their immune systems have evolved in such a way as to suppress any inflammatory response to viral infections, thereby allowing them to become tolerant hosts for evolving viruses, and consequently provide major reservoirs of zoonotic viruses. They are associated with more zoonotic viruses per host species than any other mammal, and molecular studies have demonstrated that they are the natural hosts for several high-profile zoonotic viruses, including severe acute respiratory syndrome – related coronaviruses and Ebola / Marburg hemorrhagic fever filoviruses. In terms of their potential for spillover events, bats have taken over the leading role previously assigned to rodents. Viruses can be transmitted from bats via several mechanisms, including bites, aerosolization of saliva (e.g., during echolocation ), and feces/urine. Due to their distinct ecology /behavior, bats are naturally more susceptible to viral infection and transmission. Several bat species (e.g., brown bats) aggregate in crowded roosts, which promotes intra- and interspecies viral transmission. Moreover, as bats are widespread in urban areas, humans occasionally encroach on their habitats which are contaminated with guano and urine. Their ability to fly and migration patterns also means that bats are able to spread disease over a large geographic area, while also acquiring new viruses. Additionally, bats experience persistent viral infections which, together with their extreme longevity (some bat species have lifespans of 35 years), helps to maintain viruses and transmit them to other species. Other bat characteristics which contribute to their potency as viral hosts include: their food choices, torpor / hibernation habits, and susceptibility to reinfection. Viral emergence is often a consequence of both nature and human activity . In particular, ecological changes can greatly facilitate the emergence and re-emergence of zoonotic viruses. Factors such as deforestation , reforestation , habitat fragmentation , and irrigation can all impact the ways in which humans come into contact with wild animal species and consequently promote virus emergence. In particular, habitat loss of reservoir host species plays a significant role in emerging zoonoses . Additionally, climate change can affect ecosystems and vector distribution, which in turn can affect the emergence of vector-borne viruses. Other ecological changes — for example, species introduction and predator loss — can also affect virus emergence and prevalence. Some agricultural practices — for example, livestock intensification and inappropriate management/disposal of farm animal feces — are also associated with an increased risk of zoonosis. Viruses may also emerge due to the establishment of human populations that are vulnerable to infection. For example, a virus may emerge following loss of cross-protective immunity , which may occur due to loss of a wild virus or termination of vaccination program. Well-developed countries also have higher proportions of aging citizens and obesity-related disease , thus meaning that their populations may be more immunosuppressed and therefore at risk of infection. Contrastingly, poorer nations may have immunocompromised populations due to malnutrition or chronic infection; these countries are also unlikely to have stable vaccination program. Additionally, changes in human demographics — for example, the birth and/or migration of immunologically naïve individuals — can lead to the development of a susceptible population that enables large-scale virus infection. Other factors which can promote viral emergence include globalization ; in particular, international trade and human travel/ migration can result in the introduction of viruses into new areas. Moreover, as densely populated cities promote rapid pathogen transmission, uncontrolled urbanization (i.e., the increased movement and settling of individuals in urban areas ) can promote viral emergence. Animal migration can also lead to the emergence of viruses, as was the case for the West Nile virus which was spread by migrating bird populations. Additionally, human practices regarding food production and consumption can also contribute to the risk of viral emergence. In particular, wet markets (i.e., live animal markets) are an ideal environment for virus transfer, due to the high density of people and wild/farmed animals present. Consumption of bushmeat is also associated with pathogen emergence. Control and prevention of zoonotic diseases depends on appropriate global surveillance at various levels, including identification of novel pathogens, public health surveillance (including serological surveys ), and analysis of the risks of transmission. The complexity of zoonotic events around the world predicates a multidisciplinary approach to prevention. The One Health Model has been proposed as a global strategy to help prevent the emergence of zoonotic diseases in humans, including novel viral diseases. The One Health concept aims to promote the health of animals, humans, and the environment, both locally and globally, by fostering understanding and collaboration between practitioners of different interrelated disciplines, including wildlife biology , veterinary science , medicine , agriculture , ecology , microbiology , epidemiology , and biomedical engineering . As hosts are immunologically naïve to pathogens they have not encountered before, emergent viruses are often extremely virulent in terms of their capacity to cause disease. Their high virulence is also due to a lack of adaptation to the new host; viruses normally exert strong selection pressure on the immune systems of their natural hosts, which in turn exerts a strong selection pressure on viruses. This coevolution means that the natural host is able to manage infection. However, when the virus jumps to a new host (e.g., humans), the new host is unable to deal with infection due to a lack of coevolution, which results in mismatch between host immunoeffectors and virus immunomodulators . [ citation needed ] Additionally, in order to maximize transmission, viruses often naturally undergo attenuation (i.e., virulence is reduced) so that infected animals can survive long enough to infect other animals more efficiently. However, as attenuation takes time to achieve, new host populations will not initially benefit from this phenomenon. Moreover, as zoonotic viruses also naturally exist in animal reservoirs , their survival is not dependent on transmission between new hosts; this means that emergent viruses are even more unlikely to attenuate for the purpose of maximal transmission, and they remain virulent. [ citation needed ] Although emergent viruses are frequently highly virulent, they are limited by several host factors including: innate immunity , natural antibodies , and receptor specificity . If the host has previously been infected by a pathogen that is similar to the emergent virus, the host may also benefit from cross-protective immunity . [ citation needed ]Influenza is a highly contagious respiratory infection, which affects approximately 9% of the global population and causes 300,000 to 500,000 deaths annually. Based on their core proteins, influenza viruses are classified into types A, B, C, and D. While both influenza A and B can cause epidemics in humans, influenza A also has pandemic potential and a higher mutation rate and is therefore most significant to public health. Influenza A viruses are further classified into subtypes, based on the combinations of the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). The primary natural reservoir for most influenza A subtypes are wild aquatic birds; however, through a series of mutations, a small subset of these viruses have adapted for infection of humans (and other animals). A key determinant of whether a particular influenza A subtype can infect humans is its binding specificity. Avian influenza A preferentially binds to cell surface receptors with a terminal α2,3‐linked sialic acid , while human influenza A preferentially binds to cell surface receptors with a terminal α2,6‐linked sialic acid. Via mutation, some avian influenza A viruses have successfully altered their binding specificity from α2,3‐ to α2,6‐linked sialic acid. However, in order to emerge in humans, avian influenza A viruses must also adapt their RNA polymerases for function in mammalian cells, as well as mutating for stability in the acidic respiratory tract of humans. Following adaptation and host switch , influenza A viruses have the potential to cause epidemics and pandemics in humans. Minor changes in HA and NA structure ( antigenic drift ) occur frequently, which enables the virus to cause repetitive outbreaks (i.e., seasonal influenza ) by evading immune recognition. Major changes in HA and NA structure ( antigenic shift ), which are caused by genetic reassortment between different influenza A subtypes (e.g., between human and animal subtypes), can instead cause large regional/global pandemics . Due to the emergence of antigenically different influenza A strains in humans, four influenza pandemics occurred in the 20th century alone. Additionally, although animal influenza A viruses (e.g., swine influenza ) are distinct from human influenza viruses, they can still cause zoonotic infection in humans. These infections are largely acquired following direct contact with infected animals or contaminated environments, but do not result in efficient human-to-human transmission; examples of this include H5N1 influenza and H7N9 influenza . In 2002, a highly pathogenic SARS-CoV (severe acute respiratory syndrome coronavirus) strain emerged from a zoonotic reservoir; approximately 8,000 people were infected worldwide, and mortality rates approached 50% or more in the elderly. As SARS-CoV-1 is most contagious post-symptoms, the introduction of strict public health measures effectively halted the epidemic. The natural reservoir host for SARS-CoV-1 is thought to be horseshoe bats , although the virus has also been identified in several small carnivores (e.g., palm civets and racoon dogs ). The emergence of SARS-CoV-1 is believed to have been facilitated by Chinese wet markets, in which civets positive for the virus acted as intermediate hosts and passed SARS-CoV-1 onto humans (and other species). However, more recent analysis suggests that SARS-CoV-1 may have directly jumped from bats to humans, with subsequent cross-transmission between humans and civets. In order to infect cells, SARS-CoV-1 uses the spike surface glycoprotein to recognize and bind to host ACE-2 , which it uses as a cellular entry receptor; the development of this characteristic was crucial in enabling SARS-CoV-1 to 'jump' from bats to other species. First reported in 2012, MERS-CoV (Middle East respiratory syndrome coronavirus) marks the second known introduction of a highly pathogenic coronavirus from a zoonotic reservoir into humans. The case mortality rate of this emergent virus is approximately 35%, with 80% of all cases reported by Saudi Arabia. Although MERS-CoV is likely to have originated in bats, dromedary camels have been implicated as probable intermediate hosts. MERS-CoV is believed to have been circulating in these mammals for over 20 years, and it is thought that novel camel farming practices drove the spillover of MERS-CoV into humans. Studies have shown that humans can be infected with MERS-CoV via direct or indirect contact within infected dromedary camels, while human-to-human transmission is limited. MERS-CoV gains cellular entry by using a spike surface protein to bind to the host DPP4 surface receptor; the core subdomain of this spike surface protein shares similarities with that of SARS-CoV, but its receptor binding subdomain (RBSD) significantly differs. Bluetongue disease is a non-contagious vector-borne disease caused by bluetongue virus, which affects species of ruminants (particularly sheep ). Climate change has been implicated in the emergence and global spread of this disease, due to its impact on vector distribution. The natural vector of the bluetongue virus is the African midge C. imicola , which is normally limited to Africa and subtropical Asia. However, global warming has extended the geographic range of C. imicola , so that it now overlaps with a different vector ( C. pulcaris or C. obsoletus ) with a much more northward geographic range. This change enabled the bluetongue virus to jump vector, thus causing the northward spread of bluetongue disease into Europe. Influenza is a highly contagious respiratory infection, which affects approximately 9% of the global population and causes 300,000 to 500,000 deaths annually. Based on their core proteins, influenza viruses are classified into types A, B, C, and D. While both influenza A and B can cause epidemics in humans, influenza A also has pandemic potential and a higher mutation rate and is therefore most significant to public health. Influenza A viruses are further classified into subtypes, based on the combinations of the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA). The primary natural reservoir for most influenza A subtypes are wild aquatic birds; however, through a series of mutations, a small subset of these viruses have adapted for infection of humans (and other animals). A key determinant of whether a particular influenza A subtype can infect humans is its binding specificity. Avian influenza A preferentially binds to cell surface receptors with a terminal α2,3‐linked sialic acid , while human influenza A preferentially binds to cell surface receptors with a terminal α2,6‐linked sialic acid. Via mutation, some avian influenza A viruses have successfully altered their binding specificity from α2,3‐ to α2,6‐linked sialic acid. However, in order to emerge in humans, avian influenza A viruses must also adapt their RNA polymerases for function in mammalian cells, as well as mutating for stability in the acidic respiratory tract of humans. Following adaptation and host switch , influenza A viruses have the potential to cause epidemics and pandemics in humans. Minor changes in HA and NA structure ( antigenic drift ) occur frequently, which enables the virus to cause repetitive outbreaks (i.e., seasonal influenza ) by evading immune recognition. Major changes in HA and NA structure ( antigenic shift ), which are caused by genetic reassortment between different influenza A subtypes (e.g., between human and animal subtypes), can instead cause large regional/global pandemics . Due to the emergence of antigenically different influenza A strains in humans, four influenza pandemics occurred in the 20th century alone. Additionally, although animal influenza A viruses (e.g., swine influenza ) are distinct from human influenza viruses, they can still cause zoonotic infection in humans. These infections are largely acquired following direct contact with infected animals or contaminated environments, but do not result in efficient human-to-human transmission; examples of this include H5N1 influenza and H7N9 influenza . In 2002, a highly pathogenic SARS-CoV (severe acute respiratory syndrome coronavirus) strain emerged from a zoonotic reservoir; approximately 8,000 people were infected worldwide, and mortality rates approached 50% or more in the elderly. As SARS-CoV-1 is most contagious post-symptoms, the introduction of strict public health measures effectively halted the epidemic. The natural reservoir host for SARS-CoV-1 is thought to be horseshoe bats , although the virus has also been identified in several small carnivores (e.g., palm civets and racoon dogs ). The emergence of SARS-CoV-1 is believed to have been facilitated by Chinese wet markets, in which civets positive for the virus acted as intermediate hosts and passed SARS-CoV-1 onto humans (and other species). However, more recent analysis suggests that SARS-CoV-1 may have directly jumped from bats to humans, with subsequent cross-transmission between humans and civets. In order to infect cells, SARS-CoV-1 uses the spike surface glycoprotein to recognize and bind to host ACE-2 , which it uses as a cellular entry receptor; the development of this characteristic was crucial in enabling SARS-CoV-1 to 'jump' from bats to other species.First reported in 2012, MERS-CoV (Middle East respiratory syndrome coronavirus) marks the second known introduction of a highly pathogenic coronavirus from a zoonotic reservoir into humans. The case mortality rate of this emergent virus is approximately 35%, with 80% of all cases reported by Saudi Arabia. Although MERS-CoV is likely to have originated in bats, dromedary camels have been implicated as probable intermediate hosts. MERS-CoV is believed to have been circulating in these mammals for over 20 years, and it is thought that novel camel farming practices drove the spillover of MERS-CoV into humans. Studies have shown that humans can be infected with MERS-CoV via direct or indirect contact within infected dromedary camels, while human-to-human transmission is limited. MERS-CoV gains cellular entry by using a spike surface protein to bind to the host DPP4 surface receptor; the core subdomain of this spike surface protein shares similarities with that of SARS-CoV, but its receptor binding subdomain (RBSD) significantly differs. Bluetongue disease is a non-contagious vector-borne disease caused by bluetongue virus, which affects species of ruminants (particularly sheep ). Climate change has been implicated in the emergence and global spread of this disease, due to its impact on vector distribution. The natural vector of the bluetongue virus is the African midge C. imicola , which is normally limited to Africa and subtropical Asia. However, global warming has extended the geographic range of C. imicola , so that it now overlaps with a different vector ( C. pulcaris or C. obsoletus ) with a much more northward geographic range. This change enabled the bluetongue virus to jump vector, thus causing the northward spread of bluetongue disease into Europe.

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influenza virus

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Antigenic shift

Antigenic shift is the process by which two or more different strains of a virus , or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains. The term is often applied specifically to influenza , as that is the best-known example, but the process is also known to occur with other viruses, such as visna virus in sheep. Antigenic shift is a specific case of reassortment or viral shift that confers a phenotypic change. Antigenic shift is contrasted with antigenic drift , which is the natural mutation over time of known strains of influenza (or other things, in a more general sense) which may lead to a loss of immunity, or in vaccine mismatch. Antigenic drift occurs in all types of influenza including influenza A , influenza B and influenza C . Antigenic shift, however, occurs only in influenza A because it infects more than just humans. Affected species include other mammals and birds , giving influenza A the opportunity for a major reorganization of surface antigens. Influenza B and C principally infect humans, minimizing the chance that a reassortment will change its phenotype drastically. In 1940s, Maurice Hilleman discovered antigenic shift, which is important for the emergence of new viral pathogens as it is a pathway that viruses may follow to enter a new niche . Influenza A viruses are found in many different animals, including ducks, chickens, pigs, humans, whales, horses, and seals. Influenza B viruses circulate widely principally among humans, though it has recently been found in seals. Flu strains are named after their types of hemagglutinin and neuraminidase surface proteins (of which there are 18 and 9 respectively), so they will be called, for example, H3N2 for type-3 hemagglutinin and type-2 neuraminidase. Some strains of avian influenza (from which all other strains of influenza A are believed to stem ) can infect pigs or other mammalian hosts. When two different strains of influenza infect the same cell simultaneously, their protein capsids and lipid envelopes are removed, exposing their RNA , which is then transcribed to mRNA . The host cell then forms new viruses that combine their antigens; for example, H3N2 and H5N1 can form H5N2 this way. Because the human immune system has difficulty recognizing the new influenza strain, it may be highly dangerous, and result in a new pandemic. Influenza viruses which have undergone antigenic shift have caused the Asian Flu pandemic of 1957, the Hong Kong Flu pandemic of 1968, and the Swine Flu scare of 1976. Until recently, such combinations were believed to have caused the infamous Spanish flu outbreak of 1918 which killed 40~100 million people worldwide. However, more recent research suggests the 1918 pandemic was caused by the antigenic drift of a fully avian virus to a form that could infect humans efficiently. The most recent 2009 H1N1 outbreak was a result of antigenic shift and reassortment between human, avian, and swine viruses. Pigs are especially important in antigenic shift of influenza viruses. Because pigs can be infected with strains of influenza that infect various other species of animals, they act as 'mixing pots' for the virus. When multiple virus strains, such as a duck and human influenza strain, infect the same pig, antigenic shift is likely to occur. While most of the virus strains resulting from this will be dead-end strains, a few have the potential to become pandemic viruses.

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influenza virus

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Zanamivir

AU : B1 (2 R ,3 R ,4 S )-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1 R ,2 R )-1,2,3-trihydroxypropyl)-3,4-dihydro-2 H -pyran-6-carboxylic acid O=C(O)C=1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(=O)C)[C@@H](/N=C()N)C=1 InChI=1S/C12H20N4O7/c1-4(18)15-8-5(16-12(13)14)2-7(11(21)22)23-10(8)9(20)6(19)3-17/h2,5-6,8-10,17,19-20H,3H2,1H3,(H,15,18)(H,21,22)(H4,13,14,16)/t5-,6+,8+,9+,10+/m0/s1 Y Key:ARAIBEBZBOPLMB-UFGQHTETSA-N Y Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses . It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and approved in the US in 1999, only for use as a treatment for influenza. In 2006, it was approved for prevention of influenza A and B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.Zanamivir room temperature solubility in water is 36 mg/mL, in DMSO is 66 mg/mL. It's insoluble in ethanol. Zanamivir is used for the treatment of infections caused by influenza A and influenza B viruses, but in otherwise-healthy individuals, benefits overall appear to be small. It decreases the risk of one's getting symptomatic, but not asymptomatic influenza. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of zanamivir for the prophylaxis and treatment of healthy individuals. Since then, genes expressing resistance to zanamivir were found in Chinese people infected with avian influenza A H7N9 during treatment with zanamivir. In otherwise-healthy individuals, benefits overall appear to be small. Zanamivir shortens the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. In children with asthma there was no clear effect on the time to first alleviation of symptoms. Whether it affects the risk of one's need to be hospitalized or the risk of death is not clear. There is no proof that zanamivir reduced hospitalizations or pneumonia and other complications of influenza, such as bronchitis , middle ear infection , and sinusitis . Zanamivir did not reduce the risk of self reported investigator mediated pneumonia or radiologically confirmed pneumonia in adults. The effect on pneumonia in children was also not significant. Low to moderate evidence indicates it decreases the risk of one's getting influenza by 1 to 12% in those exposed. Prophylaxis trials showed that zanamivir reduced the risk of symptomatic influenza in individuals and households, but there was no evidence of an effect on asymptomatic influenza or on other, influenza-like illnesses. Also there was no evidence of reduction of risk of person-to-person spread of the influenza virus. The evidence for a benefit in preventing influenza is weak in children, with concerns of publication bias in the literature. As of 2009, no influenza had shown any signs of resistance in the US. A meta-analysis from 2011 found that zanamivir resistance had been rarely reported. Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., immunosuppressed ). In 2013 genes expressing resistance to zanamivir (and oseltamivir ) were found in Chinese patients infected with avian influenza A H7N9. In otherwise-healthy individuals, benefits overall appear to be small. Zanamivir shortens the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. In children with asthma there was no clear effect on the time to first alleviation of symptoms. Whether it affects the risk of one's need to be hospitalized or the risk of death is not clear. There is no proof that zanamivir reduced hospitalizations or pneumonia and other complications of influenza, such as bronchitis , middle ear infection , and sinusitis . Zanamivir did not reduce the risk of self reported investigator mediated pneumonia or radiologically confirmed pneumonia in adults. The effect on pneumonia in children was also not significant. Low to moderate evidence indicates it decreases the risk of one's getting influenza by 1 to 12% in those exposed. Prophylaxis trials showed that zanamivir reduced the risk of symptomatic influenza in individuals and households, but there was no evidence of an effect on asymptomatic influenza or on other, influenza-like illnesses. Also there was no evidence of reduction of risk of person-to-person spread of the influenza virus. The evidence for a benefit in preventing influenza is weak in children, with concerns of publication bias in the literature. As of 2009, no influenza had shown any signs of resistance in the US. A meta-analysis from 2011 found that zanamivir resistance had been rarely reported. Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., immunosuppressed ). In 2013 genes expressing resistance to zanamivir (and oseltamivir ) were found in Chinese patients infected with avian influenza A H7N9. Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce bronchospasms . In 2006 the Food and Drug Administration (FDA) found that breathing problems (bronchospasm), including deaths, were reported in some patients after the initial approval of Relenza. Most of these patients had asthma or chronic obstructive pulmonary disease. Relenza therefore was not recommended for treatment or prophylaxis of seasonal influenza in individuals with asthma or chronic obstructive pulmonary disease. In 2009 the zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease. GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza having received zanamivir inhalation powder, which was solubilized and administered by mechanical ventilation. In adults there was no increased risk of reported adverse events in trials. There was little evidence of the possible harms associated with the treatment of children with zanamivir. Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body. Zanamivir works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others. It is also an inhibitor of influenza virus replication in vitro and in vivo . In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms. [ citation needed ] The bioavailability of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and oropharynx , where up to 15% of the dose is absorbed and excreted in urine. Zanamivir was first made in 1989 by scientists led by Peter Colman and Joseph Varghese at the Australian CSIRO , in collaboration with the Victorian College of Pharmacy , and the Monash University . Zanamivir was the first of the neuraminidase inhibitors . The discovery was initially funded by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design . Its strategy relied on the availability of the structure of influenza neuraminidase by X-ray crystallography . It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro- N -acetylneuraminic acid (DANA), a sialic acid analogue, is an inhibitor of neuraminidase. Computational chemistry techniques were used to probe the active site of the enzyme, in an attempt to design derivatives of DANA that would bind tightly to the amino acid residues of the catalytic site, so would be potent and specific inhibitors of the enzyme. The GRID software by Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This investigation showed a negatively charged zone occurs in the neuraminidase active site that aligns with the C 4 hydroxyl group of DANA. This hydroxyl is, therefore, replaced with a positively charged amino group; the 4-amino DANA was shown to be 100 times better as an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. Glu 119 was also noticed to be at the bottom of a conserved pocket in the active site that is just big enough to accommodate the larger, but more basic guanidine functional group . Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result. In 1999, the product was approved for marketing in the US and Europe for treatment of influenza A and B. The FDA advisory committee had recommended by a vote 13 to 4 that it should not be approved, because it lacked efficacy and was no more effective than placebo when the patients were on other drugs such as paracetamol. But the FDA leadership overruled the committee and criticised its reviewer, biostatistician Michael Elashoff. The review of oseltamivir, which was also in approval process at that time, was taken away from him, and reassigned to someone else. In 2006 zanamivir was approved in the US and Europe for prevention of influenza A and B.

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influenza virus

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Influenza A virus subtype H6N2

H6N2 is an avian influenza virus with two forms: one has a low and the other a high pathogenicity . It can cause a serious problem for poultry , and also infects ducks as well. H6N2 subtype is considered to be a non-pathogenic chicken virus, the host still unknown, but could strain from feral animals, and/or aquatic bird reservoirs. H6N2 along with H6N6 are viruses that are found to replicate in mice without preadaptation, and some have acquired the ability to bind to human-like receptors. Genetic markers for H6N2 include 22-amino acid stalk deletion in neuraminidase (NA) protein gene, increased N-glycosylation , and a D144 mutation of the Haemagglutinin (HA) protein gene. Transmission of avian influenza viruses from wild aquatic birds to domestic birds usually cause subclinical infections, and occasionally, respiratory disease and drops in egg production. Some histological features presented in chicken infected with H6N2 are fibrinous yolk peritonitis, salpingitis, oophoritis, nephritis, along with swollen kidneys as well. sneezing and lacrimation prostration anorexia and fever sometimes swelling of the infraorbital sinuses with nasal mucous

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influenza virus

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Wuhan virus

Wuhan virus (named for Wuhan, China) may refer to:

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influenza virus

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Influenza A virus subtype H7N4

H7N4 is a subtype of the species Influenza A virus (sometimes called bird flu virus). [ citation needed ] A highly pathogenic strain of it caused a minor flu outbreak in 1997 in New South Wales , Australia in chicken . On February 14, 2018, the Hong Kong Centre for Health Protection was notified by the National Health and Family Planning Commission of the People's Republic of China, that a 68-year-old female patient living in Changzhou of Jiangsu Province developed symptoms on Christmas day of 2017. According to the NHFPC, she was admitted to a hospital for medical treatment on the New Year's Day of 2018, and was discharged on January 22. She had had contact with live poultry before the onset of symptoms. No one who she had close contact with had any symptoms during the medical surveillance period.

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influenza virus

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1510 influenza pandemic

In 1510, an acute respiratory disease emerged in Asia before spreading through North Africa and Europe during the first chronicled, inter-regional flu pandemic generally recognized by medical historians and epidemiologists. Influenza-like illnesses had been documented in Europe since at least Charlemagne , with 1357's outbreak the first to be called influenza , but the 1510 flu pandemic is the first to be pathologically described following communication advances brought about by the printing press . Flu became more widely referred to as coqueluche and coccolucio in France and Sicily during this pandemic, variations of which became the most popular names for flu in early modern Europe . The pandemic caused significant disruption in government, church, and society with near-universal infection and a mortality rate of around 1%. The 1510 flu is suspected of originating in East Asia, possibly China . Gregor Horst writes in Operum medicorum tombus primus (1661) that the disease came from Asia and spread along trade routes before attacking the Middle East and North Africa. German medical writer Justus Hecker suggested the 1510 influenza most likely came from Asia because of the historical nature of other influenzas to originate there in more recent pandemics. The flu spread along trade routes towards North Africa, traveling southwest through the Middle East. Frequently visited cities like Jerusalem and Mecca would have almost certainly been reached by the flu, with large volumes of people destined to travel to Egypt , North Africa, and the Ottoman Empire . [ citation needed ]The flu spread along trade routes towards North Africa, traveling southwest through the Middle East. Frequently visited cities like Jerusalem and Mecca would have almost certainly been reached by the flu, with large volumes of people destined to travel to Egypt , North Africa, and the Ottoman Empire . [ citation needed ]It is generally understood that the 1510 influenza had spread in Africa before Europe. Influenza was likely widespread in North Africa before crossing continents through the Mediterranean, arriving in Malta where British medical historian Thomas Short believed that the "island of Melite in Africa " became the 1510 flu's springboard into Europe. Europe's internationally traveled cities and flu's highly contagious nature enabled its spread through European populations. The 1510 flu disrupted royal courts, church services, and social life across Europe. Contemporary chroniclers and those who have read their accounts observed how entire populations were attacked at once, which is how the disease first received the name influenza (from the belief that such outbreaks were caused by influences like stars or cold). Turin professor Francisco Vallerioli (aka Valleriola) writes that the 1510 flu featured "Constriction of breathing, and beginning with a hoarseness of voice and... shivering. Not long after that there being a cooked humor which fills the lungs." Physicians like Valleriola described the 1510 flu as more fatal to children and those who were bled. Lawyer Francesco Muralto noted that "the disease killed 10 people out of a thousand in one day," supporting a fatality rate of around 1%. The first cases of influenza began to appear in Sicily around July after the arrival of infected merchant ships from Malta . In Sicily it was commonly called coccolucio for the hood (resembling a coqueluchon - a kind of monk's cowl) the sick often wore over their heads. Influenza quickly spread out along the Mediterranean coasts of Italy and southern France via merchant ships leaving the island. In Emilia-Romagna , Tommasino de' Bianchi recorded the recovery of Modena's first cases on 13 July 1510, writing that in the city "there appears an illness that lasts three days with a great fever, and headache and then they rise... but there remains a terrible cough that lasts maybe eight days, and then they recover." This data would indicate that the first cases of flu, which has an incubation period of one to four days, began to fall ill in the Emilia-Romagna region around late June or early July. Pope Julius II attributed the outbreaks in Rome and the Holy See to God's wrath. Flu spread over the Alps into Switzerland and the Holy Roman Empire . In Switzerland it is documented as being called das Gruppie by the Mellingen chronicler Anton Tegenfeld, the flu nickname then preferred by German-speaking Europeans. A respiratory illness seemed to have menaced the Canton of Aargua in June, with the population falling ill with sniffling, coughing, and fatigue. German physician Achilles Gasser recorded a deadly epidemic spreading over the Holy Roman Empire's upper kingdoms, branching into the cities and the "whole mankind:" Mira qua edam Epidemia mortales per urbes hanc totamque adeo superiorem Germaniam corripiebat, qua aegri IV vel V ad summum dies molestissimis destillationibus laborabant ac ration privati instar phrenicorum furebant, atque inde iterum convalescebant, paucissimis ad Gorcum demissis. André de Burgo's letters dated 24 August 1510 indicate Margaret of Austria had to intervene at a royal assembly between her father, Holy Roman Emperor Maximilian I , and Louis XII of France because the King of France was too sick with "coqueluche" to be spoken to. Influenza spread out from the Holy Roman Empire towards Northern Europe, the Baltic states , and west towards France and England . Arriving aboard infected sailors from Sicily, influenza struck the Kingdom of France through the ports of Marseille and Nice and spread through the international crowds of the shipyards. Merchants, pilgrims, and other travelers from the south and east spread the virus throughout the western Mediterranean in July. It was referred to as " cephalie catarrhal " among French physicians, but more commonly just called coqueluche . Historian François Eudes de Mézeray traced the etymology of "coqueluche" to an outbreak 1410s during which sufferers wore hoods resembling coqueluchons, a kind of monk's cowl. French surgeon Ambroise Paré described the outbreak as having been a "rheumatic affliction of the head...with constriction of the heart and lungs." By August it had appeared in Tours and after it had propagated itself throughout France over summer, sickening the entire country by September. French poet and historian Jean Bouchet, employed by King Louis XII's Royal Court, wrote that the epidemic "appeared in the entire Kingdom of France, as much in the towns as in the countryside." Coqueluche filled up the hospitals in France. King Louis XII's National Assembly of Bishops , Prelates , and university professors scheduled for September 1510 was delayed because of the intensity of the flu in Paris . Jean Fernel (aka Fernelius), physician to Henry III of France , compares the 1557 influenza to the 1510 epidemic which attacked everyone with fever, a heaviness in their head, and profound coughing. Up to 1000 Parisians per day were dying at the height of the "1510 peste." Mézeray mentions that it disrupted judicial proceedings and colleges, and that the 1510 flu was more widespread and deadly in France than in other countries. Cardinal Georges d'Amboise , a close friend and advisor to the King of France, is sometimes believed to have died of influenza since his health sharply declined after arriving in Lyons in May 1510. The cardinal, also known as Monseigneur le Ledat, made his final testimony and recited Sacraments around 22 May before he died on the 25th. His sudden decline in health and flu's arrival in Europe around early summer have created uncertainty as to whether he died of gout or influenza, but "coqueluche" is not mentioned in French royal correspondence that year until August. British medical historian Charles Creighton claimed there is one foreign account of the 1510 flu in England, but did not elaborate. Fernel and Paré suggested that the 1510 influenza "spread to almost all countries of the world" (not concerning Spain's territories in the New World). An epidemiological study of past influenza pandemics reviewing previous medical historians' data has found England was affected in 1510 and there were reports of symptoms like "gastrodynia" and noteworthy murrain among cattle. The 1510 flu is also recorded to have reached Ireland . Influenza reached the Iberian Peninsula early after Italy, due to the highly interconnected trade and pilgrimage routes between Spain, Portugal, and the Italian kingdoms. Cases began to appear in Portugal around the same time the disease entered the Holy Roman Empire. Spanish cities were reportedly "dispopulated" by the 1510 flu. The first cases of influenza began to appear in Sicily around July after the arrival of infected merchant ships from Malta . In Sicily it was commonly called coccolucio for the hood (resembling a coqueluchon - a kind of monk's cowl) the sick often wore over their heads. Influenza quickly spread out along the Mediterranean coasts of Italy and southern France via merchant ships leaving the island. In Emilia-Romagna , Tommasino de' Bianchi recorded the recovery of Modena's first cases on 13 July 1510, writing that in the city "there appears an illness that lasts three days with a great fever, and headache and then they rise... but there remains a terrible cough that lasts maybe eight days, and then they recover." This data would indicate that the first cases of flu, which has an incubation period of one to four days, began to fall ill in the Emilia-Romagna region around late June or early July. Pope Julius II attributed the outbreaks in Rome and the Holy See to God's wrath. Flu spread over the Alps into Switzerland and the Holy Roman Empire . In Switzerland it is documented as being called das Gruppie by the Mellingen chronicler Anton Tegenfeld, the flu nickname then preferred by German-speaking Europeans. A respiratory illness seemed to have menaced the Canton of Aargua in June, with the population falling ill with sniffling, coughing, and fatigue. German physician Achilles Gasser recorded a deadly epidemic spreading over the Holy Roman Empire's upper kingdoms, branching into the cities and the "whole mankind:" Mira qua edam Epidemia mortales per urbes hanc totamque adeo superiorem Germaniam corripiebat, qua aegri IV vel V ad summum dies molestissimis destillationibus laborabant ac ration privati instar phrenicorum furebant, atque inde iterum convalescebant, paucissimis ad Gorcum demissis. André de Burgo's letters dated 24 August 1510 indicate Margaret of Austria had to intervene at a royal assembly between her father, Holy Roman Emperor Maximilian I , and Louis XII of France because the King of France was too sick with "coqueluche" to be spoken to. Influenza spread out from the Holy Roman Empire towards Northern Europe, the Baltic states , and west towards France and England . Arriving aboard infected sailors from Sicily, influenza struck the Kingdom of France through the ports of Marseille and Nice and spread through the international crowds of the shipyards. Merchants, pilgrims, and other travelers from the south and east spread the virus throughout the western Mediterranean in July. It was referred to as " cephalie catarrhal " among French physicians, but more commonly just called coqueluche . Historian François Eudes de Mézeray traced the etymology of "coqueluche" to an outbreak 1410s during which sufferers wore hoods resembling coqueluchons, a kind of monk's cowl. French surgeon Ambroise Paré described the outbreak as having been a "rheumatic affliction of the head...with constriction of the heart and lungs." By August it had appeared in Tours and after it had propagated itself throughout France over summer, sickening the entire country by September. French poet and historian Jean Bouchet, employed by King Louis XII's Royal Court, wrote that the epidemic "appeared in the entire Kingdom of France, as much in the towns as in the countryside." Coqueluche filled up the hospitals in France. King Louis XII's National Assembly of Bishops , Prelates , and university professors scheduled for September 1510 was delayed because of the intensity of the flu in Paris . Jean Fernel (aka Fernelius), physician to Henry III of France , compares the 1557 influenza to the 1510 epidemic which attacked everyone with fever, a heaviness in their head, and profound coughing. Up to 1000 Parisians per day were dying at the height of the "1510 peste." Mézeray mentions that it disrupted judicial proceedings and colleges, and that the 1510 flu was more widespread and deadly in France than in other countries. Cardinal Georges d'Amboise , a close friend and advisor to the King of France, is sometimes believed to have died of influenza since his health sharply declined after arriving in Lyons in May 1510. The cardinal, also known as Monseigneur le Ledat, made his final testimony and recited Sacraments around 22 May before he died on the 25th. His sudden decline in health and flu's arrival in Europe around early summer have created uncertainty as to whether he died of gout or influenza, but "coqueluche" is not mentioned in French royal correspondence that year until August. British medical historian Charles Creighton claimed there is one foreign account of the 1510 flu in England, but did not elaborate. Fernel and Paré suggested that the 1510 influenza "spread to almost all countries of the world" (not concerning Spain's territories in the New World). An epidemiological study of past influenza pandemics reviewing previous medical historians' data has found England was affected in 1510 and there were reports of symptoms like "gastrodynia" and noteworthy murrain among cattle. The 1510 flu is also recorded to have reached Ireland . Influenza reached the Iberian Peninsula early after Italy, due to the highly interconnected trade and pilgrimage routes between Spain, Portugal, and the Italian kingdoms. Cases began to appear in Portugal around the same time the disease entered the Holy Roman Empire. Spanish cities were reportedly "dispopulated" by the 1510 flu. There are no records of influenza affecting the New World in 1510, even though Spain was sending fleets of ships across the Atlantic. The first recorded flu outbreak in the New World had afflicted the Isle of Santo Domingo (Now Haiti and the Dominican Republic ) in 1493 . Amerindian populations sharp decline due to Spanish-imported diseases in these 1490s and early 1500s is however documented, most notably due to smallpox . [ citation needed ]Blistering on the back of the head and shoulders was one form of treatment prescribed in Europe for the flu. Paré regarded the common treatments of bloodletting and purgation to be especially dangerous to 1510's flu patients. Supraorbital pain and vision problems were symptoms of coqueluche , so sufferers may have felt tempted to wear hoods due to light sensitivity. Short describes some medicinal treatments for the 1510 flu including "Bole Armoniac, oily lintus, pectoral troches, and decoctions." Justus Hecker and John Parkin presumed the 1510 influenza originated from East Asia because of the historical nature of other influenza pandemics to originate there, while in 1661 Gregor Horst wrote that the 1510 flu spread along trade routes from East Asia to Africa before reaching Europe. Influenza viruses sometimes leap from Asia's migratory water fowl after massive migrations congregate near water sources for humans and domesticated animals, in which cross-species infections trigger antigenic shift and create new strains of flu human beings have little immunity to. European chroniclers noticed that the 1510 influenza did appear in North Africa before Europe, which has led some medical historians to suggest it may have developed there (parts of North Africa also lie along migratory bird ways, specifically the east Africa-West Asia and Black Sea-Mediterranean routes, that make it vulnerable to spontaneous reassortment of pandemic flu viruses). There remains no chronicled or biological evidence to suggest the 1510 flu originated from, as opposed to just spread in, Africa before reaching Europe. [ citation needed ]The 1510 "coqueluche" has been recognized as influenza by modern epidemiologists and medical historians. Suggestions that the 1510 coqueluche was whooping cough have been doubted because adult sufferers often experienced "precipitous" symptoms described by contemporaries like Tommasino de Bianchi or Valleriola as high fever for 3 days, headache, prostration, loss of sleep and appetite, delirium, a cough most severe on the 5th to 10th days, lung congestion, and slow recovery beginning on the second week. Adults with pertussis will usually cough for weeks before becoming gradually more ill then recovering over a period of months. The coqueluche of 1510 is considered to be influenza by experts because of its sudden symptoms, explosive spread, and timelines of sickness to recovery. The first outbreak of whooping cough to be agreed on by most medical historians is Guillaume de Baillou's description of an outbreak in Paris in 1578 .

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influenza virus

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Zoonosis

A zoonosis ( / z oʊ ˈ ɒ n ə s ɪ s , ˌ z oʊ ə ˈ n oʊ s ɪ s / ; plural zoonoses ) or zoonotic disease is an infectious disease of humans caused by a pathogen (an infectious agent, such as a bacterium , virus , parasite , or prion ) that can jump from a non-human (usually a vertebrate ) to a human and vice versa. Major modern diseases such as Ebola and salmonellosis are zoonoses. HIV was a zoonotic disease transmitted to humans in the early part of the 20th century, though it has now evolved into a separate human-only disease. Human infection with animal influenza viruses is rare, as they do not transmit easily to or among humans. However, avian and swine influenza viruses in particular possess high zoonotic potential, and these occasionally recombine with human strains of the flu and can cause pandemics such as the 2009 swine flu . Taenia solium infection is one of the neglected tropical diseases with public health and veterinary concern in endemic regions. Zoonoses can be caused by a range of disease pathogens such as emergent viruses , bacteria, fungi and parasites; of 1,415 pathogens known to infect humans, 61% were zoonotic. Most human diseases originated in non-humans; however, only diseases that routinely involve non-human to human transmission, such as rabies , are considered direct zoonoses. Zoonoses have different modes of transmission. In direct zoonosis the disease is directly transmitted from non-humans to humans through media such as air (influenza) or bites and saliva (rabies). In contrast, transmission can also occur via an intermediate species (referred to as a vector ), which carry the disease pathogen without getting sick. When humans infect non-humans, it is called reverse zoonosis or anthroponosis. The term is from Greek : ζῷον zoon "animal" and νόσος nosos "sickness". Host genetics plays an important role in determining which non-human viruses will be able to make copies of themselves in the human body. Dangerous non-human viruses are those that require few mutations to begin replicating themselves in human cells. These viruses are dangerous since the required combinations of mutations might randomly arise in the natural reservoir . The emergence of zoonotic diseases originated with the domestication of animals. Zoonotic transmission can occur in any context in which there is contact with or consumption of animals, animal products, or animal derivatives. This can occur in a companionistic (pets), economic (farming, trade, butchering, etc.), predatory (hunting, butchering, or consuming wild game), or research context. Recently, there has been a rise in frequency of appearance of new zoonotic diseases. "Approximately 1.67 million undescribed viruses are thought to exist in mammals and birds, up to half of which are estimated to have the potential to spill over into humans", says a study led by researchers at the University of California, Davis . According to a report from the United Nations Environment Programme and International Livestock Research Institute a large part of the causes are environmental like climate change , unsustainable agriculture, exploitation of wildlife, and land use change . Others are linked to changes in human society such as an increase in mobility. The organizations propose a set of measures to stop the rise. The most significant zoonotic pathogens causing foodborne diseases are Escherichia coli O157:H7 , Campylobacter , Caliciviridae , and Salmonella . In 2006 a conference held in Berlin focused on the issue of zoonotic pathogen effects on food safety , urging government intervention and public vigilance against the risks of catching food-borne diseases from farm-to-table dining. Many food-borne outbreaks can be linked to zoonotic pathogens. Many different types of food that have an animal origin can become contaminated. Some common food items linked to zoonotic contaminations include eggs, seafood, meat, dairy, and even some vegetables. Outbreaks involving contaminated food should be handled in preparedness plans to prevent widespread outbreaks and to efficiently and effectively contain outbreaks. Contact with farm animals can lead to disease in farmers or others that come into contact with infected farm animals. Glanders primarily affects those who work closely with horses and donkeys. Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses , tanneries , and wool mills . Close contact with sheep who have recently given birth can lead to infection with the bacterium Chlamydia psittaci , causing chlamydiosis (and enzootic abortion in pregnant women), as well as increase the risk of Q fever , toxoplasmosis , and listeriosis , in the pregnant or otherwise immunocompromised . Echinococcosis is caused by a tapeworm, which can spread from infected sheep by food or water contaminated by feces or wool. Avian influenza is common in chickens, and, while it is rare in humans, the main public health worry is that a strain of avian influenza will recombine with a human influenza virus and cause a pandemic like the 1918 Spanish flu . [ citation needed ] In 2017, free-range chickens in the UK were temporarily ordered to remain inside due to the threat of avian influenza. Cattle are an important reservoir of cryptosporidiosis , which mainly affects the immunocompromised. Reports have shown mink can also become infected. In Western countries, hepatitis E burden is largely dependent on exposure to animal products, and pork is a significant source of infection, in this respect. Veterinarians are exposed to unique occupational hazards when it comes to zoonotic disease. In the US, studies have highlighted an increased risk of injuries and lack of veterinary awareness of these hazards. Research has proved the importance for continued clinical veterinarian education on occupational risks associated with musculoskeletal injuries, animal bites, needle-sticks, and cuts. A July 2020 report by the United Nations Environment Programme stated that the increase in zoonotic pandemics is directly attributable to anthropogenic destruction of nature and the increased global demand for meat and that the industrial farming of pigs and chickens in particular will be a primary risk factor for the spillover of zoonotic diseases in the future. Habitat loss of viral reservoir species has been identified as a significant source in at least one spillover event . The wildlife trade may increase spillover risk because it directly increases the number of interactions across animal species, sometimes in small spaces. The origin of the ongoing COVID-19 pandemic is traced to the wet markets in China . Zoonotic disease emergence is demonstrably linked to the consumption of wildlife meat, exacerbated by human encroachment into natural habitats and amplified by the unsanitary conditions of wildlife markets. These markets, where diverse species converge, facilitate the mixing and transmission of pathogens, including those responsible for outbreaks of HIV-1, Ebola, and mpox , and potentially even the COVID-19 pandemic. Notably, small mammals often harbor a vast array of zoonotic bacteria and viruses, yet endemic bacterial transmission among wildlife remains largely unexplored. Therefore, accurately determining the pathogenic landscape of traded wildlife is crucial for guiding effective measures to combat zoonotic diseases and documenting the societal and environmental costs associated with this practice. Pets can transmit a number of diseases. Dogs and cats are routinely vaccinated against rabies . Pets can also transmit ringworm and Giardia , which are endemic in both animal and human populations. Toxoplasmosis is a common infection of cats; in humans it is a mild disease although it can be dangerous to pregnant women. Dirofilariasis is caused by Dirofilaria immitis through mosquitoes infected by mammals like dogs and cats. Cat-scratch disease is caused by Bartonella henselae and Bartonella quintana , which are transmitted by fleas that are endemic to cats. Toxocariasis is the infection of humans by any of species of roundworm , including species specific to dogs ( Toxocara canis ) or cats ( Toxocara cati ). Cryptosporidiosis can be spread to humans from pet lizards, such as the leopard gecko . Encephalitozoon cuniculi is a microsporidial parasite carried by many mammals, including rabbits, and is an important opportunistic pathogen in people immunocompromised by HIV/AIDS , organ transplantation , or CD4+ T-lymphocyte deficiency. Pets may also serve as a reservoir of viral disease and contribute to the chronic presence of certain viral diseases in the human population. For instance, approximately 20% of domestic dogs, cats, and horses carry anti-hepatitis E virus antibodies and thus these animals probably contribute to human hepatitis E burden as well. For non-vulnerable populations (e.g., people who are not immunocompromised) the associated disease burden is, however, small. [ citation needed ] Furthermore, the trade of non domestic animals such as wild animals as pets can also increase the risk of zoonosis spread. Outbreaks of zoonoses have been traced to human interaction with, and exposure to, other animals at fairs , live animal markets , petting zoos , and other settings. In 2005, the Centers for Disease Control and Prevention (CDC) issued an updated list of recommendations for preventing zoonosis transmission in public settings. The recommendations, developed in conjunction with the National Association of State Public Health Veterinarians , include educational responsibilities of venue operators, limiting public animal contact, and animal care and management. Hunting involves humans tracking, chasing, and capturing wild animals, primarily for food or materials like fur. However, other reasons like pest control or managing wildlife populations can also exist. Transmission of zoonotic diseases, those leaping from animals to humans, can occur through various routes: direct physical contact, airborne droplets or particles, bites or vector transport by insects, oral ingestion, or even contact with contaminated environments. Wildlife activities like hunting and trade bring humans closer to dangerous zoonotic pathogens, threatening global health. According to the Center for Diseases Control and Prevention (CDC) hunting and consuming wild animal meat ("bushmeat") in regions like Africa can expose people to infectious diseases due to the types of animals involved, like bats and primates. Unfortunately, common preservation methods like smoking or drying aren't enough to eliminate these risks. Although bushmeat provides protein and income for many, the practice is intricately linked to numerous emerging infectious diseases like Ebola, HIV, and SARS , raising critical public health concerns. A review published in 2022 found evidence that zoonotic spillover linked to wildmeat consumption has been reported across all continents. Kate Jones , Chair of Ecology and Biodiversity at University College London , says zoonotic diseases are increasingly linked to environmental change and human behavior. The disruption of pristine forests driven by logging, mining, road building through remote places, rapid urbanization, and population growth is bringing people into closer contact with animal species they may never have been near before. The resulting transmission of disease from wildlife to humans, she says, is now "a hidden cost of human economic development". In a guest article, published by IPBES , President of the EcoHealth Alliance and zoologist Peter Daszak , along with three co-chairs of the 2019 Global Assessment Report on Biodiversity and Ecosystem Services , Josef Settele, Sandra Díaz , and Eduardo Brondizio, wrote that "rampant deforestation, uncontrolled expansion of agriculture, intensive farming , mining and infrastructure development, as well as the exploitation of wild species have created a 'perfect storm' for the spillover of diseases from wildlife to people." Joshua Moon, Clare Wenham, and Sophie Harman said that there is evidence that decreased biodiversity has an effect on the diversity of hosts and frequency of human-animal interactions with potential for pathogenic spillover. An April 2020 study, published in the Proceedings of the Royal Society ' s Part B journal, found that increased virus spillover events from animals to humans can be linked to biodiversity loss and environmental degradation , as humans further encroach on wildlands to engage in agriculture, hunting, and resource extraction they become exposed to pathogens which normally would remain in these areas. Such spillover events have been tripling every decade since 1980. An August 2020 study, published in Nature , concludes that the anthropogenic destruction of ecosystems for the purpose of expanding agriculture and human settlements reduces biodiversity and allows for smaller animals such as bats and rats, which are more adaptable to human pressures and also carry the most zoonotic diseases, to proliferate. This in turn can result in more pandemics. In October 2020, the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services published its report on the 'era of pandemics' by 22 experts in a variety of fields and concluded that anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals – in particular birds and mammals – to humans. The increased pressure on ecosystems is being driven by the "exponential rise" in consumption and trade of commodities such as meat, palm oil , and metals, largely facilitated by developed nations, and by a growing human population . According to Peter Daszak, the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic, or of any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." According to a report from the United Nations Environment Programme and International Livestock Research Institute , entitled "Preventing the next pandemic – Zoonotic diseases and how to break the chain of transmission", climate change is one of the 7 human-related causes of the increase in the number of zoonotic diseases. The University of Sydney issued a study, in March 2021, that examines factors increasing the likelihood of epidemics and pandemics like the COVID-19 pandemic. The researchers found that "pressure on ecosystems, climate change and economic development are key factors" in doing so. More zoonotic diseases were found in high-income countries . A 2022 study dedicated to the link between climate change and zoonosis found a strong link between climate change and the epidemic emergence in the last 15 years, as it caused a massive migration of species to new areas, and consequently contact between species which do not normally come in contact with one another. Even in a scenario with weak climatic changes, there will be 15,000 spillover of viruses to new hosts in the next decades. The areas with the most possibilities for spillover are the mountainous tropical regions of Africa and southeast Asia. Southeast Asia is especially vulnerable as it has a large number of bat species that generally do not mix, but could easily if climate change forced them to begin migrating. A 2021 study found possible links between climate change and transmission of COVID-19 through bats. The authors suggest that climate-driven changes in the distribution and robustness of bat species harboring coronaviruses may have occurred in eastern Asian hotspots (southern China, Myanmar, and Laos), constituting a driver behind the evolution and spread of the virus. The most significant zoonotic pathogens causing foodborne diseases are Escherichia coli O157:H7 , Campylobacter , Caliciviridae , and Salmonella . In 2006 a conference held in Berlin focused on the issue of zoonotic pathogen effects on food safety , urging government intervention and public vigilance against the risks of catching food-borne diseases from farm-to-table dining. Many food-borne outbreaks can be linked to zoonotic pathogens. Many different types of food that have an animal origin can become contaminated. Some common food items linked to zoonotic contaminations include eggs, seafood, meat, dairy, and even some vegetables. Outbreaks involving contaminated food should be handled in preparedness plans to prevent widespread outbreaks and to efficiently and effectively contain outbreaks. Contact with farm animals can lead to disease in farmers or others that come into contact with infected farm animals. Glanders primarily affects those who work closely with horses and donkeys. Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses , tanneries , and wool mills . Close contact with sheep who have recently given birth can lead to infection with the bacterium Chlamydia psittaci , causing chlamydiosis (and enzootic abortion in pregnant women), as well as increase the risk of Q fever , toxoplasmosis , and listeriosis , in the pregnant or otherwise immunocompromised . Echinococcosis is caused by a tapeworm, which can spread from infected sheep by food or water contaminated by feces or wool. Avian influenza is common in chickens, and, while it is rare in humans, the main public health worry is that a strain of avian influenza will recombine with a human influenza virus and cause a pandemic like the 1918 Spanish flu . [ citation needed ] In 2017, free-range chickens in the UK were temporarily ordered to remain inside due to the threat of avian influenza. Cattle are an important reservoir of cryptosporidiosis , which mainly affects the immunocompromised. Reports have shown mink can also become infected. In Western countries, hepatitis E burden is largely dependent on exposure to animal products, and pork is a significant source of infection, in this respect. Veterinarians are exposed to unique occupational hazards when it comes to zoonotic disease. In the US, studies have highlighted an increased risk of injuries and lack of veterinary awareness of these hazards. Research has proved the importance for continued clinical veterinarian education on occupational risks associated with musculoskeletal injuries, animal bites, needle-sticks, and cuts. A July 2020 report by the United Nations Environment Programme stated that the increase in zoonotic pandemics is directly attributable to anthropogenic destruction of nature and the increased global demand for meat and that the industrial farming of pigs and chickens in particular will be a primary risk factor for the spillover of zoonotic diseases in the future. Habitat loss of viral reservoir species has been identified as a significant source in at least one spillover event . The wildlife trade may increase spillover risk because it directly increases the number of interactions across animal species, sometimes in small spaces. The origin of the ongoing COVID-19 pandemic is traced to the wet markets in China . Zoonotic disease emergence is demonstrably linked to the consumption of wildlife meat, exacerbated by human encroachment into natural habitats and amplified by the unsanitary conditions of wildlife markets. These markets, where diverse species converge, facilitate the mixing and transmission of pathogens, including those responsible for outbreaks of HIV-1, Ebola, and mpox , and potentially even the COVID-19 pandemic. Notably, small mammals often harbor a vast array of zoonotic bacteria and viruses, yet endemic bacterial transmission among wildlife remains largely unexplored. Therefore, accurately determining the pathogenic landscape of traded wildlife is crucial for guiding effective measures to combat zoonotic diseases and documenting the societal and environmental costs associated with this practice.Pets can transmit a number of diseases. Dogs and cats are routinely vaccinated against rabies . Pets can also transmit ringworm and Giardia , which are endemic in both animal and human populations. Toxoplasmosis is a common infection of cats; in humans it is a mild disease although it can be dangerous to pregnant women. Dirofilariasis is caused by Dirofilaria immitis through mosquitoes infected by mammals like dogs and cats. Cat-scratch disease is caused by Bartonella henselae and Bartonella quintana , which are transmitted by fleas that are endemic to cats. Toxocariasis is the infection of humans by any of species of roundworm , including species specific to dogs ( Toxocara canis ) or cats ( Toxocara cati ). Cryptosporidiosis can be spread to humans from pet lizards, such as the leopard gecko . Encephalitozoon cuniculi is a microsporidial parasite carried by many mammals, including rabbits, and is an important opportunistic pathogen in people immunocompromised by HIV/AIDS , organ transplantation , or CD4+ T-lymphocyte deficiency. Pets may also serve as a reservoir of viral disease and contribute to the chronic presence of certain viral diseases in the human population. For instance, approximately 20% of domestic dogs, cats, and horses carry anti-hepatitis E virus antibodies and thus these animals probably contribute to human hepatitis E burden as well. For non-vulnerable populations (e.g., people who are not immunocompromised) the associated disease burden is, however, small. [ citation needed ] Furthermore, the trade of non domestic animals such as wild animals as pets can also increase the risk of zoonosis spread. Outbreaks of zoonoses have been traced to human interaction with, and exposure to, other animals at fairs , live animal markets , petting zoos , and other settings. In 2005, the Centers for Disease Control and Prevention (CDC) issued an updated list of recommendations for preventing zoonosis transmission in public settings. The recommendations, developed in conjunction with the National Association of State Public Health Veterinarians , include educational responsibilities of venue operators, limiting public animal contact, and animal care and management.Hunting involves humans tracking, chasing, and capturing wild animals, primarily for food or materials like fur. However, other reasons like pest control or managing wildlife populations can also exist. Transmission of zoonotic diseases, those leaping from animals to humans, can occur through various routes: direct physical contact, airborne droplets or particles, bites or vector transport by insects, oral ingestion, or even contact with contaminated environments. Wildlife activities like hunting and trade bring humans closer to dangerous zoonotic pathogens, threatening global health. According to the Center for Diseases Control and Prevention (CDC) hunting and consuming wild animal meat ("bushmeat") in regions like Africa can expose people to infectious diseases due to the types of animals involved, like bats and primates. Unfortunately, common preservation methods like smoking or drying aren't enough to eliminate these risks. Although bushmeat provides protein and income for many, the practice is intricately linked to numerous emerging infectious diseases like Ebola, HIV, and SARS , raising critical public health concerns. A review published in 2022 found evidence that zoonotic spillover linked to wildmeat consumption has been reported across all continents. Kate Jones , Chair of Ecology and Biodiversity at University College London , says zoonotic diseases are increasingly linked to environmental change and human behavior. The disruption of pristine forests driven by logging, mining, road building through remote places, rapid urbanization, and population growth is bringing people into closer contact with animal species they may never have been near before. The resulting transmission of disease from wildlife to humans, she says, is now "a hidden cost of human economic development". In a guest article, published by IPBES , President of the EcoHealth Alliance and zoologist Peter Daszak , along with three co-chairs of the 2019 Global Assessment Report on Biodiversity and Ecosystem Services , Josef Settele, Sandra Díaz , and Eduardo Brondizio, wrote that "rampant deforestation, uncontrolled expansion of agriculture, intensive farming , mining and infrastructure development, as well as the exploitation of wild species have created a 'perfect storm' for the spillover of diseases from wildlife to people." Joshua Moon, Clare Wenham, and Sophie Harman said that there is evidence that decreased biodiversity has an effect on the diversity of hosts and frequency of human-animal interactions with potential for pathogenic spillover. An April 2020 study, published in the Proceedings of the Royal Society ' s Part B journal, found that increased virus spillover events from animals to humans can be linked to biodiversity loss and environmental degradation , as humans further encroach on wildlands to engage in agriculture, hunting, and resource extraction they become exposed to pathogens which normally would remain in these areas. Such spillover events have been tripling every decade since 1980. An August 2020 study, published in Nature , concludes that the anthropogenic destruction of ecosystems for the purpose of expanding agriculture and human settlements reduces biodiversity and allows for smaller animals such as bats and rats, which are more adaptable to human pressures and also carry the most zoonotic diseases, to proliferate. This in turn can result in more pandemics. In October 2020, the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services published its report on the 'era of pandemics' by 22 experts in a variety of fields and concluded that anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals – in particular birds and mammals – to humans. The increased pressure on ecosystems is being driven by the "exponential rise" in consumption and trade of commodities such as meat, palm oil , and metals, largely facilitated by developed nations, and by a growing human population . According to Peter Daszak, the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic, or of any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." According to a report from the United Nations Environment Programme and International Livestock Research Institute , entitled "Preventing the next pandemic – Zoonotic diseases and how to break the chain of transmission", climate change is one of the 7 human-related causes of the increase in the number of zoonotic diseases. The University of Sydney issued a study, in March 2021, that examines factors increasing the likelihood of epidemics and pandemics like the COVID-19 pandemic. The researchers found that "pressure on ecosystems, climate change and economic development are key factors" in doing so. More zoonotic diseases were found in high-income countries . A 2022 study dedicated to the link between climate change and zoonosis found a strong link between climate change and the epidemic emergence in the last 15 years, as it caused a massive migration of species to new areas, and consequently contact between species which do not normally come in contact with one another. Even in a scenario with weak climatic changes, there will be 15,000 spillover of viruses to new hosts in the next decades. The areas with the most possibilities for spillover are the mountainous tropical regions of Africa and southeast Asia. Southeast Asia is especially vulnerable as it has a large number of bat species that generally do not mix, but could easily if climate change forced them to begin migrating. A 2021 study found possible links between climate change and transmission of COVID-19 through bats. The authors suggest that climate-driven changes in the distribution and robustness of bat species harboring coronaviruses may have occurred in eastern Asian hotspots (southern China, Myanmar, and Laos), constituting a driver behind the evolution and spread of the virus. During most of human prehistory groups of hunter-gatherers were probably very small. Such groups probably made contact with other such bands only rarely. Such isolation would have caused epidemic diseases to be restricted to any given local population, because propagation and expansion of epidemics depend on frequent contact with other individuals who have not yet developed an adequate immune response . To persist in such a population, a pathogen either had to be a chronic infection, staying present and potentially infectious in the infected host for long periods, or it had to have other additional species as reservoir where it can maintain itself until further susceptible hosts are contacted and infected. In fact, for many "human" diseases, the human is actually better viewed as an accidental or incidental victim and a dead-end host . Examples include rabies, anthrax, tularemia, and West Nile fever. Thus, much of human exposure to infectious disease has been zoonotic. Many diseases, even epidemic ones, have zoonotic origin and measles , smallpox , influenza , HIV, and diphtheria are particular examples. Various forms of the common cold and tuberculosis also are adaptations of strains originating in other species. [ citation needed ] Some experts have suggested that all human viral infections were originally zoonotic. Zoonoses are of interest because they are often previously unrecognized diseases or have increased virulence in populations lacking immunity. The West Nile virus first appeared in the United States in 1999 , in the New York City area. Bubonic plague is a zoonotic disease, as are salmonellosis , Rocky Mountain spotted fever , and Lyme disease . A major factor contributing to the appearance of new zoonotic pathogens in human populations is increased contact between humans and wildlife. This can be caused either by encroachment of human activity into wilderness areas or by movement of wild animals into areas of human activity. An example of this is the outbreak of Nipah virus in peninsular Malaysia, in 1999, when intensive pig farming began within the habitat of infected fruit bats. The unidentified infection of these pigs amplified the force of infection, transmitting the virus to farmers, and eventually causing 105 human deaths. Similarly, in recent times avian influenza and West Nile virus have spilled over into human populations probably due to interactions between the carrier host and domestic animals. [ citation needed ] Highly mobile animals, such as bats and birds, may present a greater risk of zoonotic transmission than other animals due to the ease with which they can move into areas of human habitation. Because they depend on the human host for part of their life-cycle, diseases such as African schistosomiasis , river blindness , and elephantiasis are not defined as zoonotic, even though they may depend on transmission by insects or other vectors . The first vaccine against smallpox by Edward Jenner in 1800 was by infection of a zoonotic bovine virus which caused a disease called cowpox . Jenner had noticed that milkmaids were resistant to smallpox. Milkmaids contracted a milder version of the disease from infected cows that conferred cross immunity to the human disease. Jenner abstracted an infectious preparation of 'cowpox' and subsequently used it to inoculate persons against smallpox. As a result of vaccination, smallpox has been eradicated globally, and mass inoculation against this disease ceased in 1981. There are a variety of vaccine types, including traditional inactivated pathogen vaccines, subunit vaccines , live attenuated vaccines . There are also new vaccine technologies such as viral vector vaccines and DNA/RNA vaccines , which include many of the COVID-19 vaccines .

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influenza virus

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2009 swine flu pandemic in the United States

The 2009 flu pandemic in the United States was caused by a novel strain of the Influenza A/H1N1 virus, commonly referred to as " swine flu ", that was first detected on 15 April 2009. While the 2009 H1N1 virus strain was commonly referred to as "swine flu", there is no evidence that it is endemic to pigs (i.e. actually a swine flu) or of transmission from pigs to people; instead, the virus spreads from person to person. On April 25, the World Health Organization declared a public health emergency, followed concurringly by the Obama administration on April 26. The U.S. Centers for Disease Control and Prevention (CDC) reported that during the outbreak about half of all influenza viruses being reported were 2009 H1N1 viruses, with the other half being those of the regular seasonal influenza. Unique to this particular strain, about 60% of the 2009 H1N1 influenza cases were occurring among people between 5 years and 24 years of age, and 40% of the hospitalizations were occurring among children and young adults. About 80% of the deaths were in people younger than 65 years of age. The CDC noted that this differed greatly from typical seasonal influenza epidemics, during which about 70% to 90% of deaths are estimated to occur in people 65 years and older. Antibody studies showed that children had no existing cross-reactive antibody to the 2009 H1N1 influenza virus, while about one-third of adults older than 60 years of age had cross-reactive antibody. By April 21, 2009, CDC had begun working to develop a virus that could be used to make a vaccine to protect against the new virus. Following preparation for distribution beginning in June, the first doses were administered in October 2009. On August 10, 2010, WHO declared an end to the global 2009 H1N1 influenza pandemic. However, the virus continues to circulate as a seasonal flu virus, and cause illness, hospitalization, and deaths worldwide every year. From April 12, 2009, to April 10, 2010, the CDC estimates there were 60.8 million cases (range: 43.3 - 89.3 million), 274,304 hospitalizations (range: 195,086 - 402,719), and 12,469 deaths (range: 8868 - 18,306) in the United States due to the virus. A follow-up study done in September 2010 showed that the risk of serious illness resulting from the 2009 H1N1 flu was no higher than that of the yearly seasonal flu . For comparison, the CDC estimates the global H1N1 death toll at 284,000 and the WHO estimates that 250,000 to 500,000 people die of seasonal flu annually. The earliest reported cases in the US began appearing in early April 2009, in California. In late April, the Centers for Disease Control and Prevention (CDC) activated its Emergency Operations Center and declared a public health emergency. On April 25, the World Health Organization (WHO) declared a public health emergency of international concern. WHO declared H1N1 a pandemic on June 11. [ citation needed ] By the end of May, the flu had infected people in all 50 states. As of June 16, the total number of confirmed cases was 27,717 and on June 25, the CDC said there were over one million (1,000,000) cases, most of which had not been reported or diagnosed. Deaths relating to influenza began appearing in the US in late April, and by early June, 15 states had reported fatalities related to or directly occurring from the virus. By October 5, the first doses of an H1N1 vaccine were given in the U.S. The CDC distributed vaccines for the flu using mechanisms already in place for its Vaccines for Children (VFC) program. On October 24, and the CDC said more than 1,000 had died from the flu. President Obama declared a national emergency. On December 10, 2009, the CDC reported an estimated 50 million Americans or 1 in 6 had been infected and 10,000 had died. On December 23, 2009, the CDC reported a reduction of the disease by 59% percent. On February 12, the CDC reported 57 million Americans had been sickened, 257,000 had been hospitalized and 11,690 people had died (including 1,180 children) due to flu from April through to mid-January. The Centers for Disease Control and Prevention (CDC) identified the first two A/09(H1N1) swine flu cases in California on April 17, 2009, via the Border Infectious Disease Program, for a San Diego County child, and a naval research facility studying a special diagnostic test, where influenza sample from the child from Imperial County was tested. By April 21, enhanced surveillance was established to search for additional cases in both California and Texas and the CDC determined that the virus strain was genetically similar to the previously known A(H1N1) swine flu circulating among pigs in the United States since about 1999. [ citation needed ] It was established that the virus was a combination of human, North American swine, and Eurasian swine influenza viruses; the viruses from the initial two Californian cases were also noted to be resistant to amantadine and rimantadine , two common influenza antiviral drugs. No contact with pigs was found for any of the seven Californian nor either of the two Texas cases, suggesting human-to-human transmission of the virus. [ citation needed ] On April 28, 2009, the director of the Centers for Disease Control and Prevention confirmed the first official US death of swine flu. Tests confirmed that a 23-month-old toddler from Mexico, who was probably infected there, died on April 27 from the flu while visiting Texas. Cases of H1N1 spread rapidly across the United States, with particularly severe outbreaks in Texas, New York, Utah, and California. Early cases were associated with recent travel to Mexico; many were students who had traveled to Mexico for spring break. On May 4, 2009, the CDC reported one death, 286 confirmed cases of H1N1 flu across 36 states, 35 hospitalizations, and expected H1N1 to eventually spread to all states. A large number of cases, according to medics, have happened in the days that preceded the launch of the alert and came out only in these days due to a massive backlog. By May 5, 2009, the number had risen to 403 and a second death was reported in Texas. The CDC and government officials had expressed cautious optimism about the severity and spread of H1N1. Changes in surveillance of cases of influenza-like illness , including new guidelines for identifying cases to test, increased laboratory testing, and new test kits able to distinguish this novel strain, resulted in a spike in the percent of cases tested positive for influenza. Of the positive cases, about a third were due to the novel strain. Also found were a substantial number of cases where the strain could not be subtyped. The proportion of US deaths due to pneumonia and influenza climbed above the epidemic threshold in the 2007–2008 winter flu season but not in the 2008–2009 season. Although the 2009 H1N1 outbreak reached epidemic levels of infection early in 2009, it did not contribute to epidemic levels of pneumonia and influenza related deaths until October 2009. [ citation needed ] In early October 2009, the Centers for Disease Control and Prevention announced that swine flu was widespread across the country. It also said there was significant flu activity in virtually all states, which was considered to be quite unusual for this time of year. There was particular worry about pregnant women. As of late August, 100 had been hospitalized in intensive care units and 28 had died since the beginning of the outbreak in April. On October 1, it was acknowledged that a recruit in basic training in Fort Jackson, South Carolina, was the Army's first swine flu death. The recruit fell ill on September 1 and died of pneumonia on September 10. [ citation needed ] Dell Children's Medical Center in Austin, Texas, erected two tents in its parking lot to handle emergency room visits, and hospitals around Colorado Springs recorded a 30 percent spike in flu visits. As pediatric cases were increasing, the Dept. of Health and Human Services released 300,000 courses of children's liquid Tamiflu from the national pandemic stockpile in late September, with the first batches sent to Texas and Colorado. [ citation needed ] In late September, the disease centers reported that 936 had died of flu symptoms or of flu-associated pneumonia since August 30, when it began a new count of deaths, including some without laboratory-confirmed swine flu. The Agriculture Department reported on October 16 that three pigs at the Minnesota State Fair, in St. Paul, were tested positive in late August for H1N1 virus, which were the first cases in the country, although infected pigs had been found in eight other countries. There were 103 pigs tested at the Fair, including the three infected, though all appeared healthy. Scientists said the virus was already spreading widely among people, and, in fact, was more common in humans than in pigs, so humans were more likely to catch it from others than from pigs. In mid-October, it was reported that flu caused by the H1N1 virus was widespread in 41 states, and flu-like illnesses accounted for 6.1 percent of all doctor visits, which was considered high [ citation needed ] , particularly for October. Forty-three children had died from H1N1 since August 30, which is approximately the number that usually dies in an entire flu season. Nineteen of the forty-three were teenagers while sixteen were between ages five to eleven. The rest were under five. [ citation needed ] It is reported that the severity of the disease was not increasing. About fifteen to twenty percent of the patients hospitalized for the flu were placed in the intensive care unit, a level similar to that for seasonal flu. [ citation needed ] Projections of the supply of H1N1 vaccine had decreased significantly from a level of 120 million doses ready in October, estimated during the summer, to an estimate of 28 to 30 million doses by the end of the month. On October 14, 11.4 million doses of the H1N1 vaccine were said to be available. As of November 20, 2009, the CDC reported sharp declines in H1N1 activity throughout the United States, with influenza-like illness (which may also include meningitis, pneumonia, strep pharyngitis, gastroenteritis, and the common cold) accounting for 5.5% of doctors visits, down sharply from 8% in late October, the peak of the second wave. However, taking the vaccine is still urged by the CDC, as a third wave of the disease may sweep across the US, possibly in January/February 2010. [ needs update ] As of December 24, the second wave of H1N1 has clearly peaked, with pneumonia and influenza deaths falling below the epidemic threshold for the first time in 11 weeks, and the proportion of doctors visits due to influenza-like illness falling to baseline (2.3%), down from 5.5% 1 month before, on November 20. However, it was reported that influenza activity was beginning to increase in West Virginia, with 5.2% of patients treated by West Virginia health care providers having influenza-like illness, a major increase from 2% of patients treated by West Virginia health care providers having influenza-like illness in November. [ citation needed ] On August 10, 2010, WHO declared an end to the global 2009 H1N1 influenza pandemic. However, the virus continues to circulate as a seasonal flu virus, and cause illness, hospitalization, and deaths worldwide every year. In early October 2009, the Centers for Disease Control and Prevention announced that swine flu was widespread across the country. It also said there was significant flu activity in virtually all states, which was considered to be quite unusual for this time of year. There was particular worry about pregnant women. As of late August, 100 had been hospitalized in intensive care units and 28 had died since the beginning of the outbreak in April. On October 1, it was acknowledged that a recruit in basic training in Fort Jackson, South Carolina, was the Army's first swine flu death. The recruit fell ill on September 1 and died of pneumonia on September 10. [ citation needed ] Dell Children's Medical Center in Austin, Texas, erected two tents in its parking lot to handle emergency room visits, and hospitals around Colorado Springs recorded a 30 percent spike in flu visits. As pediatric cases were increasing, the Dept. of Health and Human Services released 300,000 courses of children's liquid Tamiflu from the national pandemic stockpile in late September, with the first batches sent to Texas and Colorado. [ citation needed ] In late September, the disease centers reported that 936 had died of flu symptoms or of flu-associated pneumonia since August 30, when it began a new count of deaths, including some without laboratory-confirmed swine flu. The Agriculture Department reported on October 16 that three pigs at the Minnesota State Fair, in St. Paul, were tested positive in late August for H1N1 virus, which were the first cases in the country, although infected pigs had been found in eight other countries. There were 103 pigs tested at the Fair, including the three infected, though all appeared healthy. Scientists said the virus was already spreading widely among people, and, in fact, was more common in humans than in pigs, so humans were more likely to catch it from others than from pigs. In mid-October, it was reported that flu caused by the H1N1 virus was widespread in 41 states, and flu-like illnesses accounted for 6.1 percent of all doctor visits, which was considered high [ citation needed ] , particularly for October. Forty-three children had died from H1N1 since August 30, which is approximately the number that usually dies in an entire flu season. Nineteen of the forty-three were teenagers while sixteen were between ages five to eleven. The rest were under five. [ citation needed ] It is reported that the severity of the disease was not increasing. About fifteen to twenty percent of the patients hospitalized for the flu were placed in the intensive care unit, a level similar to that for seasonal flu. [ citation needed ] Projections of the supply of H1N1 vaccine had decreased significantly from a level of 120 million doses ready in October, estimated during the summer, to an estimate of 28 to 30 million doses by the end of the month. On October 14, 11.4 million doses of the H1N1 vaccine were said to be available. As of November 20, 2009, the CDC reported sharp declines in H1N1 activity throughout the United States, with influenza-like illness (which may also include meningitis, pneumonia, strep pharyngitis, gastroenteritis, and the common cold) accounting for 5.5% of doctors visits, down sharply from 8% in late October, the peak of the second wave. However, taking the vaccine is still urged by the CDC, as a third wave of the disease may sweep across the US, possibly in January/February 2010. [ needs update ] As of December 24, the second wave of H1N1 has clearly peaked, with pneumonia and influenza deaths falling below the epidemic threshold for the first time in 11 weeks, and the proportion of doctors visits due to influenza-like illness falling to baseline (2.3%), down from 5.5% 1 month before, on November 20. However, it was reported that influenza activity was beginning to increase in West Virginia, with 5.2% of patients treated by West Virginia health care providers having influenza-like illness, a major increase from 2% of patients treated by West Virginia health care providers having influenza-like illness in November. [ citation needed ] On August 10, 2010, WHO declared an end to the global 2009 H1N1 influenza pandemic. However, the virus continues to circulate as a seasonal flu virus, and cause illness, hospitalization, and deaths worldwide every year. The new strain was identified as a combination of several different strains of Influenzavirus A , subtype H1N1 , including separate strains of this subtype circulating in humans (see human influenza ) and in pigs (see swine influenza ). The strain transmits between humans and was initially reported to have a relatively high mortality rate in Mexico. In April 2009 the World Health Organization (WHO) and the U.S. Centers for Disease Control and Prevention (CDC) expressed serious concerns that the new strain had the potential to become an influenza pandemic . On April 25 it was reported that, because the virus was already widespread, containment would be "nearly impossible." By this time, there had also been speculation that the flu death toll in Mexico could be lower than first thought. Gerald Evans, head of the Association of Medical Microbiology and Infectious Disease Canada and a member of a federal pandemic-planning committee, said on April 29: There was a lot of speculation and what seemed to be evidence there were dozens and dozens of deaths. Careful analysis showed these people likely died of something else, and not influenza. That's really good news, and that would fit with what we've seen outside of Mexico. Another Canadian expert, Neil Rau, criticized the WHO's decision to raise its pandemic alert to level 5, saying: I don't agree with (the WHO) because I think it's a panic metre, not a pandemic metre. [...] If that flu-like illness is not deadly, I don't know what the cause for alarm is for people who are not really sickened by this virus. [...] I'm really eager to know how much worse this is than seasonal flu. So far it's looking like it's not that serious. CNN noted on April 28, 2009, that in any individual week between January 1 and April 18, there had been at least 800 deaths in the U.S. due to normal influenza, which is higher than the 150 total deaths worldwide from the swine flu up to that time. As of May 28, 2010, the official U.S. death toll attributed directly to the novel H1N1 and seasonal influenza was 2,117. This total exceeds the 849 U.S. deaths directly attributed to seasonal influenza in 2006. Many of the other deaths commonly attributed to influenza are caused by complicated influenza, where a second infection causes death, usually pneumonia (of which 48,657 of 55,477 official deaths in 2006 occurred in people aged 65 years and older). The final estimate was of over 12,000 deaths over the course of the pandemic (April 2009 – April 2010). The CDC reported that during the outbreak about half of all influenza viruses being detected through laboratory reports were 2009 H1N1 viruses, with the other half being those of the regular seasonal influenza viruses. Surveillance reports indicated that about 57% of the 2009 H1N1 influenza confirmed and probable cases were occurring among people between 5 years and 24 years of age, and 41% of the hospitalizations were occurring among older children and young adults. The highest rates of hospitalization were among children younger than 5 years of age; the next highest hospitalization rate was in people 5 years to 24 years of age. Antibody studies showed that children had no existing cross-reactive antibody to the 2009 H1N1 influenza virus, while about one-third of adults older than 60 years of age had cross-reactive antibody. One possible explanation for this pre-existing antibody in older adults was that they may have had previous exposure, either through infection or vaccination, to an influenza A H1N1 virus that was more closely related to the 2009 H1N1 flu virus. Based on data from previous influenza pandemics and seasonal influenza, pregnant women had been recognized as a high-risk group early in the outbreak. People with other previously recognized medical conditions that placed them at high risk of complications from seasonal influenza also appeared to be at increased risk of complications from 2009 H1N1 influenza. One report found that seventy-one percent of hospitalized patients had one or more underlying chronic medical conditions and reported deaths had occurred in people ranging in age from 22 months old to 57 years old. Also, only 13% of hospitalizations had occurred in people 50 years and older, and there were few cases and no deaths in people older than 65 years, which was unusual when compared with seasonal flu. The CDC reported that during the outbreak about half of all influenza viruses being detected through laboratory reports were 2009 H1N1 viruses, with the other half being those of the regular seasonal influenza viruses. Surveillance reports indicated that about 57% of the 2009 H1N1 influenza confirmed and probable cases were occurring among people between 5 years and 24 years of age, and 41% of the hospitalizations were occurring among older children and young adults. The highest rates of hospitalization were among children younger than 5 years of age; the next highest hospitalization rate was in people 5 years to 24 years of age. Antibody studies showed that children had no existing cross-reactive antibody to the 2009 H1N1 influenza virus, while about one-third of adults older than 60 years of age had cross-reactive antibody. One possible explanation for this pre-existing antibody in older adults was that they may have had previous exposure, either through infection or vaccination, to an influenza A H1N1 virus that was more closely related to the 2009 H1N1 flu virus. Based on data from previous influenza pandemics and seasonal influenza, pregnant women had been recognized as a high-risk group early in the outbreak. People with other previously recognized medical conditions that placed them at high risk of complications from seasonal influenza also appeared to be at increased risk of complications from 2009 H1N1 influenza. One report found that seventy-one percent of hospitalized patients had one or more underlying chronic medical conditions and reported deaths had occurred in people ranging in age from 22 months old to 57 years old. Also, only 13% of hospitalizations had occurred in people 50 years and older, and there were few cases and no deaths in people older than 65 years, which was unusual when compared with seasonal flu. The Federal response remained at US Pandemic Stage 0, congruent with the World Health Organization (WHO) Pandemic Phases 1, 2 and 3; however, the WHO's Pandemic Phase was raised to 4 on April 27, which is congruent with US Pandemic Stage 2. On April 29, the WHO raised the pandemic alert level to phase 5. The United States federal government declared a public health emergency , and several U.S. states then indicated that they may follow suit. Secretary of Homeland Security Janet Napolitano noted that this declaration was standard operating procedure, which was also done for the 2009 presidential inauguration and for flooding. After many days of deliberation the WHO declared that the current influenza had become a true pandemic, raising the Pandemic Alert level to Phase 6, the highest on the WHO scale and congruent with U.S. Federal Government Response Stages 3–6. An official for the White House said on April 24 that "the White House is taking the situation seriously and monitoring for any new developments. The president has been fully briefed." President Barack Obama stated that "We are closely monitoring the emerging cases of swine flu." He also noted, "This is obviously a cause for concern ... but it is not a cause for alarm." Obama suggested that U.S. schools should consider shutting down, as a future possibility, if their students were to become infected. White House Press Secretary Robert Gibbs said the effort to get a team in place to respond to the health scare had not been hindered by the lack of a secretary of Health and Human Services or appointees in any of the department's 19 key posts. The president's nominee, Kansas Gov. Kathleen Sebelius , was still awaiting confirmation from the U.S. Senate until passing on April 28. The President had not yet made appointments to either the Commissioner of the Food and Drug Administration , the Surgeon General , or the Director of the Centers for Disease Control and Prevention . The current acting Surgeon General, Steven K. Galson , was also currently serving as the Acting Assistant Secretary for Health. On April 30, it was reported that an aide to Steven Chu , the US Energy Secretary, had fallen ill from the virus after helping arrange President Obama's trip to Mexico. However, the White House stated that the President was not at risk of contracting the flu. Kathleen Sebelius was confirmed as the Secretary of Health and Human Services by the Senate on April 28, 2009, with a vote of 65–31. On October 24, President Obama declared the 2009 H1N1 swine flu a national emergency. The declaration made it easier for U.S. medical facilities to handle a surge in flu patients by allowing the waiver of some requirements of Medicare , Medicaid and other federal health insurance programs as needed. During the week of April 19, 2009, the CDC activated its Emergency Operations Center (EOC), with RADM Stephen Redd as the Incident Commander, to augment the ongoing investigation of human cases of swine influenza A (H1N1). More than 250 CDC professionals worked from the CDC EOC as part of the agency's response. As of May 4, 2009, the CDC reported that it had deployed 25% of the supplies and medicines in the Strategic National Stockpile to the various states. As of April 29, only the CDC could confirm U.S. swine flu cases. Besser stated during an April 30 press briefing that California and New York had diagnostic test kits, and that the kits would be sent to all states starting the following day. On May 6, the CDC announced that testing kits were now available for all states. It was expected this would generate an increase in the number of confirmed cases as more states began doing their own tests. In the United States, the majority of the 70 National Respiratory and Enteric Virus Surveillance System (NREVSS) laboratories do not report the influenza A subtype. [ citation needed ] However, in 2007, human infection with a novel influenzavirus A became a nationally notifiable condition. Novel influenza A virus infections include all human infections with influenza A viruses that are different from currently circulating human influenza H1 and H3 viruses. These viruses include those that are subtyped as nonhuman in origin and those that are unsubtypable with standard methods and reagents. The new strain responsible for this outbreak was one such virus. [ citation needed ] Initially the CDC had issued a recommendation that schools close for as long as two weeks if a student catches swine flu. Some school districts closed all schools if a single child was classified as probable. On May 5 the CDC retracted its advice stating that schools that were closed based on previous CDC guidance related to this outbreak may reopen. By that time at least 726 schools nationwide serving more than 480,000 students had closed for at least some period of time. The CDC amended its advice, citing new information on disease severity and the limiting effectiveness of school closure as a control measure. The new advice given stated, "Decisions about school closure should be at the discretion of local authorities based on local considerations, including public concern and the impact of school absenteeism and staffing shortages." The Food and Drug Administration (FDA) authorized emergency use of medicines and diagnostic tests for flu. (FDA is part of Department of Health and Human Services.) The FDA stated it was also responding to this threat by: working with other government agencies and manufacturers on a series of issues related to antiviral medications. growing the 2009 H1N1 flu virus and preparing to make vaccine seed lots, which may be used eventually to produce a safe and effective vaccine. helping to prepare reagents needed for vaccine production and coordinating closely with other public health agencies for clinical development and testing. accelerating access to new diagnostic tools for this 2009 H1N1 flu virus On May 6, 2009, the FDA announced that it had approved a new manufacturing facility for seasonal flu vaccine, owned by Sanofi Pasteur, which could also be used for manufacturing a vaccine for the new H1N1 flu strain. The FDA also issued a warning for consumers to be wary of products claiming to cure or prevent swine flu. Secretary Napolitano stated that DHS was the principal federal office for incidents such as the H1N1 flu outbreak, and "Under that role, we have been leading a true collaborative effort." The Department of Homeland Security issued a document, dated November 1, 2005, entitled "National Strategy for Pandemic Influenza", detailing planning for potential pandemics. https://web.archive.org/web/20090507013213/http://www.pandemicflu.gov/plan/federal/pandemic-influenza.pdf The State Department suggested travelers to Mexico stay alert and comply with guidance from Mexican public health officials, but did not impose any travel restrictions on US citizens to Mexico. However, the State Department did recommend US citizens avoid non-essential travel to Mexico. The Department of Agriculture (USDA) reported no swine in the US have been infected so far, but the USDA is monitoring swine across the US for signs of infection. The Department of Commerce sent a letter to Russia and China requesting that those countries lift their ban on American pork products. The Department of Defense (DOD) monitored the swine flu situation and had contingency plans to deal with such outbreaks. As of May 7, 2009, the DOD reported 104 confirmed cases among Armed Forces personnel and their families. DOD maintained a daily summary and map. The Department of Education provided guidance to schools in the US affected by swine flu, as well as precautions to take. Schools closed in many states in response to local flu outbreaks. By April 30, 2009, 300 U.S. schools and school districts had announced closures in response to the outbreak, giving 169,000 students time off. On May 4, 2009, about 533 schools in 24 states in the U.S. were closed, affecting about 330,000 students. On September 25, 2009, 42 schools were closed in eight states as the second wave of the pandemic began. On May 5, Kathleen Sebelius stated in a CDC news conference that school closures for single confirmed cases of H1N1 influenza were unnecessary, but that children displaying an influenza-like illness should stay home. Several US airlines waived fees for cancellations and flight changes. At least one cruise line changed itinerary to avoid Mexican ports of call. An official for the White House said on April 24 that "the White House is taking the situation seriously and monitoring for any new developments. The president has been fully briefed." President Barack Obama stated that "We are closely monitoring the emerging cases of swine flu." He also noted, "This is obviously a cause for concern ... but it is not a cause for alarm." Obama suggested that U.S. schools should consider shutting down, as a future possibility, if their students were to become infected. White House Press Secretary Robert Gibbs said the effort to get a team in place to respond to the health scare had not been hindered by the lack of a secretary of Health and Human Services or appointees in any of the department's 19 key posts. The president's nominee, Kansas Gov. Kathleen Sebelius , was still awaiting confirmation from the U.S. Senate until passing on April 28. The President had not yet made appointments to either the Commissioner of the Food and Drug Administration , the Surgeon General , or the Director of the Centers for Disease Control and Prevention . The current acting Surgeon General, Steven K. Galson , was also currently serving as the Acting Assistant Secretary for Health. On April 30, it was reported that an aide to Steven Chu , the US Energy Secretary, had fallen ill from the virus after helping arrange President Obama's trip to Mexico. However, the White House stated that the President was not at risk of contracting the flu. Kathleen Sebelius was confirmed as the Secretary of Health and Human Services by the Senate on April 28, 2009, with a vote of 65–31. On October 24, President Obama declared the 2009 H1N1 swine flu a national emergency. The declaration made it easier for U.S. medical facilities to handle a surge in flu patients by allowing the waiver of some requirements of Medicare , Medicaid and other federal health insurance programs as needed.During the week of April 19, 2009, the CDC activated its Emergency Operations Center (EOC), with RADM Stephen Redd as the Incident Commander, to augment the ongoing investigation of human cases of swine influenza A (H1N1). More than 250 CDC professionals worked from the CDC EOC as part of the agency's response. As of May 4, 2009, the CDC reported that it had deployed 25% of the supplies and medicines in the Strategic National Stockpile to the various states. As of April 29, only the CDC could confirm U.S. swine flu cases. Besser stated during an April 30 press briefing that California and New York had diagnostic test kits, and that the kits would be sent to all states starting the following day. On May 6, the CDC announced that testing kits were now available for all states. It was expected this would generate an increase in the number of confirmed cases as more states began doing their own tests. In the United States, the majority of the 70 National Respiratory and Enteric Virus Surveillance System (NREVSS) laboratories do not report the influenza A subtype. [ citation needed ] However, in 2007, human infection with a novel influenzavirus A became a nationally notifiable condition. Novel influenza A virus infections include all human infections with influenza A viruses that are different from currently circulating human influenza H1 and H3 viruses. These viruses include those that are subtyped as nonhuman in origin and those that are unsubtypable with standard methods and reagents. The new strain responsible for this outbreak was one such virus. [ citation needed ] Initially the CDC had issued a recommendation that schools close for as long as two weeks if a student catches swine flu. Some school districts closed all schools if a single child was classified as probable. On May 5 the CDC retracted its advice stating that schools that were closed based on previous CDC guidance related to this outbreak may reopen. By that time at least 726 schools nationwide serving more than 480,000 students had closed for at least some period of time. The CDC amended its advice, citing new information on disease severity and the limiting effectiveness of school closure as a control measure. The new advice given stated, "Decisions about school closure should be at the discretion of local authorities based on local considerations, including public concern and the impact of school absenteeism and staffing shortages." During the week of April 19, 2009, the CDC activated its Emergency Operations Center (EOC), with RADM Stephen Redd as the Incident Commander, to augment the ongoing investigation of human cases of swine influenza A (H1N1). More than 250 CDC professionals worked from the CDC EOC as part of the agency's response. As of May 4, 2009, the CDC reported that it had deployed 25% of the supplies and medicines in the Strategic National Stockpile to the various states. As of April 29, only the CDC could confirm U.S. swine flu cases. Besser stated during an April 30 press briefing that California and New York had diagnostic test kits, and that the kits would be sent to all states starting the following day. On May 6, the CDC announced that testing kits were now available for all states. It was expected this would generate an increase in the number of confirmed cases as more states began doing their own tests. In the United States, the majority of the 70 National Respiratory and Enteric Virus Surveillance System (NREVSS) laboratories do not report the influenza A subtype. [ citation needed ] However, in 2007, human infection with a novel influenzavirus A became a nationally notifiable condition. Novel influenza A virus infections include all human infections with influenza A viruses that are different from currently circulating human influenza H1 and H3 viruses. These viruses include those that are subtyped as nonhuman in origin and those that are unsubtypable with standard methods and reagents. The new strain responsible for this outbreak was one such virus. [ citation needed ]Initially the CDC had issued a recommendation that schools close for as long as two weeks if a student catches swine flu. Some school districts closed all schools if a single child was classified as probable. On May 5 the CDC retracted its advice stating that schools that were closed based on previous CDC guidance related to this outbreak may reopen. By that time at least 726 schools nationwide serving more than 480,000 students had closed for at least some period of time. The CDC amended its advice, citing new information on disease severity and the limiting effectiveness of school closure as a control measure. The new advice given stated, "Decisions about school closure should be at the discretion of local authorities based on local considerations, including public concern and the impact of school absenteeism and staffing shortages." The Food and Drug Administration (FDA) authorized emergency use of medicines and diagnostic tests for flu. (FDA is part of Department of Health and Human Services.) The FDA stated it was also responding to this threat by: working with other government agencies and manufacturers on a series of issues related to antiviral medications. growing the 2009 H1N1 flu virus and preparing to make vaccine seed lots, which may be used eventually to produce a safe and effective vaccine. helping to prepare reagents needed for vaccine production and coordinating closely with other public health agencies for clinical development and testing. accelerating access to new diagnostic tools for this 2009 H1N1 flu virus On May 6, 2009, the FDA announced that it had approved a new manufacturing facility for seasonal flu vaccine, owned by Sanofi Pasteur, which could also be used for manufacturing a vaccine for the new H1N1 flu strain. The FDA also issued a warning for consumers to be wary of products claiming to cure or prevent swine flu. Secretary Napolitano stated that DHS was the principal federal office for incidents such as the H1N1 flu outbreak, and "Under that role, we have been leading a true collaborative effort." The Department of Homeland Security issued a document, dated November 1, 2005, entitled "National Strategy for Pandemic Influenza", detailing planning for potential pandemics. https://web.archive.org/web/20090507013213/http://www.pandemicflu.gov/plan/federal/pandemic-influenza.pdf The State Department suggested travelers to Mexico stay alert and comply with guidance from Mexican public health officials, but did not impose any travel restrictions on US citizens to Mexico. However, the State Department did recommend US citizens avoid non-essential travel to Mexico. The Department of Agriculture (USDA) reported no swine in the US have been infected so far, but the USDA is monitoring swine across the US for signs of infection. The Department of Commerce sent a letter to Russia and China requesting that those countries lift their ban on American pork products. The Department of Defense (DOD) monitored the swine flu situation and had contingency plans to deal with such outbreaks. As of May 7, 2009, the DOD reported 104 confirmed cases among Armed Forces personnel and their families. DOD maintained a daily summary and map. The Department of Education provided guidance to schools in the US affected by swine flu, as well as precautions to take. Secretary Napolitano stated that DHS was the principal federal office for incidents such as the H1N1 flu outbreak, and "Under that role, we have been leading a true collaborative effort." The Department of Homeland Security issued a document, dated November 1, 2005, entitled "National Strategy for Pandemic Influenza", detailing planning for potential pandemics. https://web.archive.org/web/20090507013213/http://www.pandemicflu.gov/plan/federal/pandemic-influenza.pdfThe State Department suggested travelers to Mexico stay alert and comply with guidance from Mexican public health officials, but did not impose any travel restrictions on US citizens to Mexico. However, the State Department did recommend US citizens avoid non-essential travel to Mexico. The Department of Agriculture (USDA) reported no swine in the US have been infected so far, but the USDA is monitoring swine across the US for signs of infection. The Department of Commerce sent a letter to Russia and China requesting that those countries lift their ban on American pork products. The Department of Defense (DOD) monitored the swine flu situation and had contingency plans to deal with such outbreaks. As of May 7, 2009, the DOD reported 104 confirmed cases among Armed Forces personnel and their families. DOD maintained a daily summary and map. The Department of Education provided guidance to schools in the US affected by swine flu, as well as precautions to take. Schools closed in many states in response to local flu outbreaks. By April 30, 2009, 300 U.S. schools and school districts had announced closures in response to the outbreak, giving 169,000 students time off. On May 4, 2009, about 533 schools in 24 states in the U.S. were closed, affecting about 330,000 students. On September 25, 2009, 42 schools were closed in eight states as the second wave of the pandemic began. On May 5, Kathleen Sebelius stated in a CDC news conference that school closures for single confirmed cases of H1N1 influenza were unnecessary, but that children displaying an influenza-like illness should stay home. Several US airlines waived fees for cancellations and flight changes. At least one cruise line changed itinerary to avoid Mexican ports of call. [ citation needed ]

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influenza virus

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Cap snatching

The first step of transcription for some negative, single-stranded RNA viruses is cap snatching , in which the first 10 to 20 residues of a host cell RNA are removed (snatched) and used as the 5′ cap and primer to initiate the synthesis of the nascent viral mRNA. The viral RNA-dependent RNA polymerase (RdRp) can then proceed to replicate the negative-sense genome from the positive-sense template. Cap-snatching also explains why some viral mRNA have 5' terminal extensions of 10-20 nucleotides that are not encoded for in the genome. Examples of viruses that engage in cap-snatching include influenza viruses ( Orthomyxoviridae ), Lassa virus ( Arenaviridae ), hantaan virus ( Hantaviridae ) and rift valley fever virus ( Phenuiviridae ). Most viruses snatch 15-20 nucleotides except for the families Arenaviridae and Nairoviridae and the genus Thogotovirus ( Orthomyxoviridae ) which use a shorter strand. In the influenza virus , cap snatching occurs in the nucleus of the cell. The cap snatching endonuclease function is contained in the PA subunit of the RNA polymerase . In Arenaviridae and Bunyavirales , cap-snatching takes place in the cytoplasm. Cap-snatching occurs in three general steps: 1) The viral RdRp or N protein binds to the host mRNA 5'-methylated cap-1 or cap-2 structure. 2) Viral endonuclease cleaves mRNA several nucleotides downstream of the cap. 3) Capped RNA utilized as a primer to initiate viral mRNA synthesis carried out by the RdRp. Cap snatching is best described in influenza viruses, especially influenza A. In Orthomyxoviridae , the viral family of influenza, the RdRp is divided into three subunits: PA, PB1 and PB2. PB1 first binds the 5' end of the viral RNA (vRNA), activating PB2 and causing the 3' end of the vRNA to form a double-stranded zone with the 5' end. The PB2 proceeds to bind cellular mRNA at the N7-methyl guanosine (m 7 G) capped 5' end. The PA subunit subsequently cleaves the sequence 10-13 nucleotides from the cap structure via endonuclease activity at the N terminus. The exact cleavage location is dependent both on the distance between the PB2 and the PA of the RdRp (around 50 angstroms or 10-13 nucleotides) and also the sequence of the mRNA. Then, the PB1 subunit, which contains the polymerase activity, initially adds on two new nucleotides. The cap snatched primer moves through the product exit tunnel in the PB1 domain to serve as the primer for transcription. The vRNA 3'-UCGUUUU nucleotides are not bound to the polymerase but rather are free for complementary binding with the capped RNA primer to confer stability. Transcription then begins with G or C residue on the 3' end of the capped primer. Finally, the PB1 subunit completes chain elongation in the canonical 5' to 3' direction, releasing the cap, but keeping the 5' end bound. The viral 3' poly-A tail is added at the end of transcription by polymerase stuttering from the steric hindrance of the vRNA loop. The resulting viral mRNA looks is identical to host mRNA, allowing endogenous cellular machinery to carry out processing and nuclear export. The de-capped host mRNAs are targeted degradation, which lead to the downregulation of cellular mRNA. Influenza RdRp also interacts with the cell Polymerase II (Pol II) C terminal domain, which potentially promotes viral transcription by changing the conformation of the RdRp. Additionally, by reducing Pol II abundance, influenza can begin to shut off critical host transcription. Cap snatching is not used during replication. Instead, the RdRp performs a "prime and realign" step ensure that the genome is fully copied. In this mechanism, the RdRp sets down a primer internally, then the vRNA is realigned to continue replication. Influenza's PB2 cap-binding domain has a unique fold, but it uses aromatic stacking to execute m 7 G cap-binding similar to other cap-binding proteins. PA is a member of the PD(D/E)XK nuclease family, which uses divalent metal ions to cleave nucleic acid. However, it has a peculiar active site histidine residue which ligates the Mn2+ ion used for cleavage. In October 2018, the United States FDA approved baloxavir marboxil for treatment of acute uncomplicated influenza , marking the first new influenza anti-viral drug class in over two decades. The drug utilizes knowledge about cap snatching by targeting and inhibiting the endonuclease function of the PA subunit, which will prevent the virus from initiating transcription. Baloxavir marboxil (Xofluza) is effective against both influenza A and B. The family Arenaviridae and order Bunyavirales are also segmented negative, single-stranded RNA viruses. A verified Mn 2+ dependent endonuclease is located at the N-terminus of the L protein. TN-terminal domain is conserved between various families, suggesting evolutionary similarity. However, the cap-binding domain is not confirmed for every virus family, but it is believed to be located in the L or nucleocapsid (N or NP) protein. In the bunyavirales, endonuclease cleavage and nucleotide motif preferences vary between families, genera and species. This variation occurs because of a need to some base pairing with the 3' end of the viral genome. The nucleoprotein structure in Lassa virus ( Arenaviridae ) contains a second nuclease. Researchers propose that it is involved in attenuating interferon response, but it also contains a dTTP-binding site which may be used for cap-snatching. In this model, the L and N proteins cooperate in the cap-snatching process. The two-domain model has also been prosed for hantaviruses, but the N protein in the rift valley fever virus ( Phenuiviridae ) does not possess the same features. Cap snatching has also been investigated in depth for the family Hantaviridae ( Bunyavirales ). There is evidence that the N protein binds to the 5' cap and protects them from degradation by cellular machinery. The N protein accumulates in cytoplasmic cellular processing bodies (P bodies), sequestering the protected 5' caps as a pool of available primers for the RdRp to begin viral mRNA synthesis. There are four nucleotides on the vRNA that are adjacent the 5' cap for binding. The virus preferentially cleaves mRNA cap at a G residue 14 nucleotides downstream from the cap. Additionally, it usually cleaves caps from nonsense mRNA instead of actively translated mRNA. The N protein can guard host mRNA caps without P-bodies, but they are not used as efficiently by the RdRp. The Hantaviridae RdRp can also engage in a "prime and realign" mechanism: The host oligonucleotide primes mRNA transcription and initiates transcription with a terminal G residue. After several nucleotides are added, the nascent RNA realigns by moving two nucleotides backwards on the repeated terminal sequence (AUCAUCAUC) so that the host G is once again the first nucleotide, creating a 5' end extension. Cap snatching has also been investigated in depth for the family Hantaviridae ( Bunyavirales ). There is evidence that the N protein binds to the 5' cap and protects them from degradation by cellular machinery. The N protein accumulates in cytoplasmic cellular processing bodies (P bodies), sequestering the protected 5' caps as a pool of available primers for the RdRp to begin viral mRNA synthesis. There are four nucleotides on the vRNA that are adjacent the 5' cap for binding. The virus preferentially cleaves mRNA cap at a G residue 14 nucleotides downstream from the cap. Additionally, it usually cleaves caps from nonsense mRNA instead of actively translated mRNA. The N protein can guard host mRNA caps without P-bodies, but they are not used as efficiently by the RdRp. The Hantaviridae RdRp can also engage in a "prime and realign" mechanism: The host oligonucleotide primes mRNA transcription and initiates transcription with a terminal G residue. After several nucleotides are added, the nascent RNA realigns by moving two nucleotides backwards on the repeated terminal sequence (AUCAUCAUC) so that the host G is once again the first nucleotide, creating a 5' end extension.

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influenza virus

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Viral evolution

Viral evolution is a subfield of evolutionary biology and virology that is specifically concerned with the evolution of viruses . Viruses have short generation times, and many—in particular RNA viruses —have relatively high mutation rates (on the order of one point mutation or more per genome per round of replication). Although most viral mutations confer no benefit and often even prove deleterious to viruses, the rapid rate of viral mutation combined with natural selection allows viruses to quickly adapt to changes in their host environment. In addition, because viruses typically produce many copies in an infected host, mutated genes can be passed on to many offspring quickly. Although the chance of mutations and evolution can change depending on the type of virus (e.g., double stranded DNA, double stranded RNA, single strand DNA), viruses overall have high chances for mutations. Viral evolution is an important aspect of the epidemiology of viral diseases such as influenza ( influenza virus ), AIDS ( HIV ), and hepatitis (e.g. HCV ). The rapidity of viral mutation also causes problems in the development of successful vaccines and antiviral drugs , as resistant mutations often appear within weeks or months after the beginning of a treatment. One of the main theoretical models applied to viral evolution is the quasispecies model , which defines a viral quasispecies as a group of closely related viral strains competing within an environment.Viruses are ancient. Studies at the molecular level have revealed relationships between viruses infecting organisms from each of the three domains of life , suggesting viral proteins that pre-date the divergence of life and thus infecting the last universal common ancestor . This indicates that some viruses emerged early in the evolution of life, and that they have probably arisen multiple times. It has been suggested that new groups of viruses have repeatedly emerged at all stages of evolution, often through the displacement of ancestral structural and genome replication genes. There are three classical hypotheses on the origins of viruses and how they evolved: Virologists are in the process of re-evaluating these hypotheses. One of the problems for studying viral origins and evolution is the high rate of viral mutation, particularly the case in RNA retroviruses like HIV/AIDS. A recent study based on comparisons of viral protein folding structures, however, is offering some new evidence. Fold Super Families (FSFs) are proteins that show similar folding structures independent of the actual sequence of amino acids, and have been found to show evidence of viral phylogeny . The proteome of a virus, the viral proteome , still contains traces of ancient evolutionary history that can be studied today. The study of protein FSFs suggests the existence of ancient cellular lineages common to both cells and viruses before the appearance of the 'last universal cellular ancestor' that gave rise to modern cells. Evolutionary pressure to reduce genome and particle size may have eventually reduced viro-cells into modern viruses, whereas other coexisting cellular lineages eventually evolved into modern cells. Furthermore, the long genetic distance between RNA and DNA FSFs suggests that the RNA world hypothesis may have new experimental evidence, with a long intermediary period in the evolution of cellular life. Definitive exclusion of a hypothesis on the origin of viruses is difficult to make on Earth given the ubiquitous interactions between viruses and cells, and the lack of availability of rocks that are old enough to reveal traces of the earliest viruses on the planet. From an astrobiological perspective, it has therefore been proposed that on celestial bodies such as Mars not only cells but also traces of former virions or viroids should be actively searched for: possible findings of traces of virions in the apparent absence of cells could provide support for the virus-first hypothesis. Viruses are ancient. Studies at the molecular level have revealed relationships between viruses infecting organisms from each of the three domains of life , suggesting viral proteins that pre-date the divergence of life and thus infecting the last universal common ancestor . This indicates that some viruses emerged early in the evolution of life, and that they have probably arisen multiple times. It has been suggested that new groups of viruses have repeatedly emerged at all stages of evolution, often through the displacement of ancestral structural and genome replication genes. There are three classical hypotheses on the origins of viruses and how they evolved: Virologists are in the process of re-evaluating these hypotheses. One of the problems for studying viral origins and evolution is the high rate of viral mutation, particularly the case in RNA retroviruses like HIV/AIDS. A recent study based on comparisons of viral protein folding structures, however, is offering some new evidence. Fold Super Families (FSFs) are proteins that show similar folding structures independent of the actual sequence of amino acids, and have been found to show evidence of viral phylogeny . The proteome of a virus, the viral proteome , still contains traces of ancient evolutionary history that can be studied today. The study of protein FSFs suggests the existence of ancient cellular lineages common to both cells and viruses before the appearance of the 'last universal cellular ancestor' that gave rise to modern cells. Evolutionary pressure to reduce genome and particle size may have eventually reduced viro-cells into modern viruses, whereas other coexisting cellular lineages eventually evolved into modern cells. Furthermore, the long genetic distance between RNA and DNA FSFs suggests that the RNA world hypothesis may have new experimental evidence, with a long intermediary period in the evolution of cellular life. Definitive exclusion of a hypothesis on the origin of viruses is difficult to make on Earth given the ubiquitous interactions between viruses and cells, and the lack of availability of rocks that are old enough to reveal traces of the earliest viruses on the planet. From an astrobiological perspective, it has therefore been proposed that on celestial bodies such as Mars not only cells but also traces of former virions or viroids should be actively searched for: possible findings of traces of virions in the apparent absence of cells could provide support for the virus-first hypothesis. Viruses do not form fossils in the traditional sense, because they are much smaller than the finest colloidal fragments forming sedimentary rocks that fossilize plants and animals. However, the genomes of many organisms contain endogenous viral elements (EVEs). These DNA sequences are the remnants of ancient virus genes and genomes that ancestrally 'invaded' the host germline . For example, the genomes of most vertebrate species contain hundreds to thousands of sequences derived from ancient retroviruses . These sequences are a valuable source of retrospective evidence about the evolutionary history of viruses, and have given birth to the science of paleovirology . The evolutionary history of viruses can to some extent be inferred from analysis of contemporary viral genomes. The mutation rates for many viruses have been measured, and application of a molecular clock allows dates of divergence to be inferred. Viruses evolve through changes in their RNA (or DNA), some quite rapidly, and the best adapted mutants quickly outnumber their less fit counterparts. In this sense their evolution is Darwinian . The way viruses reproduce in their host cells makes them particularly susceptible to the genetic changes that help to drive their evolution. The RNA viruses are especially prone to mutations. In host cells there are mechanisms for correcting mistakes when DNA replicates and these kick in whenever cells divide. These important mechanisms prevent potentially lethal mutations from being passed on to offspring. But these mechanisms do not work for RNA and when an RNA virus replicates in its host cell, changes in their genes are occasionally introduced in error, some of which are lethal. One virus particle can produce millions of progeny viruses in just one cycle of replication, therefore the production of a few "dud" viruses is not a problem. Most mutations are "silent" and do not result in any obvious changes to the progeny viruses, but others confer advantages that increase the fitness of the viruses in the environment. These could be changes to the virus particles that disguise them so they are not identified by the cells of the immune system or changes that make antiviral drugs less effective. Both of these changes occur frequently with HIV . Many viruses (for example, influenza A virus) can "shuffle" their genes with other viruses when two similar strains infect the same cell. This phenomenon is called genetic shift , and is often the cause of new and more virulent strains appearing. Other viruses change more slowly as mutations in their genes gradually accumulate over time, a process known as antigenic drift . Through these mechanisms new viruses are constantly emerging and present a continuing challenge in attempts to control the diseases they cause. Most species of viruses are now known to have common ancestors, and although the "virus first" hypothesis has yet to gain full acceptance, there is little doubt that the thousands of species of modern viruses have evolved from less numerous ancient ones. The morbilliviruses , for example, are a group of closely related, but distinct viruses that infect a broad range of animals. The group includes measles virus, which infects humans and primates; canine distemper virus , which infects many animals including dogs, cats, bears, weasels and hyaenas; rinderpest , which infected cattle and buffalo; and other viruses of seals, porpoises and dolphins. Although it is not possible to prove which of these rapidly evolving viruses is the earliest, for such a closely related group of viruses to be found in such diverse hosts suggests the possibility that their common ancestor is ancient. Escherichia virus T4 (phage T4) is a species of bacteriophage that infects Escherichia coli bacteria. It is a double-stranded DNA virus in the family Myoviridae . Phage T4 is an obligate intracellular parasite that reproduces within the host bacterial cell and its progeny are released when the host is destroyed by lysis . The complete genome sequence of phage T4 encodes about 300 gene products . These virulent viruses are among the largest, most complex viruses that are known and one of the best studied model organisms . They have played a key role in the development of virology and molecular biology . The numbers of reported genetic homologies between phage T4 and bacteria and between phage T4 and eukaryotes are similar suggesting that phage T4 shares ancestry with both bacteria and eukaryotes and has about equal similarity to each. Phage T4 may have diverged in evolution from a common ancestor of bacteria and eukaryotes or from an early evolved member of either lineage. Most of the phage genes showing homology with bacteria and eukaryotes encode enzymes acting in the ubiquitous processes of DNA replication , DNA repair , recombination and nucleotide synthesis. These processes likely evolved very early. The adaptive features of the enzymes catalyzing these early processes may have been maintained in the phage T4, bacterial, and eukaryotic lineages because they were established well-tested solutions to basic functional problems by the time these lineages diverged.Escherichia virus T4 (phage T4) is a species of bacteriophage that infects Escherichia coli bacteria. It is a double-stranded DNA virus in the family Myoviridae . Phage T4 is an obligate intracellular parasite that reproduces within the host bacterial cell and its progeny are released when the host is destroyed by lysis . The complete genome sequence of phage T4 encodes about 300 gene products . These virulent viruses are among the largest, most complex viruses that are known and one of the best studied model organisms . They have played a key role in the development of virology and molecular biology . The numbers of reported genetic homologies between phage T4 and bacteria and between phage T4 and eukaryotes are similar suggesting that phage T4 shares ancestry with both bacteria and eukaryotes and has about equal similarity to each. Phage T4 may have diverged in evolution from a common ancestor of bacteria and eukaryotes or from an early evolved member of either lineage. Most of the phage genes showing homology with bacteria and eukaryotes encode enzymes acting in the ubiquitous processes of DNA replication , DNA repair , recombination and nucleotide synthesis. These processes likely evolved very early. The adaptive features of the enzymes catalyzing these early processes may have been maintained in the phage T4, bacterial, and eukaryotic lineages because they were established well-tested solutions to basic functional problems by the time these lineages diverged.Viruses have been able to continue their infectious existence due to evolution. Their rapid mutation rates and natural selection has given viruses the advantage to continue to spread. One way that viruses have been able to spread is with the evolution of virus transmission . The virus can find a new host through: Droplet transmission- passed on through body fluids (sneezing on someone) An example is the influenza virus Airborne transmission- passed on through the air (brought in by breathing) An example would be how viral meningitis is passed on Vector transmission- picked up by a carrier and brought to a new host An example is viral encephalitis Waterborne transmission- leaving a host, infecting the water, and being consumed in a new host Poliovirus is an example for this Sit-and-wait-transmission- the virus is living outside a host for long periods of time The smallpox virus is also an example for this Virulence , or the harm that the virus does on its host, depends on various factors. In particular, the method of transmission tends to affect how the level of virulence will change over time. Viruses that transmit through vertical transmission (transmission to the offspring of the host) will evolve to have lower levels of virulence. Viruses that transmit through horizontal transmission (transmission between members of the same species that don't have a parent-child relationship) will usually evolve to have a higher virulence.

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influenza virus

https://api.wikimedia.org/core/v1/wikipedia/en/page/RNA_virus/html

RNA virus

An RNA virus is a virus — other than a retrovirus — that has ribonucleic acid ( RNA ) as its genetic material . The nucleic acid is usually single-stranded RNA ( ssRNA ) but it may be double-stranded (dsRNA). Notable human diseases caused by RNA viruses include the common cold , influenza , SARS , MERS , COVID-19 , Dengue virus , hepatitis C , hepatitis E , West Nile fever , Ebola virus disease , rabies , polio , mumps , and measles . The International Committee on Taxonomy of Viruses (ICTV) classifies RNA viruses as those that belong to Group III , Group IV or Group V of the Baltimore classification system. This category excludes Group VI , viruses with RNA genetic material but which use DNA intermediates in their life cycle : these are called retroviruses , including HIV-1 and HIV-2 which cause AIDS . As of May 2020, all known RNA viruses encoding an RNA-directed RNA polymerase are believed to form a monophyletic group, known as the realm Riboviria . The majority of such RNA viruses fall into the kingdom Orthornavirae and the rest have a positioning not yet defined . The realm does not contain all RNA viruses: Deltavirus , Asunviroidae , and Pospiviroidae are taxa of RNA viruses that were mistakenly included in 2019, [lower-alpha 1] but corrected in 2020. RNA viruses can be further classified according to the sense or polarity of their RNA into negative-sense and positive-sense , or ambisense RNA viruses. Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA-dependent RNA polymerase before translation. Purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. In contrast, purified RNA of a negative-sense virus is not infectious by itself as it needs to be transcribed into positive-sense RNA; each virion can be transcribed to several positive-sense RNAs. Ambisense RNA viruses resemble negative-sense RNA viruses, except they translate genes from their negative and positive strands. The double-stranded (ds)RNA viruses represent a diverse group of viruses that vary widely in host range (humans, animals, plants, fungi , [lower-alpha 2] and bacteria ), genome segment number (one to twelve), and virion organization ( Triangulation number , capsid layers, spikes, turrets, etc.). Members of this group include the rotaviruses , which are the most common cause of gastroenteritis in young children, and picobirnaviruses , which are the most common virus in fecal samples of both humans and animals with or without signs of diarrhea. Bluetongue virus is an economically important pathogen that infects cattle and sheep. In recent years, progress has been made in determining atomic and subnanometer resolution structures of a number of key viral proteins and virion capsids of several dsRNA viruses, highlighting the significant parallels in the structure and replicative processes of many of these viruses. [ page needed ] RNA viruses generally have very high mutation rates compared to DNA viruses , because viral RNA polymerases lack the proofreading ability of DNA polymerases . The genetic diversity of RNA viruses is one reason why it is difficult to make effective vaccines against them. Retroviruses also have a high mutation rate even though their DNA intermediate integrates into the host genome (and is thus subject to host DNA proofreading once integrated), because errors during reverse transcription are embedded into both strands of DNA before integration. Some genes of RNA virus are important to the viral replication cycles and mutations are not tolerated. For example, the region of the hepatitis C virus genome that encodes the core protein is highly conserved , because it contains an RNA structure involved in an internal ribosome entry site . On average, dsRNA viruses show a lower sequence redundancy relative to ssRNA viruses. Contrarily, dsDNA viruses contain the most redundant genome sequences while ssDNA viruses have the least. The sequence complexity of viruses has been shown to be a key characteristic for accurate reference-free viral classification. RNA viruses can be further classified according to the sense or polarity of their RNA into negative-sense and positive-sense , or ambisense RNA viruses. Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell. Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA-dependent RNA polymerase before translation. Purified RNA of a positive-sense virus can directly cause infection though it may be less infectious than the whole virus particle. In contrast, purified RNA of a negative-sense virus is not infectious by itself as it needs to be transcribed into positive-sense RNA; each virion can be transcribed to several positive-sense RNAs. Ambisense RNA viruses resemble negative-sense RNA viruses, except they translate genes from their negative and positive strands. The double-stranded (ds)RNA viruses represent a diverse group of viruses that vary widely in host range (humans, animals, plants, fungi , [lower-alpha 2] and bacteria ), genome segment number (one to twelve), and virion organization ( Triangulation number , capsid layers, spikes, turrets, etc.). Members of this group include the rotaviruses , which are the most common cause of gastroenteritis in young children, and picobirnaviruses , which are the most common virus in fecal samples of both humans and animals with or without signs of diarrhea. Bluetongue virus is an economically important pathogen that infects cattle and sheep. In recent years, progress has been made in determining atomic and subnanometer resolution structures of a number of key viral proteins and virion capsids of several dsRNA viruses, highlighting the significant parallels in the structure and replicative processes of many of these viruses. [ page needed ]RNA viruses generally have very high mutation rates compared to DNA viruses , because viral RNA polymerases lack the proofreading ability of DNA polymerases . The genetic diversity of RNA viruses is one reason why it is difficult to make effective vaccines against them. Retroviruses also have a high mutation rate even though their DNA intermediate integrates into the host genome (and is thus subject to host DNA proofreading once integrated), because errors during reverse transcription are embedded into both strands of DNA before integration. Some genes of RNA virus are important to the viral replication cycles and mutations are not tolerated. For example, the region of the hepatitis C virus genome that encodes the core protein is highly conserved , because it contains an RNA structure involved in an internal ribosome entry site . On average, dsRNA viruses show a lower sequence redundancy relative to ssRNA viruses. Contrarily, dsDNA viruses contain the most redundant genome sequences while ssDNA viruses have the least. The sequence complexity of viruses has been shown to be a key characteristic for accurate reference-free viral classification. Animal RNA viruses are classified by the ICTV. There are three distinct groups of RNA viruses depending on their genome and mode of replication: Retroviruses (Group VI) have a single-stranded RNA genome but, in general, are not considered RNA viruses because they use DNA intermediates to replicate. Reverse transcriptase , a viral enzyme that comes from the virus itself after it is uncoated, converts the viral RNA into a complementary strand of DNA, which is copied to produce a double-stranded molecule of viral DNA. After this DNA is integrated into the host genome using the viral enzyme integrase , expression of the encoded genes may lead to the formation of new virions.Numerous RNA viruses are capable of genetic recombination when at least two viral genomes are present in the same host cell. Very rarely viral RNA can recombine with host RNA. RNA recombination appears to be a major driving force in determining genome architecture and the course of viral evolution among Picornaviridae ( (+)ssRNA ), e.g. poliovirus . In the Retroviridae ((+)ssRNA), e.g. HIV , damage in the RNA genome appears to be avoided during reverse transcription by strand switching, a form of recombination. Recombination also occurs in the Reoviridae (dsRNA), e.g. reovirus; Orthomyxoviridae ((-)ssRNA), e.g. influenza virus ; and Coronaviridae ((+)ssRNA), e.g. SARS . Recombination in RNA viruses appears to be an adaptation for coping with genome damage. Recombination can occur infrequently between animal viruses of the same species but of divergent lineages. The resulting recombinant viruses may sometimes cause an outbreak of infection in humans. Classification is based principally on the type of genome (double-stranded, negative- or positive-single-strand) and gene number and organization. Currently, there are 5 orders and 47 families of RNA viruses recognized. There are also many unassigned species and genera. Related to but distinct from the RNA viruses are the viroids and the RNA satellite viruses . These are not currently classified as RNA viruses and are described on their own pages. A study of several thousand RNA viruses has shown the presence of at least five main taxa: a levivirus and relatives group; a picornavirus supergroup; an alphavirus supergroup plus a flavivirus supergroup; the dsRNA viruses; and the -ve strand viruses. The lentivirus group appears to be basal to all the remaining RNA viruses. The next major division lies between the picornasupragroup and the remaining viruses. The dsRNA viruses appear to have evolved from a +ve RNA ancestor and the -ve RNA viruses from within the dsRNA viruses. The closest relation to the -ve stranded RNA viruses is the Reoviridae . This is the single largest group of RNA viruses and has been organized by the ICTV into the phyla Kitrinoviricota , Lenarviricota , and Pisuviricota in the kingdom Orthornavirae and realm Riboviria . Positive-strand RNA viruses can also be classified based on the RNA-dependent RNA polymerase. Three groups have been recognised: Bymoviruses, comoviruses, nepoviruses, nodaviruses, picornaviruses, potyviruses, sobemoviruses and a subset of luteoviruses (beet western yellows virus and potato leafroll virus)—the picorna like group (Picornavirata). Carmoviruses, dianthoviruses, flaviviruses, pestiviruses, statoviruses, tombusviruses, single-stranded RNA bacteriophages, hepatitis C virus and a subset of luteoviruses (barley yellow dwarf virus)—the flavi like group (Flavivirata). Alphaviruses, carlaviruses, furoviruses, hordeiviruses, potexviruses, rubiviruses, tobraviruses, tricornaviruses, tymoviruses, apple chlorotic leaf spot virus, beet yellows virus and hepatitis E virus—the alpha like group (Rubivirata). A division of the alpha-like (Sindbis-like) supergroup on the basis of a novel domain located near the N termini of the proteins involved in viral replication has been proposed. The two groups proposed are: the 'altovirus' group (alphaviruses, furoviruses, hepatitis E virus, hordeiviruses, tobamoviruses, tobraviruses, tricornaviruses and probably rubiviruses); and the 'typovirus' group (apple chlorotic leaf spot virus, carlaviruses, potexviruses and tymoviruses). The alpha like supergroup can be further divided into three clades : the rubi-like, tobamo-like, and tymo-like viruses. Additional work has identified five groups of positive-stranded RNA viruses containing four, three, three, three, and one order(s), respectively. These fourteen orders contain 31 virus families (including 17 families of plant viruses) and 48 genera (including 30 genera of plant viruses). This analysis suggests that alphaviruses and flaviviruses can be separated into two families—the Togaviridae and Flaviridae, respectively—but suggests that other taxonomic assignments, such as the pestiviruses, hepatitis C virus, rubiviruses, hepatitis E virus, and arteriviruses, may be incorrect. The coronaviruses and toroviruses appear to be distinct families in distinct orders and not distinct genera of the same family as currently classified. The luteoviruses appear to be two families rather than one, and apple chlorotic leaf spot virus appears not to be a closterovirus but a new genus of the Potexviridae. The evolution of the picornaviruses based on an analysis of their RNA polymerases and helicases appears to date to the divergence of eukaryotes . Their putative ancestors include the bacterial group II retroelements , the family of HtrA proteases and DNA bacteriophages . Partitiviruses are related to and may have evolved from a totivirus ancestor. Hypoviruses and barnaviruses appear to share an ancestry with the potyvirus and sobemovirus lineages respectively. This analysis also suggests that the dsRNA viruses are not closely related to each other but instead belong to four additional classes—Birnaviridae, Cystoviridae, Partitiviridae, and Reoviridae—and one additional order (Totiviridae) of one of the classes of positive ssRNA viruses in the same subphylum as the positive-strand RNA viruses. One study has suggested that there are two large clades: One includes the families Caliciviridae , Flaviviridae , and Picornaviridae and a second that includes the families Alphatetraviridae , Birnaviridae , Cystoviridae , Nodaviridae , and Permutotretraviridae . These viruses have multiple types of genome ranging from a single RNA molecule up to eight segments. Despite their diversity it appears that they may have originated in arthropods and to have diversified from there. A number of satellite viruses—viruses that require the assistance of another virus to complete their life cycle—are also known. Their taxonomy has yet to be settled. The following four genera have been proposed for positive sense single stranded RNA satellite viruses that infect plants— Albetovirus , Aumaivirus , Papanivirus and Virtovirus . A family— Sarthroviridae which includes the genus Macronovirus —has been proposed for the positive sense single stranded RNA satellite viruses that infect arthropods .This is the single largest group of RNA viruses and has been organized by the ICTV into the phyla Kitrinoviricota , Lenarviricota , and Pisuviricota in the kingdom Orthornavirae and realm Riboviria . Positive-strand RNA viruses can also be classified based on the RNA-dependent RNA polymerase. Three groups have been recognised: Bymoviruses, comoviruses, nepoviruses, nodaviruses, picornaviruses, potyviruses, sobemoviruses and a subset of luteoviruses (beet western yellows virus and potato leafroll virus)—the picorna like group (Picornavirata). Carmoviruses, dianthoviruses, flaviviruses, pestiviruses, statoviruses, tombusviruses, single-stranded RNA bacteriophages, hepatitis C virus and a subset of luteoviruses (barley yellow dwarf virus)—the flavi like group (Flavivirata). Alphaviruses, carlaviruses, furoviruses, hordeiviruses, potexviruses, rubiviruses, tobraviruses, tricornaviruses, tymoviruses, apple chlorotic leaf spot virus, beet yellows virus and hepatitis E virus—the alpha like group (Rubivirata). A division of the alpha-like (Sindbis-like) supergroup on the basis of a novel domain located near the N termini of the proteins involved in viral replication has been proposed. The two groups proposed are: the 'altovirus' group (alphaviruses, furoviruses, hepatitis E virus, hordeiviruses, tobamoviruses, tobraviruses, tricornaviruses and probably rubiviruses); and the 'typovirus' group (apple chlorotic leaf spot virus, carlaviruses, potexviruses and tymoviruses). The alpha like supergroup can be further divided into three clades : the rubi-like, tobamo-like, and tymo-like viruses. Additional work has identified five groups of positive-stranded RNA viruses containing four, three, three, three, and one order(s), respectively. These fourteen orders contain 31 virus families (including 17 families of plant viruses) and 48 genera (including 30 genera of plant viruses). This analysis suggests that alphaviruses and flaviviruses can be separated into two families—the Togaviridae and Flaviridae, respectively—but suggests that other taxonomic assignments, such as the pestiviruses, hepatitis C virus, rubiviruses, hepatitis E virus, and arteriviruses, may be incorrect. The coronaviruses and toroviruses appear to be distinct families in distinct orders and not distinct genera of the same family as currently classified. The luteoviruses appear to be two families rather than one, and apple chlorotic leaf spot virus appears not to be a closterovirus but a new genus of the Potexviridae. The evolution of the picornaviruses based on an analysis of their RNA polymerases and helicases appears to date to the divergence of eukaryotes . Their putative ancestors include the bacterial group II retroelements , the family of HtrA proteases and DNA bacteriophages . Partitiviruses are related to and may have evolved from a totivirus ancestor. Hypoviruses and barnaviruses appear to share an ancestry with the potyvirus and sobemovirus lineages respectively. The evolution of the picornaviruses based on an analysis of their RNA polymerases and helicases appears to date to the divergence of eukaryotes . Their putative ancestors include the bacterial group II retroelements , the family of HtrA proteases and DNA bacteriophages . Partitiviruses are related to and may have evolved from a totivirus ancestor. Hypoviruses and barnaviruses appear to share an ancestry with the potyvirus and sobemovirus lineages respectively. This analysis also suggests that the dsRNA viruses are not closely related to each other but instead belong to four additional classes—Birnaviridae, Cystoviridae, Partitiviridae, and Reoviridae—and one additional order (Totiviridae) of one of the classes of positive ssRNA viruses in the same subphylum as the positive-strand RNA viruses. One study has suggested that there are two large clades: One includes the families Caliciviridae , Flaviviridae , and Picornaviridae and a second that includes the families Alphatetraviridae , Birnaviridae , Cystoviridae , Nodaviridae , and Permutotretraviridae . These viruses have multiple types of genome ranging from a single RNA molecule up to eight segments. Despite their diversity it appears that they may have originated in arthropods and to have diversified from there. A number of satellite viruses—viruses that require the assistance of another virus to complete their life cycle—are also known. Their taxonomy has yet to be settled. The following four genera have been proposed for positive sense single stranded RNA satellite viruses that infect plants— Albetovirus , Aumaivirus , Papanivirus and Virtovirus . A family— Sarthroviridae which includes the genus Macronovirus —has been proposed for the positive sense single stranded RNA satellite viruses that infect arthropods .There are twelve families and a number of unassigned genera and species recognised in this group. There are three orders and 34 families recognised in this group. In addition, there are a number of unclassified species and genera. Satellite viruses An unclassified astrovirus/hepevirus-like virus has also been described. With the exception of the Hepatitis D virus , this group of viruses has been placed into a single phylum— Negarnaviricota . This phylum has been divided into two subphyla— Haploviricotina and Polyploviricotina . Within the subphylum Haploviricotina four classes are currently recognised: Chunqiuviricetes , Milneviricetes , Monjiviricetes and Yunchangviricetes . In the subphylum Polyploviricotina two classes are recognised: Ellioviricetes and Insthoviricetes . Six classes, seven orders and twenty four families are currently recognized in this group. A number of unassigned species and genera are yet to be classified.

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Virus quantification

Virus quantification is counting or calculating the number of virus particles (virions) in a sample to determine the virus concentration. It is used in both research and development (R&D) in academic and commercial laboratories as well as in production situations where the quantity of virus at various steps is an important variable that must be monitored. For example, the production of virus-based vaccines , recombinant proteins using viral vectors, and viral antigens all require virus quantification to continually monitor and/or modify the process in order to optimize product quality and production yields and to respond to ever changing demands and applications. Other examples of specific instances where viruses need to be quantified include clone screening, multiplicity of infection (MOI) optimization, and adaptation of methods to cell culture . There are many ways to categorize virus quantification methods. Here, the methods are grouped according to what is being measured and in what biological context. For example, cell-based assays typically measure infectious units (active virus). Other methods may measure the concentration of viral proteins, DNA, RNA, or molecular particles, but not necessarily measure infectivity. Each method has its own advantages and disadvantages, which often determines which method is used for specific applications. Plaque -based assays are a commonly used method to determine virus concentration in terms of infectious dose . Plaque assays determine the number of plaque forming units (PFU) in a virus sample, which is one measure of virus quantity. This assay is based on a microbiological method conducted in petri dishes or multi-well cell culture plates. Specifically, a confluent monolayer of host cells is infected by applying a sample containing the virus at varying dilutions and then covered with a semi-solid medium , such as agar or carboxymethyl cellulose , to prevent the virus infection from spreading indiscriminately, as would occur in a liquid medium. A viral plaque is formed after a virus infects a cell within the fixed cell monolayer. The virus-infected cell will lyse and spread the infection to adjacent cells, where the infection-to-lysis cycle is repeated. This will create an area of infected, lysed cells (viral plaque) surrounded by uninfected, intact cells. The plaque can be seen with an optical microscope or visually using cell staining techniques (e.g., staining with a crystal violet solution to visualize intact vs. lysed cells). Plaque formation can take 3–14 days, depending on the virus being analyzed. Plaques are generally counted manually, and the plaque count, in combination with the dilution factor of the infection solution (the sample initially applied to the cells), is used to calculate the number of plaque forming units per sample unit volume (PFU/mL). The PFU/mL number represents the concentration of infectious virus particles within the sample and is based on the assumption that each plaque formed is representative of an initial infection by one infectious virus particle. The focus forming assay (FFA) is a variation of the plaque assay, but instead of depending on cell lysis in order to detect plaque formation, the FFA employs immunostaining techniques using fluorescently labeled antibodies specific for a viral antigen to detect infected host cells and infectious virus particles before an actual plaque is formed. The FFA is particularly useful for quantifying classes of viruses that do not lyse the cell membranes, as these viruses would not be amenable to the plaque assay. Like the plaque assay, host cell monolayers are infected with various dilutions of the virus sample and allowed to incubate for a relatively brief incubation period (e.g., 24–72 hours) under a semisolid overlay medium that restricts the spread of infectious virus, creating localized clusters (foci) of infected cells. Plates are subsequently probed with fluorescently labeled antibodies against a viral antigen, and fluorescence microscopy is used to count and quantify the number of foci. The FFA method typically yields results in less time than plaque assays or fifty-percent-tissue-culture-infective-dose (TCID 50 ) assays (see below), but it can be more expensive in terms of required reagents and equipment. Assay completion time is also dependent on the size of area that the user is counting. A larger area will require more time but can provide a more accurate representation of the sample. Results of the FFA are expressed as focus forming units per milliliter, or FFU/mL. The TCID 50 (50% Tissue Culture Infectious Dose) assay is the measure of infectious virus titer . This endpoint dilution assay quantifies the amount of virus required to kill 50% of infected hosts or to produce a cytopathic effect in 50% of inoculated tissue culture cells. This assay may be more common in clinical research applications where the lethal dose of virus must be determined or if the virus does not form plaques. [ citation needed ] When used in the context of tissue culture, host cells are plated and serial dilutions of the virus are added. After incubation, the percentage of cell death (i.e. infected cells) is manually observed and recorded for each virus dilution, and results are used to mathematically calculate a TCID 50 result. Due to distinct differences in assay methods and principles, TCID 50 and pfu/mL or other infectivity assay results are not equivalent. This method can take up to a week due to cell infectivity time. Two methods commonly used to calculate TCID 50 (can also be used to calculate other types of 50% endpoint such EC50 , IC50 , and LD50 ) are: The theoretical relationship between TCID 50 and PFU is approximately 0.69 PFU = 1 TCID 50 based on the Poisson distribution , a probability distribution which describes how many random events (virus particles) occurring at a known average rate (virus titer) are likely to occur in a fixed space (the amount of virus medium in a well). However, it must be emphasized that in practice, this relationship may not hold even for the same virus + cell combination, as the two types of assay are set up differently and virus infectivity is very sensitive to various factors such as cell age, overlay media, etc. But the following reference defines the relationship differently: From ATTC : "Assuming that the same cell system is used, that the virus forms plaques on those cells, and that no procedures are added which would inhibit plaque formation, 1 mL of virus stock would be expected to have about half of the number of plaque forming units (PFUs) as TCID 50 . This is only an estimate but is based on the rationale that the limiting dilution which would infect 50% of the cell layers challenged would often be expected to initially produce a single plaque in the cell layers which become infected. In some instances, two or more plaques might by chance form, and thus the actual number of PFUs should be determined experimentally. "Mathematically, the expected PFUs would be somewhat greater than one-half the TCID 50 , since the negative tubes in the TCID 50 represent zero plaque forming units and the positive tubes each represent one or more plaque forming units. A more precise estimate is obtained by applying the Poisson distribution. Where P ( o ) {\displaystyle P(o)} is the proportion of negative tubes and m is the mean number of infectious units per volume (PFU/ml), P ( o ) = exp ⁡ ( − m ) {\displaystyle P(o)=\exp(-m)} . For any titer expressed as a TCID 50 , P ( o ) = 0.5 {\displaystyle P(o)=0.5} . Thus exp ⁡ ( − m ) = 0.5 {\displaystyle \exp(-m)=0.5} and m = − ln ⁡ 0.5 {\displaystyle m=-\ln 0.5} which is ~ 0.7. "Therefore, one could multiply the TCID 50 titer (per ml) by 0.7 to predict the mean number of PFU/ml. When actually applying such calculations, remember the calculated mean will only be valid if the changes in protocol required to visualize plaques do not alter the expression of infectious virus as compared with expression under conditions employed for TCID 50 . "Thus as a working estimate, one can assume material with a TCID 50 of 1 × 10 5 TCID 50 /mL will produce 0.7 × 10 5 PFUs/mL." Plaque -based assays are a commonly used method to determine virus concentration in terms of infectious dose . Plaque assays determine the number of plaque forming units (PFU) in a virus sample, which is one measure of virus quantity. This assay is based on a microbiological method conducted in petri dishes or multi-well cell culture plates. Specifically, a confluent monolayer of host cells is infected by applying a sample containing the virus at varying dilutions and then covered with a semi-solid medium , such as agar or carboxymethyl cellulose , to prevent the virus infection from spreading indiscriminately, as would occur in a liquid medium. A viral plaque is formed after a virus infects a cell within the fixed cell monolayer. The virus-infected cell will lyse and spread the infection to adjacent cells, where the infection-to-lysis cycle is repeated. This will create an area of infected, lysed cells (viral plaque) surrounded by uninfected, intact cells. The plaque can be seen with an optical microscope or visually using cell staining techniques (e.g., staining with a crystal violet solution to visualize intact vs. lysed cells). Plaque formation can take 3–14 days, depending on the virus being analyzed. Plaques are generally counted manually, and the plaque count, in combination with the dilution factor of the infection solution (the sample initially applied to the cells), is used to calculate the number of plaque forming units per sample unit volume (PFU/mL). The PFU/mL number represents the concentration of infectious virus particles within the sample and is based on the assumption that each plaque formed is representative of an initial infection by one infectious virus particle. The focus forming assay (FFA) is a variation of the plaque assay, but instead of depending on cell lysis in order to detect plaque formation, the FFA employs immunostaining techniques using fluorescently labeled antibodies specific for a viral antigen to detect infected host cells and infectious virus particles before an actual plaque is formed. The FFA is particularly useful for quantifying classes of viruses that do not lyse the cell membranes, as these viruses would not be amenable to the plaque assay. Like the plaque assay, host cell monolayers are infected with various dilutions of the virus sample and allowed to incubate for a relatively brief incubation period (e.g., 24–72 hours) under a semisolid overlay medium that restricts the spread of infectious virus, creating localized clusters (foci) of infected cells. Plates are subsequently probed with fluorescently labeled antibodies against a viral antigen, and fluorescence microscopy is used to count and quantify the number of foci. The FFA method typically yields results in less time than plaque assays or fifty-percent-tissue-culture-infective-dose (TCID 50 ) assays (see below), but it can be more expensive in terms of required reagents and equipment. Assay completion time is also dependent on the size of area that the user is counting. A larger area will require more time but can provide a more accurate representation of the sample. Results of the FFA are expressed as focus forming units per milliliter, or FFU/mL. The TCID 50 (50% Tissue Culture Infectious Dose) assay is the measure of infectious virus titer . This endpoint dilution assay quantifies the amount of virus required to kill 50% of infected hosts or to produce a cytopathic effect in 50% of inoculated tissue culture cells. This assay may be more common in clinical research applications where the lethal dose of virus must be determined or if the virus does not form plaques. [ citation needed ] When used in the context of tissue culture, host cells are plated and serial dilutions of the virus are added. After incubation, the percentage of cell death (i.e. infected cells) is manually observed and recorded for each virus dilution, and results are used to mathematically calculate a TCID 50 result. Due to distinct differences in assay methods and principles, TCID 50 and pfu/mL or other infectivity assay results are not equivalent. This method can take up to a week due to cell infectivity time. Two methods commonly used to calculate TCID 50 (can also be used to calculate other types of 50% endpoint such EC50 , IC50 , and LD50 ) are: The theoretical relationship between TCID 50 and PFU is approximately 0.69 PFU = 1 TCID 50 based on the Poisson distribution , a probability distribution which describes how many random events (virus particles) occurring at a known average rate (virus titer) are likely to occur in a fixed space (the amount of virus medium in a well). However, it must be emphasized that in practice, this relationship may not hold even for the same virus + cell combination, as the two types of assay are set up differently and virus infectivity is very sensitive to various factors such as cell age, overlay media, etc. But the following reference defines the relationship differently: From ATTC : "Assuming that the same cell system is used, that the virus forms plaques on those cells, and that no procedures are added which would inhibit plaque formation, 1 mL of virus stock would be expected to have about half of the number of plaque forming units (PFUs) as TCID 50 . This is only an estimate but is based on the rationale that the limiting dilution which would infect 50% of the cell layers challenged would often be expected to initially produce a single plaque in the cell layers which become infected. In some instances, two or more plaques might by chance form, and thus the actual number of PFUs should be determined experimentally. "Mathematically, the expected PFUs would be somewhat greater than one-half the TCID 50 , since the negative tubes in the TCID 50 represent zero plaque forming units and the positive tubes each represent one or more plaque forming units. A more precise estimate is obtained by applying the Poisson distribution. Where P ( o ) {\displaystyle P(o)} is the proportion of negative tubes and m is the mean number of infectious units per volume (PFU/ml), P ( o ) = exp ⁡ ( − m ) {\displaystyle P(o)=\exp(-m)} . For any titer expressed as a TCID 50 , P ( o ) = 0.5 {\displaystyle P(o)=0.5} . Thus exp ⁡ ( − m ) = 0.5 {\displaystyle \exp(-m)=0.5} and m = − ln ⁡ 0.5 {\displaystyle m=-\ln 0.5} which is ~ 0.7. "Therefore, one could multiply the TCID 50 titer (per ml) by 0.7 to predict the mean number of PFU/ml. When actually applying such calculations, remember the calculated mean will only be valid if the changes in protocol required to visualize plaques do not alter the expression of infectious virus as compared with expression under conditions employed for TCID 50 . "Thus as a working estimate, one can assume material with a TCID 50 of 1 × 10 5 TCID 50 /mL will produce 0.7 × 10 5 PFUs/mL." There are several variations of protein- and antibody-based virus quantification assays. In general, these methods quantify either the amount of all protein or the amount of a specific virus protein in the sample rather than the number of infected cells or virus particles. Quantification commonly relies on colorimetric or fluorescence detection. Some assay variations quantify proteins directly in a sample, while other variations require host cell infection and incubation to allow virus growth prior to quantification. The variation used depends primarily on the amount of protein (i.e. viral protein) in the initial sample and the sensitivity of the assay itself. If incubation and virus growth are required, cell and/or virus lysis/digestion are often conducted prior to analysis. Most protein-based methods are relatively fast and sensitive [ citation needed ] but require quality standards for accurate calibration, and quantify protein, not actual virus particle concentrations. Below are specific examples of widely used protein-based assays. The hemagglutination assay (HA) is a common non-fluorescence protein quantification assay specific for influenza . It relies on the fact that hemagglutinin , a surface protein of influenza viruses, agglutinates red blood cells (i.e. causes red blood cells to clump together). In this assay, dilutions of an influenza sample are incubated with a 1% erythrocyte solution for one hour and the virus dilution at which agglutination first occurs is visually determined. The assay produces a result of hemagglutination units (HAU), with typical PFU to HAU ratios in the 10 6 range. This assay takes ~1–2 hours to complete. The hemagglutination inhibition assay is a common variation of the HA assay used to measure flu-specific antibody levels in blood serum. In this variation, serum antibodies to the influenza virus will interfere with the virus attachment to red blood cells. Therefore, hemagglutination is inhibited when antibodies are present at a sufficient concentration. The bicinchoninic acid assay (BCA; a.k.a. Smith assay) is based on a simple colorimetric measurement and is a commonly used protein quantification assay. BCA is similar to the Lowry or Bradford protein assays. The BCA assay reagent was first developed and made commercially by Pierce Chemical Company (now owned by Thermo Fisher Scientific ) which held the patent until 2006. In the BCA assay, a protein's peptide bonds quantitatively reduce Cu 2+ to Cu 1+ , which produces a light blue color. BCA chelates Cu 1+ at a 2:1 ratio resulting in a more intensely colored species that absorbs at562 nm. Absorbance of a sample at 562 nm is used to determine the bulk protein concentration in the sample. Assay results are compared with known standard curves after analysis with a spectrophotometer or plate reader . Total assay time is 30 minutes to one hour. While this assay is ubiquitous and fast, it lacks specificity to viral proteins since it counts all protein in the sample. Thus the virus preparation to be quantified must contain very low levels of host cell proteins. Enzyme-linked immunosorbent assay ( ELISA ) is an antibody -based assay that utilizes an antigen -specific antibody chemically linked to an enzyme (or bound to a second antibody linked to an enzyme) to detect the presence of an unknown amount of the antigen (e.g., viral protein) in a sample. The antibody-antigen binding event is detected and/or quantified through the enzyme's ability to convert a substrate reagent to produce a detectable signal that can then be used to calculate the concentration of the target antigen in the sample. Horseradish peroxidase (HRP) is a common enzyme utilized in ELISA schemes due to its ability to amplify signal and increase assay sensitivity. There are many variations, or types of ELISA assays but they can generally be classified as either indirect , competitive , sandwich or reverse . Single radial immunodiffusion assay (SRID), also known as the Mancini method, is a protein assay that detects the amount of specific viral antigen by immunodiffusion in a semi-solid medium (e.g. agar). The medium contains antiserum specific to the antigen of interest and the antigen is placed in the center of the disc. As the antigen diffuses into the medium it creates a precipitate ring that grows until equilibrium is reached. Assay time can range from 10 hours to days depending on equilibration time of the antigen and antibody. The zone diameter from the ring is linearly related to the log of protein concentration and is compared to zone diameters for known protein standards for quantification. The hemagglutination assay (HA) is a common non-fluorescence protein quantification assay specific for influenza . It relies on the fact that hemagglutinin , a surface protein of influenza viruses, agglutinates red blood cells (i.e. causes red blood cells to clump together). In this assay, dilutions of an influenza sample are incubated with a 1% erythrocyte solution for one hour and the virus dilution at which agglutination first occurs is visually determined. The assay produces a result of hemagglutination units (HAU), with typical PFU to HAU ratios in the 10 6 range. This assay takes ~1–2 hours to complete. The hemagglutination inhibition assay is a common variation of the HA assay used to measure flu-specific antibody levels in blood serum. In this variation, serum antibodies to the influenza virus will interfere with the virus attachment to red blood cells. Therefore, hemagglutination is inhibited when antibodies are present at a sufficient concentration. The bicinchoninic acid assay (BCA; a.k.a. Smith assay) is based on a simple colorimetric measurement and is a commonly used protein quantification assay. BCA is similar to the Lowry or Bradford protein assays. The BCA assay reagent was first developed and made commercially by Pierce Chemical Company (now owned by Thermo Fisher Scientific ) which held the patent until 2006. In the BCA assay, a protein's peptide bonds quantitatively reduce Cu 2+ to Cu 1+ , which produces a light blue color. BCA chelates Cu 1+ at a 2:1 ratio resulting in a more intensely colored species that absorbs at562 nm. Absorbance of a sample at 562 nm is used to determine the bulk protein concentration in the sample. Assay results are compared with known standard curves after analysis with a spectrophotometer or plate reader . Total assay time is 30 minutes to one hour. While this assay is ubiquitous and fast, it lacks specificity to viral proteins since it counts all protein in the sample. Thus the virus preparation to be quantified must contain very low levels of host cell proteins.Enzyme-linked immunosorbent assay ( ELISA ) is an antibody -based assay that utilizes an antigen -specific antibody chemically linked to an enzyme (or bound to a second antibody linked to an enzyme) to detect the presence of an unknown amount of the antigen (e.g., viral protein) in a sample. The antibody-antigen binding event is detected and/or quantified through the enzyme's ability to convert a substrate reagent to produce a detectable signal that can then be used to calculate the concentration of the target antigen in the sample. Horseradish peroxidase (HRP) is a common enzyme utilized in ELISA schemes due to its ability to amplify signal and increase assay sensitivity. There are many variations, or types of ELISA assays but they can generally be classified as either indirect , competitive , sandwich or reverse . Single radial immunodiffusion assay (SRID), also known as the Mancini method, is a protein assay that detects the amount of specific viral antigen by immunodiffusion in a semi-solid medium (e.g. agar). The medium contains antiserum specific to the antigen of interest and the antigen is placed in the center of the disc. As the antigen diffuses into the medium it creates a precipitate ring that grows until equilibrium is reached. Assay time can range from 10 hours to days depending on equilibration time of the antigen and antibody. The zone diameter from the ring is linearly related to the log of protein concentration and is compared to zone diameters for known protein standards for quantification. Quantitative PCR utilizes polymerase chain reaction chemistry to amplify viral DNA or RNA to produce high enough concentrations for detection and quantification by fluorescence. In general, quantification by qPCR relies on serial dilutions of standards of known concentration being analyzed in parallel with the unknown samples for calibration and reference. Quantitative detection can be achieved using a wide variety of fluorescence detection strategies, including sequence specific probes or non-specific fluorescent dyes such as SYBR Green . Sequence-specific probes, such as TaqMan Molecular Beacons, or Scorpion, bind only to the DNA of the appropriate sequence produced during the reaction. SYBR Green dye binds to all double-stranded DNA produced during the reaction. While SYBR Green is easy to use, its lack of specificity and lower sensitivity lead most labs to use probe-based qPCR detection schemes. [ citation needed ] There are many variations of qPCR including the comparative threshold method, which allows relative quantification through comparison of Ct values (PCR cycles that show statistically significant increases in the product) from multiple samples that include an internal standard. PCR amplifies all target nucleic acid , including ones originating from intact infectious viral particles, from defective viral particles as well as free nucleic acid in solution. Because of this, qPCR results (expressed in terms of genome copies/mL) are likely to be higher in quantity than TEM results. For viral quantification, the ratio of whole virions to copies of nucleic acid is seldom one to one. This is because during viral replication, the nucleic acid and viral proteins are not always produced in 1:1 ratio and viral assembly process results in complete virions as well as empty capsids and/or excess free viral genomes. In the example of foot-and-mouth disease virus, the ratio of whole virions to RNA copies within an actively replicating host cell is approximately 1:1000. Advantages of titration by qPCR include quick turnaround time (1–4 hours) and sensitivity (can detect much lower concentration of viruses than other methods).Quantitative PCR utilizes polymerase chain reaction chemistry to amplify viral DNA or RNA to produce high enough concentrations for detection and quantification by fluorescence. In general, quantification by qPCR relies on serial dilutions of standards of known concentration being analyzed in parallel with the unknown samples for calibration and reference. Quantitative detection can be achieved using a wide variety of fluorescence detection strategies, including sequence specific probes or non-specific fluorescent dyes such as SYBR Green . Sequence-specific probes, such as TaqMan Molecular Beacons, or Scorpion, bind only to the DNA of the appropriate sequence produced during the reaction. SYBR Green dye binds to all double-stranded DNA produced during the reaction. While SYBR Green is easy to use, its lack of specificity and lower sensitivity lead most labs to use probe-based qPCR detection schemes. [ citation needed ] There are many variations of qPCR including the comparative threshold method, which allows relative quantification through comparison of Ct values (PCR cycles that show statistically significant increases in the product) from multiple samples that include an internal standard. PCR amplifies all target nucleic acid , including ones originating from intact infectious viral particles, from defective viral particles as well as free nucleic acid in solution. Because of this, qPCR results (expressed in terms of genome copies/mL) are likely to be higher in quantity than TEM results. For viral quantification, the ratio of whole virions to copies of nucleic acid is seldom one to one. This is because during viral replication, the nucleic acid and viral proteins are not always produced in 1:1 ratio and viral assembly process results in complete virions as well as empty capsids and/or excess free viral genomes. In the example of foot-and-mouth disease virus, the ratio of whole virions to RNA copies within an actively replicating host cell is approximately 1:1000. Advantages of titration by qPCR include quick turnaround time (1–4 hours) and sensitivity (can detect much lower concentration of viruses than other methods).Tunable resistive pulse sensing (TRPS) is a method that allows high-throughput single particle measurements of individual virus particles, as they are driven through a size-tunable nanopore , one at a time. The technique has the advantage of simultaneously determining the size and concentration, of virus particles in solution with high resolution. This can be used in assessing sample stability and the contribution of aggregates, as well as total viral particle concentration (vp/mL). TRPS-based measurement occurs in an ionic buffer, and no pre-staining of samples is required prior to analysis, thus the technique is more rapid than those which require pre-treatment with fluorescent dyes, with a total preparation and measurement time of less than 10 minutes per sample. [ citation needed ] TRPS-bases virus analysis is commercially available through qViro-X systems , which have the ability to be decontaminated chemically by autoclaving after measurement has occurred. This technique is similar to Single Particle Inductively Coupled Plasma Mass Spectroscopy (SP ICP-MS ) discovered by Degueldre and Favarger (2003) and adapted later for other nanoparticles (e.g. gold colloids, see Degueldre et al. (2006)). The SP ICP-MS was adapted for the analysis of Single Virus Inductively Coupled Plasma Mass Spectroscopy (SV ICPMS) in a comprehensive study i.e. Degueldre (2021). This study suggests to adapting this method for single viruses (SV) identification and counting. With high resolution multi-channel sector field (MC SF) ICP-MS records in SV detection mode, the counting of master and key ions can allow analysis and identification of single viruses. The counting of 2-500 virial units can be performed in 20 s. Analyses are proposed to be carried out in Ar torch for master ions : 12C+, 13C+, 14N+, 15N+, and key ions 31P+, 32S+, 33S+ and 34S+. All interferences are discussed in detail. The use of high resolution MC ICP-MS is recommended while options with anaerobic/aerobic atmospheres are explored to upgrade the analysis when using quadrupole ICP-MS. Application for two virus types (SARS-COV2 and bacteriophage T5) is investigated using time scan and fixed mass analysis for the selected virus ions allowing characterisation of the species using the N/C, P/C and S/C molar ratio's and quantification of their number concentration.Tunable resistive pulse sensing (TRPS) is a method that allows high-throughput single particle measurements of individual virus particles, as they are driven through a size-tunable nanopore , one at a time. The technique has the advantage of simultaneously determining the size and concentration, of virus particles in solution with high resolution. This can be used in assessing sample stability and the contribution of aggregates, as well as total viral particle concentration (vp/mL). TRPS-based measurement occurs in an ionic buffer, and no pre-staining of samples is required prior to analysis, thus the technique is more rapid than those which require pre-treatment with fluorescent dyes, with a total preparation and measurement time of less than 10 minutes per sample. [ citation needed ] TRPS-bases virus analysis is commercially available through qViro-X systems , which have the ability to be decontaminated chemically by autoclaving after measurement has occurred.This technique is similar to Single Particle Inductively Coupled Plasma Mass Spectroscopy (SP ICP-MS ) discovered by Degueldre and Favarger (2003) and adapted later for other nanoparticles (e.g. gold colloids, see Degueldre et al. (2006)). The SP ICP-MS was adapted for the analysis of Single Virus Inductively Coupled Plasma Mass Spectroscopy (SV ICPMS) in a comprehensive study i.e. Degueldre (2021). This study suggests to adapting this method for single viruses (SV) identification and counting. With high resolution multi-channel sector field (MC SF) ICP-MS records in SV detection mode, the counting of master and key ions can allow analysis and identification of single viruses. The counting of 2-500 virial units can be performed in 20 s. Analyses are proposed to be carried out in Ar torch for master ions : 12C+, 13C+, 14N+, 15N+, and key ions 31P+, 32S+, 33S+ and 34S+. All interferences are discussed in detail. The use of high resolution MC ICP-MS is recommended while options with anaerobic/aerobic atmospheres are explored to upgrade the analysis when using quadrupole ICP-MS. Application for two virus types (SARS-COV2 and bacteriophage T5) is investigated using time scan and fixed mass analysis for the selected virus ions allowing characterisation of the species using the N/C, P/C and S/C molar ratio's and quantification of their number concentration.While most flow cytometers do not have sufficient sensitivity, [ citation needed ] there are a few commercially available flow cytometers that can be used for virus quantification. A virus counter quantifies the number of intact virus particles in a sample using fluorescence to detect colocalized proteins and nucleic acids. Samples are stained with two dyes, one specific for proteins and one specific for nucleic acids, and analyzed as they flow through a laser beam. The quantity of particles producing simultaneous events on each of the two distinct fluorescence channels is determined, along with the measured sample flow rate, to calculate a concentration of virus particles (vp/mL). The results are generally similar in absolute quantity to a TEM result. The assay has a linear working range of 10 5 –10 9 vp/mL and an analysis time of ~10 min with a short sample preparation time. [ citation needed ] TEM is a specialized type of microscopy that utilizes a beam of electrons focused with a magnetic field to image a sample. TEM provides imaging with 1000x greater spatial resolution than a light microscope (resolution down to 0.2 nm). An ultrathin, negatively stained sample is required. Sample preparations involve depositing specimens onto a coated TEM grid and negative staining with an electron-opaque liquid. Tissue embedded samples can also be examined if thinly sectioned. Sample preparations vary depending on protocol and user but generally require hours to complete. TEM images can show individual virus particles and quantitative image analysis can be used to determine virus concentrations. These high resolution images also provide particle morphology information that most other methods cannot. Quantitative TEM results will often be greater than results from other assays [ citation needed ] as all particles, regardless of infectivity, are quantified in the reported virus-like particles per mL (vlp/mL) result. Quantitative TEM generally works well for virus concentrations greater than 10 6 particles/mL. Because of high instrument cost and the amount of space and support facilities needed, TEM equipment is only available in a few laboratories.While most flow cytometers do not have sufficient sensitivity, [ citation needed ] there are a few commercially available flow cytometers that can be used for virus quantification. A virus counter quantifies the number of intact virus particles in a sample using fluorescence to detect colocalized proteins and nucleic acids. Samples are stained with two dyes, one specific for proteins and one specific for nucleic acids, and analyzed as they flow through a laser beam. The quantity of particles producing simultaneous events on each of the two distinct fluorescence channels is determined, along with the measured sample flow rate, to calculate a concentration of virus particles (vp/mL). The results are generally similar in absolute quantity to a TEM result. The assay has a linear working range of 10 5 –10 9 vp/mL and an analysis time of ~10 min with a short sample preparation time. [ citation needed ]TEM is a specialized type of microscopy that utilizes a beam of electrons focused with a magnetic field to image a sample. TEM provides imaging with 1000x greater spatial resolution than a light microscope (resolution down to 0.2 nm). An ultrathin, negatively stained sample is required. Sample preparations involve depositing specimens onto a coated TEM grid and negative staining with an electron-opaque liquid. Tissue embedded samples can also be examined if thinly sectioned. Sample preparations vary depending on protocol and user but generally require hours to complete. TEM images can show individual virus particles and quantitative image analysis can be used to determine virus concentrations. These high resolution images also provide particle morphology information that most other methods cannot. Quantitative TEM results will often be greater than results from other assays [ citation needed ] as all particles, regardless of infectivity, are quantified in the reported virus-like particles per mL (vlp/mL) result. Quantitative TEM generally works well for virus concentrations greater than 10 6 particles/mL. Because of high instrument cost and the amount of space and support facilities needed, TEM equipment is only available in a few laboratories.

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influenza virus

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Hemagglutinin esterase

Hemagglutinin esterase ( HEs ) is a glycoprotein that certain enveloped viruses possess and use as an invading mechanism. HEs helps in the attachment and destruction of certain sialic acid receptors that are found on the host cell surface . Viruses that possess HEs include influenza C virus , toroviruses , and coronaviruses of the subgenus Embecovirus (which does not include SARS-like coronaviruses ). HEs is a dimer transmembrane protein consisting of two monomers, each monomer is made of three domains . The three domains are: membrane fusion , esterase , and receptor binding domains. The different HEs enzyme activities include: receptor binding activity, receptor hydrolysis ( esterase ) activity, and membrane fusion activity. The receptor binding activity involve the attachment of HEs to N-acetyl-9-O-acetylneuraminic acid (9-O-Ac- Neu5Ac) of glycolipids and glycoproteins and in turn serve as viral receptor. Receptor hydrolysis (esterase) activity allows virus particles to escape the infected cell by removing an acetyl group from the C9 position of terminal 9-O-Ac-Neu5Ac residues. Membrane fusion activity helps in incorporation viral genome into the host cell cytoplasm by enhancing the attachment between the viral envelope and host cell membrane . In certain influenza viruses , the cell surface consists of both hemagglutinin (HA) and neuraminidase (NA) proteins that encompass enzymatic activities, whereas hemagglutinin-esterase fusion (HEF) proteins have been found to be the primary single spike protein that combines all of the enzymatic activities listed above. HEF proteins have been tested to be high-temperature and low-pH resistant and are the primary source of virulence in viruses. Influenza C have been shown to have unique HEF structure proteins that enhance its ability to infect the host cell compared to influenza A and B . The folding of different domains in the hemagglutinin-esterase protein is important for intracellular transport of proteins from the endoplasmic reticulum to the Golgi apparatus . The presence of oligosaccharide chains in the E, F, and R domains of the HE enzyme also influence intracellular transport. Acylation of the hemagglutinin-esterase has shown to play an essential role in virus particle assembly replication. The exact process of enzyme catalytic cleavage has not yet been detailed out. However, proteolytic cleavage must occur before hemagglutinin-esterase membrane fusion activity. HEF proteins have a unique spikes hexagonal arrangement. This feature is unique to influenza C virus particles. The arrangement is a covering outside of the particle.Certain studies revealed that coronavirus and toroviruses HE was originated from HEF glycoprotein that is found in influenza C viruses which resulted from alteration of hemagglutinin esterase from a trimer into a dimer glycoprotein. During this process, the receptor destroying enzyme acetyl esterase domain stayed unchanged. However, the HE receptor binding domain has been altered in which that the ligand is bound in opposite orientation than before. Both coronavirus and toroviruses HE monomers are made up of the same three domains: central esterase/hydrolase domain, receptor binding lectin domain, and membrane proximal domain which is small. The two monomers of HE dimer in both CoV and ToV involve the same two contact regions (CR 1 and 2). CR 1 contain the receptor binding domain and contact region 2 that contain membrane proximal domain. Yet, ToV HE contacts region 2 contain additional esterase domain. As a result, the CR 2 surface is larger in ToV HEs than in CoV HEs.  However, close to the carboxylic terminal membrane anchor, there are number of disulfide bridges between Cys 385 of coronavirus HE that in turn keep the HE dimers connected to each other. In CoV HE, the two R domain beta sheets are connected to each other forming a continuous intermolecular beta sheet across the dimer interface. On the other hand, in ToV they are oriented at angles. As a result, the beta sheet of receptor binding domain in ToV is more twisted, the contact region 1 is smaller, and the R domains position are shifted along the Beta strands compared to CoV. "Initial studies using electron microscopy showed that the HEF spike forms a mushroom-shaped trimer consisting of a membrane-near stalk and a globular head". Later studies were able to examine and show a higher resolution structure (4.5 à ) of the hemagglutinin esterase fusion trimer using X-ray crystallography of the bromelain -cleaved ectodomain . Both hemagglutinin and hemagglutinin esterase fusion protein are similar in terms of structure and the folding of individual segments. yet, only 12% amino acid are identical between HA and HEF. One significant difference between HE and HEF is the presence of an additional bulge in HEF globular domain (bottom part of the domain) which contains the esterase region. The receptor-binding region in both HA and HEF is found in the upper part of the domain and contain only HEF1 residues. The stalk is made of three 60 à long α- helices that contain: all sequences of HEF2 sequence, and certain HEF1 residues which are N-terminal residues (1–40), and C-terminal residues (367–432). The crystalline structure shows that the way that HEF binds to 9-O-Ac- Neu5Ac is the same as the way HA binds to Neu5Ac. The binding parts include an α-helix, a loop and an extended strand. There are hydrogen bonds between the amino acids (Tyr127, Thr170, Gly172, Tyr227 and Arg292) and the hydroxyl-groups of the ligand, and other residues form the structural support of the receptor binding site. A unique hydrophobic pocket is present in the HEF binding site that in turn accommodates the acetyl methyl group. "Initial studies using electron microscopy showed that the HEF spike forms a mushroom-shaped trimer consisting of a membrane-near stalk and a globular head". Later studies were able to examine and show a higher resolution structure (4.5 à ) of the hemagglutinin esterase fusion trimer using X-ray crystallography of the bromelain -cleaved ectodomain . Both hemagglutinin and hemagglutinin esterase fusion protein are similar in terms of structure and the folding of individual segments. yet, only 12% amino acid are identical between HA and HEF. One significant difference between HE and HEF is the presence of an additional bulge in HEF globular domain (bottom part of the domain) which contains the esterase region. The receptor-binding region in both HA and HEF is found in the upper part of the domain and contain only HEF1 residues. The stalk is made of three 60 à long α- helices that contain: all sequences of HEF2 sequence, and certain HEF1 residues which are N-terminal residues (1–40), and C-terminal residues (367–432). The crystalline structure shows that the way that HEF binds to 9-O-Ac- Neu5Ac is the same as the way HA binds to Neu5Ac. The binding parts include an α-helix, a loop and an extended strand. There are hydrogen bonds between the amino acids (Tyr127, Thr170, Gly172, Tyr227 and Arg292) and the hydroxyl-groups of the ligand, and other residues form the structural support of the receptor binding site. A unique hydrophobic pocket is present in the HEF binding site that in turn accommodates the acetyl methyl group. Glycolipids and glycoproteins contain N-acetyl-9-O-acetylneuraminic acid (9-O-Ac- Neu5Ac) that serve as viral receptor in which HEF binds to. HEF can bind to its receptor whether or not 9-O-Ac-Neu5Ac is attached by an α-2,3 or α-2,6 linkage to the next galactosyl residue. However, host specificity can be affected by terminal N-acetylneuraminic acid (Neu5Ac) and the glycosidic linkage of Neu5Ac. Influenza C virus can recognize 9-O-Ac-Neu5Ac on the surface of different cells due to its unique receptor specificity. The receptor hydrolase activity of HEF aids in the release of virus particles from an infected cell using esterase enzyme that cleaves acetyl from the C9 position of terminal 9-O-Ac-Neu5Ac. The esterase activity of HEF which is part of serine hydrolase class includes a nucleophilic attack of the hydroxyl group (OH) of a serine amino acid, with the help of two other amino acids (histidine and aspartic acid), on the carbonyl group of the substrate. Basic histidine enhances the reactivity of serine by polarizing and deprotonating its hydroxyl group. Along with that, aspartic acid polarizes histidine. X-ray crystallography of the crystalline structure of HEF showed that serine 57, aspartic acid 352 and histidine 355 are the important amino acids for the esterase activity. Also, early studies showed that mutation in Ser57 and His355 residues can completely stop the esterase activity of HEF. The membrane fusion activity between, the viral envelope and endocytic vesicles of host cell, is important to help the virus inject their genome into the cytoplasm of the cell. In order to activate membrane fusion, Cleaving the precursor proteins HEF0 and HA0 into the subunits into the subunits HEF1 and HEF2, then exposing these proteins to acidic pH must be done prior. Acidic pH causes protonation of specific amino acids that initiate certain rearrangement of the proteins.  The protonated amino acid is found to be histidine while its pKa matches the pH of endosome. Studies showed that there is about 0.7 difference in the pH value that trigger the membrane fusion activity from strain to strain of both influenza A and C. Conformational change in HEF structure that occur at low pH results in the separation of fusion peptide from its location at the lower part of the stalk and exposing the outer surface of the molecule, so it can be inserted into the endosomal membrane. Another conformational change occur which cause the bending of the ectodomain to push the fusion peptide toward the transmembrane region. As a result of that, the virus and endosomal membranes get closer, exchanging lipids with hemifusion. Then, opening of a fusion pore and eventually complete merger of both lipid bilayers. Glycolipids and glycoproteins contain N-acetyl-9-O-acetylneuraminic acid (9-O-Ac- Neu5Ac) that serve as viral receptor in which HEF binds to. HEF can bind to its receptor whether or not 9-O-Ac-Neu5Ac is attached by an α-2,3 or α-2,6 linkage to the next galactosyl residue. However, host specificity can be affected by terminal N-acetylneuraminic acid (Neu5Ac) and the glycosidic linkage of Neu5Ac. Influenza C virus can recognize 9-O-Ac-Neu5Ac on the surface of different cells due to its unique receptor specificity. The receptor hydrolase activity of HEF aids in the release of virus particles from an infected cell using esterase enzyme that cleaves acetyl from the C9 position of terminal 9-O-Ac-Neu5Ac. The esterase activity of HEF which is part of serine hydrolase class includes a nucleophilic attack of the hydroxyl group (OH) of a serine amino acid, with the help of two other amino acids (histidine and aspartic acid), on the carbonyl group of the substrate. Basic histidine enhances the reactivity of serine by polarizing and deprotonating its hydroxyl group. Along with that, aspartic acid polarizes histidine. X-ray crystallography of the crystalline structure of HEF showed that serine 57, aspartic acid 352 and histidine 355 are the important amino acids for the esterase activity. Also, early studies showed that mutation in Ser57 and His355 residues can completely stop the esterase activity of HEF. The membrane fusion activity between, the viral envelope and endocytic vesicles of host cell, is important to help the virus inject their genome into the cytoplasm of the cell. In order to activate membrane fusion, Cleaving the precursor proteins HEF0 and HA0 into the subunits into the subunits HEF1 and HEF2, then exposing these proteins to acidic pH must be done prior. Acidic pH causes protonation of specific amino acids that initiate certain rearrangement of the proteins.  The protonated amino acid is found to be histidine while its pKa matches the pH of endosome. Studies showed that there is about 0.7 difference in the pH value that trigger the membrane fusion activity from strain to strain of both influenza A and C. Conformational change in HEF structure that occur at low pH results in the separation of fusion peptide from its location at the lower part of the stalk and exposing the outer surface of the molecule, so it can be inserted into the endosomal membrane. Another conformational change occur which cause the bending of the ectodomain to push the fusion peptide toward the transmembrane region. As a result of that, the virus and endosomal membranes get closer, exchanging lipids with hemifusion. Then, opening of a fusion pore and eventually complete merger of both lipid bilayers. The folding of the hemagglutinin esterase protein and the way that the domains of the protein assembles contribute the transport of membrane and secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Researchers found that trimerization occurs at a point before exiting the ER. The monomers of the HE protein are folded before assembling is possible. Before the hemagglutinin esterase can report to the Golgi, it must be extensively folded and assembled. The structure of hemagglutinin-esterase contributes to the intracellular transport. The hemagglutinin-esterase (HE) glycoprotein of influenza C virus is composed of three domains: a stem domain active in membrane fusion (F), an acetylesterase domain (E), and a receptor-binding domain (R). The protein contains eight N-linked glycosylation sites, four (positions 26, 395, 552, and 603) in the F domain, three (positions 61, 131, and 144) in the E domain, and one (position 189) in the R domain. Oligosaccharide chains in the domains influence intracellular transport. A study showed that it was evident that glycosylation at the two sites in the F domain (positions 26 and 603), in addition to that in the E domain (position 144), is required for the HE molecule to be transported from the endoplasmic reticulum and that mutant HEs lacking one of these three sites failed to undergo the trimer assembly. Oligosaccharides are needed to maintain esterase activity in the F and R domains. If any of the domains lack an oligosaccharide chain, cell surface expression will be affected. It was found that HE monomer have acetylesterase activity because they possessed full-enzyme activity despite lack of an oligosaccharide chain. Oligosaccharide chains are important for intracellular transport, but not for fusion activity. Thus, oligosaccharide chains do not really promote membrane fusion.Acylation of the hemagglutinin-esterase enzyme is necessary for virus replication of influenza C virus . It was found that recombinant virus lacking the acylation site of HEF could be rescued, but viral titers were reduced by one log relative to wild type Flu C. The resulting virus particles have a regular protein composition and no changes in their morphology were obvious by electron microscopy, but their hemolytic activity is reduced indicating a defect in membrane fusion. This is in comparison to several HA protein subtypes that showed similar results. The hemagglutinin-esterase-fusion protein has co- and post-translational modification , such as N-glycosylation, disulfide bond formation, S-acylation and proteolytic cleavage into HEF1 and HEF2 subunits. The HEF protein of influenza C virus has only one stearate attached to a transmembrane cysteine. Whereas HA of influenza A and B virus are associated with membrane rafts, cholesterol- and sphingolipid-enriched nanodomains of the plasma membrane, HEF is thought to localize to the bulk phase of the plasma membrane. The binding and cleavage properties of the influenza C virions hemagglutinin-esterase (CHE) protein for 9- O -acetyl groups on sialic acids have been used in various assays using whole virions . Proteolytic cleavage must occur before any membrane fusion activity of HE because it enables the protein to become activated by low pH. HEF proteins from all influenza C virus strains contain a monobasic cleavage site and are in this respect similar to HAs from human, porcine, equine and low pathogenic avian influenza A viruses. Polybasic cleavage sites that are present in HA of highly pathogenic avian influenza A viruses and processed by the ubiquitous protease furin are not found in any HEF protein. Consequently, replication of influenza C virus is limited to the site of virus infection, the respiratory tract. Unlike other influenza viruses, influenza C virus does not spread to other tissues. Multiple replication cycles of influenza C virus in tissue culture are enabled by addition of trypsin, whereas embryonated eggs produce infectious virus with cleaved HEF. The enzyme catalyzing proteolytic cleavage of HEF has not been identified so far, but since both HA and HEF can be cleaved by trypsin at similar concentrations in vitro (5~20 µg/mL) it seems likely that they are also activated by the same enzymes inside cells. It is very common that HA is compared to HEF in many contexts.The only spike of influenza C virus , the hemagglutinin‐esterase‐fusion glycoprotein (HEF) combines receptor binding, receptor hydrolysis and membrane fusion activities. Like other hemagglutinating glycoproteins of influenza viruses HEF is S‐acylated, but only with stearic acid at a single cysteine located at the cytosol‐facing end of the transmembrane region. This HE protein however, has spikes in its structural organization as well. HEF trimers on the surfaces of both spherical and filamentous particles are arranged in a reticular structure that has been described to consist mainly of hexagons. This feature is unique to influenza C virus particles. Even when HEF is removed from the membrane, the polymeric reticular structure that it originally had can still be seen. These results indicate that the hexagonal arrangement is an intrinsic feature of HEF and does not require other viral proteins such as M1 and that its formation likely involves lateral interaction between the ectodomains of HEF. The formation of the spike arrangement in virus particles acts like a coat around the virus particle by creating and covering it. This is similar to the hydrophobic effect in lipid bilayer membranes where nonpolar molecules and in the interior.HEF N-glycosylation sites are located in figure 1. One sequon is located in HEF2 and six in HEF1. There are three in the globular head and 2 in the hinge region that connects the stalk with the head. The site at position 589 is not glycosylated because it is too close to the membrane-spanning region and cannot be accessed by the oligosaccharide transferase. Glycosylation is crucial for proper folding because it protects it from proteolytic degradation from the host cell and is important for the presentation of antigenic epitopes . The primary structure of HEF in influenza C contains 641 amino acids. It is a typical type 1 transmembrane protein with a short N-terminal, cleavable signal peptide, a long ectodomain, a transmembrane region and a very short cytoplasmic tail. HEF is composed of two subunits, HEF1 consisting of the N-terminal and HEF2 consisting of the transmembrane domain and the cytoplasmic tail. Electron microscopy analyzing the crystal structure of HEF showed that the spike of HEF forms a mushroom-shaped trimer consisting of a membrane-near stalk and a globular head. HEF contains only asparagine -linked carbohydrates which indicates that O-glycosylation does not occur. The location of the individual glycosylation sites in the crystal structure are located on seven of the eight highly conserved N-glycosylation sequons ; one is located in the subunit, HEF2 and the other six are located on the subunit HEF1. Three sites are in the globular head and two are in the hinge region that connects the stalk with the head. There is a site at position 589 on the crystallized structure that is not glycosylated and this may be due close location to the membrane-spanning regions and cannot be accessed by oligosaccharide transferase. The positions of HA in influenza A are quite similar to influenza C by the majority of its carbohydrate positions being located in the larger subunit. The primary structure of HEF in influenza C contains 641 amino acids. It is a typical type 1 transmembrane protein with a short N-terminal, cleavable signal peptide, a long ectodomain, a transmembrane region and a very short cytoplasmic tail. HEF is composed of two subunits, HEF1 consisting of the N-terminal and HEF2 consisting of the transmembrane domain and the cytoplasmic tail. Electron microscopy analyzing the crystal structure of HEF showed that the spike of HEF forms a mushroom-shaped trimer consisting of a membrane-near stalk and a globular head. HEF contains only asparagine -linked carbohydrates which indicates that O-glycosylation does not occur. The location of the individual glycosylation sites in the crystal structure are located on seven of the eight highly conserved N-glycosylation sequons ; one is located in the subunit, HEF2 and the other six are located on the subunit HEF1. Three sites are in the globular head and two are in the hinge region that connects the stalk with the head. There is a site at position 589 on the crystallized structure that is not glycosylated and this may be due close location to the membrane-spanning regions and cannot be accessed by oligosaccharide transferase. The positions of HA in influenza A are quite similar to influenza C by the majority of its carbohydrate positions being located in the larger subunit. In HEF1, 12/15 cysteine residues form 6 intrachain disulfide linkages that stabilizes the globular head domain. There are two cysteine residues, Cys373 and Cys399 that do not form disulfide linkages in the mature protein. They are located at the hinge that connects the globular head with the stalk region. The rest of the cysteine residues form interchain disulfide bonds with HEF in the ectodomain area, near the bottom of the trimer. These disulfide bonds in HEF2 allows the subunit to perform large conformational changes that catalyze membrane fusion. In influenza C, there are 15 cysteine residues in subunit HEF1, 12 of the residues form six intrachain disulfide links that stabilize the globular head domain. Two of the cysteine residues are not required for proper folding and function of HEF and/or they do not form a disulfide linkage in the mature protein located at the connection hinge. The remaining cysteine rescues forms an interchain disulfide bond with the only cysteine residue in the ectodomain of subunit HEF2. This residue is located at the bottom of the trimer. In comparison, influenza A, has similar disulfide bond distributions with one bond connecting HA1 with HA2, the majority are intrachain bonds. The rare occurrence of disulfide bonds in HEF2 and HA2 subunits allows these subunits to perform large conformational changes that catalyze membrane fusion. In influenza C, there are 15 cysteine residues in subunit HEF1, 12 of the residues form six intrachain disulfide links that stabilize the globular head domain. Two of the cysteine residues are not required for proper folding and function of HEF and/or they do not form a disulfide linkage in the mature protein located at the connection hinge. The remaining cysteine rescues forms an interchain disulfide bond with the only cysteine residue in the ectodomain of subunit HEF2. This residue is located at the bottom of the trimer. In comparison, influenza A, has similar disulfide bond distributions with one bond connecting HA1 with HA2, the majority are intrachain bonds. The rare occurrence of disulfide bonds in HEF2 and HA2 subunits allows these subunits to perform large conformational changes that catalyze membrane fusion. During translocation of HEF into the lumen of the ER, the N-terminal signal peptide is cleaved, and carbohydrates are attached. Disulfide bond linkages are formed and remodeled. These modifications affect the folding and trimerization of the molecule. These processes are prerequisites for exiting cargo form the ER. Later on, a fatty acid chain is attached to the cysteine located on the end of the transmembrane region and HEF is cleaved into 2 subunits, this process is essential for virus replication. In comparison, influenza A, B, and C have different spike proteins, the haemagglutinin and the neuraminidase. The HEF surface glycoprotein of influenza C consists of three activities, receptor-binding, receptor-inactivating, and fusion activity. Receptor-binding mediates the attachment of the virus to N-acetyl-9-O-acetylneuraminic acid on the cell surface, receptor-inactivating releases the 9-O-acetyl group from N-acetyl-9-O-acetylneuraminic acid and the fusion activity depends on the post-translational proteolytic cleavage of HEF into two subunits as well as exposure to an acidic environment. In low pH conditions, a conformational change of HEF occurs. In influenza A, the rearrangement of hydrophobic sequences at the N-terminus of subunit HEF2 becomes exposed and induces the fusion of the viral envelope with the membrane of the target cell. Another way that fuses the viral envelope to the host cell is with endocytic vesicles. HEF does not cleave the terminal silica acid residue from carbohydrates but removes the acetyl group from the position C9 of N-acetyl-9-O-acetylneuraminic acid. This is required to release fresh budded virus particles from infected cells, which otherwise would be trapped in the plasma membrane if the receptor is still present Influenza C is distinguishable from influenza A and B by its structural components. There are three amino acids that comprises the cytoplasmic portion of HEF, arginine-threonine-lysine, whereas in influenza A and B consists of ten hemagglutinin amino acids. A post-translational modification of HEF is the acylation with fatty acids. The fatty acid, stearic acid, was detected to be the prevailing fatty acid attached to HEF, whereas the fatty acid palmitic acid was found in all other membrane proteins. Due to the frequent reassortment of strains, it's monosubtypic and stable. This leads to a new strain that aids the virus in adapting better to its host. In comparison, influenza A, B, and C have different spike proteins, the haemagglutinin and the neuraminidase. The HEF surface glycoprotein of influenza C consists of three activities, receptor-binding, receptor-inactivating, and fusion activity. Receptor-binding mediates the attachment of the virus to N-acetyl-9-O-acetylneuraminic acid on the cell surface, receptor-inactivating releases the 9-O-acetyl group from N-acetyl-9-O-acetylneuraminic acid and the fusion activity depends on the post-translational proteolytic cleavage of HEF into two subunits as well as exposure to an acidic environment. In low pH conditions, a conformational change of HEF occurs. In influenza A, the rearrangement of hydrophobic sequences at the N-terminus of subunit HEF2 becomes exposed and induces the fusion of the viral envelope with the membrane of the target cell. Another way that fuses the viral envelope to the host cell is with endocytic vesicles. HEF does not cleave the terminal silica acid residue from carbohydrates but removes the acetyl group from the position C9 of N-acetyl-9-O-acetylneuraminic acid. This is required to release fresh budded virus particles from infected cells, which otherwise would be trapped in the plasma membrane if the receptor is still present Influenza C is distinguishable from influenza A and B by its structural components. There are three amino acids that comprises the cytoplasmic portion of HEF, arginine-threonine-lysine, whereas in influenza A and B consists of ten hemagglutinin amino acids. A post-translational modification of HEF is the acylation with fatty acids. The fatty acid, stearic acid, was detected to be the prevailing fatty acid attached to HEF, whereas the fatty acid palmitic acid was found in all other membrane proteins. Due to the frequent reassortment of strains, it's monosubtypic and stable. This leads to a new strain that aids the virus in adapting better to its host.

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List of laboratory biosecurity incidents

This list of laboratory biosecurity incidents includes accidental laboratory-acquired infections and laboratory releases of lethal pathogens, containment failures in or during transport of lethal pathogens, and incidents of exposure of lethal pathogens to laboratory personnel, improper disposal of contaminated waste, and/or the escape of laboratory animals. The list is grouped by the year in which the accident or incident occurred and does not include every reported laboratory-acquired infection. virus

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Antigenic drift

Antigenic drift is a kind of genetic variation in viruses, arising from the accumulation of mutations in the virus genes that code for virus-surface proteins that host antibodies recognize. This results in a new strain of virus particles that is not effectively inhibited by the antibodies that prevented infection by previous strains. This makes it easier for the changed virus to spread throughout a partially immune population. Antigenic drift occurs in both influenza A and influenza B viruses. (Confusion can arise with two very similar terms, antigenic shift and genetic drift . Antigenic shift is a closely related process; it refers to the more dramatic changes in the virus's surface proteins when the genetic material from two or more viruses mix together. Genetic drift is very different and much more broadly applicable; it refers to the gradual accumulation in any DNA sequence of random mutational changes that do not interfere with the DNA's function and thus that are not seen by natural selection .) The immune system recognizes viruses when antigens on the surfaces of virus particles bind to immune receptors that are specific for these antigens. These receptors can be antibodies in the bloodstream or similar proteins on the surfaces of immune-system cells. This recognition is quite precise, like a key recognizing a lock. After an infection or after vaccination , the body produces many more of these virus-specific immune receptors, which prevent re-infection by this particular strain of the virus; this is called acquired immunity . However, viral genomes are constantly mutating , producing new forms of these antigens. If one of these new forms of an antigen is sufficiently different from the old antigen, it will no longer bind to the antibodies or immune-cell receptors, allowing the mutant virus to infect people who were immune to the original strain of the virus because of prior infection or vaccination. In 1940s, Maurice Hilleman discovered antigenic drift, which is the most common way that influenza viruses change. A second type of change is antigenic shift , also discovered by Hilleman, where the virus acquires a completely new version of one of its surface-protein genes from a distantly related influenza virus. The rate of antigenic drift is dependent on two characteristics: the duration of the epidemic, and the strength of host immunity. A longer epidemic allows for selection pressure to continue over an extended period of time and stronger host immune responses increase selection pressure for development of novel antigens. In the influenza virus , the two relevant antigens are the surface proteins, hemagglutinin and neuraminidase . The hemagglutinin is responsible for binding and entry into host epithelial cells while the neuraminidase is involved in the process of new virions budding out of host cells. Sites recognized on the hemagglutinin and neuraminidase proteins by host immune systems are under constant selective pressure. Antigenic drift allows for evasion of these host immune systems by small mutations in the hemagglutinin and neuraminidase genes that make the protein unrecognizable to pre-existing host immunity. Antigenic drift is this continuous process of genetic and antigenic change among flu strains. In human populations, immune (vaccinated) individuals exert selective pressure for single point mutations in the hemagglutinin gene that increase receptor binding avidity , while naive individuals exert selective pressure for single point mutations that decrease receptor binding avidity. These dynamic selection pressures facilitate the observed rapid evolution in the hemagglutinin gene. Specifically, 18 specific codons in the HA1 domain of the hemagglutinin gene have been identified as undergoing positive selection to change their encoded amino acid. To meet the challenge of antigenic drift, vaccines that confer broad protection against heterovariant strains are needed against seasonal, epidemic and pandemic influenza. As in all RNA viruses , mutations in influenza occur frequently because the virus' RNA polymerase has no proofreading mechanism , resulting in an error rate between 1 × 10 −3 and 8 × 10 −3 substitutions per site per year during viral genome replication. Mutations in the surface proteins allow the virus to elude some host immunity , and the numbers and locations of these mutations that confer the greatest amount of immune escape has been an important topic of study for over a decade. Antigenic drift has been responsible for heavier-than-normal flu seasons in the past, like the outbreak of influenza H3N2 variant A/Fujian/411/2002 in the 2003–2004 flu season. All influenza viruses experience some form of antigenic drift, but it is most pronounced in the influenza A virus. [ citation needed ] Antigenic drift should not be confused with antigenic shift , which refers to reassortment of the virus' gene segments. As well, it is different from random genetic drift , which is an important mechanism in population genetics . [ citation needed ]

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Reassortment

Reassortment is the mixing of the genetic material of a species into new combinations in different individuals. Several different processes contribute to reassortment, including assortment of chromosomes, and chromosomal crossover . It is particularly used when two similar viruses that are infecting the same cell exchange genetic material. In particular, reassortment occurs among influenza viruses , whose genomes consist of eight distinct segments of RNA. These segments act like mini-chromosomes, and each time a flu virus is assembled, it requires one copy of each segment. If a single host (a human, a chicken, or other animal) is infected by two different strains of the influenza virus, then it is possible that new assembled viral particles will be created from segments whose origin is mixed, some coming from one strain and some coming from another. The new reassortant strain will share properties of both of its parental lineages. Reassortment is responsible for some of the major genetic shifts in the history of the influenza virus. In the 1957 " Asian flu " and 1968 " Hong Kong flu " pandemics , flu strains were caused by reassortment between an avian virus and a human virus. In addition, the H1N1 virus responsible for the 2009 swine flu pandemic has an unusual mix of swine, avian and human influenza genetic sequences. The reptarenavirus family, responsible for inclusion body disease in snakes, shows a very high degree of genetic diversity due to reassortment of genetic material from multiple strains in the same infected animal.When influenza viruses are inactivated by UV irradiation or ionizing radiation , they remain capable of multiplicity reactivation in infected host cells. If any of a virus's genome segments is damaged in such a way as to prevent replication or expression of an essential gene , the virus is inviable when it, alone, infects a host cell (single infection). However, when two or more damaged viruses infect the same cell (multiple infection), the infection can often succeed (multiplicity reactivation) due to reassortment of segments, provided that each of the eight genome segments is present in at least one undamaged copy.

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Agricultural show

An agricultural show is a public event exhibiting the equipment, animals, sports and recreation associated with agriculture and animal husbandry . The largest comprise a livestock show (a judged event or display in which breeding stock is exhibited), a trade fair , competitions, and entertainment. The work and practices of farmers , animal fanciers , cowboys , and zoologists may be displayed. The terms agricultural show and livestock show are synonymous with the North American terms county fair and state fair .The first known agricultural show was held by Salford Agricultural Society, Lancashire , in 1768. Since the 19th century, agricultural shows have provided local people with an opportunity to celebrate achievements and enjoy a break from day-to-day routine. With a combination of serious competition and light entertainment, annual shows acknowledged and rewarded the hard work and skill of primary producers and provided a venue for rural families to socialise. City shows also provide city people with an opportunity to engage directly with rural life and food production. Agriculture shows are often enlivened with competitive events, including sheaf tossing , show jumping , food competitions, and tent pegging . Demolition derbies and rodeos are popular in the US and campdrafting and wood chopping are often held in Australia. Studs are generally available for a fee. A livestock show is an event where livestock are exhibited and judged on certain phenotypical breed traits as specified by their respective breed standard . Species of livestock that may be shown include pigs , cattle , sheep , goats , horses , rabbits , llamas , and alpacas . Poultry such as chickens , geese , ducks , turkeys , and pigeons are also shown competitively. There are also competitive shows for dogs , sheepdogs , and cats . Prize-winners at agricultural shows are generally awarded inscribed medals, cups, rosettes or ribbons. The National Museum of Australia has a rare collection of medals documenting the history of agricultural shows and rural industries across Australia. The 111 medals range in date from the mid-19th to the early 20th century and many are associated with significant individuals and organizations. Related to a show is the "field day", with elements of a trade show for machinery, equipment and skills required for broadacre farming. Field days typically do not involve livestock, show bags or sideshows , but may include events such as ploughing competitions not usually associated with shows due to the larger space required. In some communities in northern England Field Days (or Club Days ) have lost their agricultural character and have become community celebrations. The events are good sources of agricultural information, as organizers can arrange for guest speakers to talk on a range of topics, such as the talk on the yellow-flowering alfalfa at the South Dakota field day. Pecan growers were given a talk on insect control by an entomologist at a recent field day at LSU AgCenter's Pecan Research/Extension Station in Shreveport, La. A Landcare survey conducted in 1992/93 revealed that field days in Australia have a high value among local farmers. New Zealand's National Agricultural Fieldays is held annually in June at Mystery Creek , near Hamilton, New Zealand , and attracts 1,000 exhibitors and over 115,000 visitors through its gates. Smaller shows, held annually in New Zealand's towns and communities, are generally called agricultural and pastoral shows ( A&P shows ).A livestock show is an event where livestock are exhibited and judged on certain phenotypical breed traits as specified by their respective breed standard . Species of livestock that may be shown include pigs , cattle , sheep , goats , horses , rabbits , llamas , and alpacas . Poultry such as chickens , geese , ducks , turkeys , and pigeons are also shown competitively. There are also competitive shows for dogs , sheepdogs , and cats . Prize-winners at agricultural shows are generally awarded inscribed medals, cups, rosettes or ribbons. The National Museum of Australia has a rare collection of medals documenting the history of agricultural shows and rural industries across Australia. The 111 medals range in date from the mid-19th to the early 20th century and many are associated with significant individuals and organizations. Related to a show is the "field day", with elements of a trade show for machinery, equipment and skills required for broadacre farming. Field days typically do not involve livestock, show bags or sideshows , but may include events such as ploughing competitions not usually associated with shows due to the larger space required. In some communities in northern England Field Days (or Club Days ) have lost their agricultural character and have become community celebrations. The events are good sources of agricultural information, as organizers can arrange for guest speakers to talk on a range of topics, such as the talk on the yellow-flowering alfalfa at the South Dakota field day. Pecan growers were given a talk on insect control by an entomologist at a recent field day at LSU AgCenter's Pecan Research/Extension Station in Shreveport, La. A Landcare survey conducted in 1992/93 revealed that field days in Australia have a high value among local farmers. New Zealand's National Agricultural Fieldays is held annually in June at Mystery Creek , near Hamilton, New Zealand , and attracts 1,000 exhibitors and over 115,000 visitors through its gates. Smaller shows, held annually in New Zealand's towns and communities, are generally called agricultural and pastoral shows ( A&P shows ).Agricultural shows can be sources of swine influenza transmission in both animal and human populations. Swine influenza is a communicable disease caused by one of several different strains of influenza A virus . Currently, the subtypes of influenza A virus which have been identified in pig populations within the United States are referred to as H1N1, H1N2, and H3N2, all named for their specific genetic makeups. These viruses are extremely common in pigs across various industries, including pig showmanship at agricultural fairs, and are easily passed between pigs when proper hygiene and safety measures are not carried out. It is rare for the virus to spread to humans; however, genetic reassortment can lead to susceptibility among humans. Due to direct contact with infected animals or a contaminated environment, swine influenza strains can be transmitted to human populations. In cases such as the 2009 flu pandemic , the virus was transmitted from swine to humans and caused a global pandemic which led to the deaths of approximately 12,000 people in the United States alone. For this reason, people who work or spend any time in close proximity with pigs are at risk for infection and must follow specific precautions to prevent the spread of swine influenza. Certain populations at agricultural fairs are at increased risk of developing serious complications after swine influenza exposure. For instance, pregnant women are more susceptible to swine influenza and have been shown to have increased rates of swine influenza mortality relative to the general population. Similarly, adolescents , infants , and those with serious medical comorbid conditions have disproportionately high rates of mortality with swine influenza. This is concerning as over 3.5 million children in the United States participate in youth agricultural programs every year. Agricultural fairs can readily lead to swine influenza infection in vulnerable populations because agricultural fairs are frequently visited by entire families, including children and pregnant women. Swine influenza variant viruses have been responsible for several recent outbreaks in the United States associated with contact with pigs at agricultural fairs. The three main Influenza A viruses responsible for these outbreaks are variants of the Influenza A viruses H1N1, H1N2, and H3N2. Recent swine influenza variant outbreaks associated with agriculture fairs in the United States: In the United States, agricultural fairs are a significant exposure source for swine influenza. Certain strains of swine influenza can be transmitted from pig to pig, pig to human, and human to human; swine influenza infection does not always show signs of illness. There are a variety of safety precautions that should be taken at agricultural fairs to prevent the spread of swine influenza. Vulnerable communities including children, people aged 65 years and older, pregnant women, and those suffering from long-term health conditions are groups who should avoid swine exposure due to their high-risk status. The CDC specifically recommends that high-risk individuals with known medical complications avoid interaction with swine at agricultural fairs. It is advised that anyone who develops flu symptoms after swine exposure at agricultural fairs contact their physician for appropriate medical consultation. There are other recommended prevention strategies to reduce the spread of swine influenza at agricultural fairs. It is suggested that people do not bring food into pig areas, do not take any items such as toys, pacifiers or similar items near the pig areas, avoid close contact with any pigs, and wash hands before and after handling pigs. Given the severity of the disease, it is prudent to adopt safety precautions to limit the spread of the swine flu.Agricultural shows can be sources of swine influenza transmission in both animal and human populations. Swine influenza is a communicable disease caused by one of several different strains of influenza A virus . Currently, the subtypes of influenza A virus which have been identified in pig populations within the United States are referred to as H1N1, H1N2, and H3N2, all named for their specific genetic makeups. These viruses are extremely common in pigs across various industries, including pig showmanship at agricultural fairs, and are easily passed between pigs when proper hygiene and safety measures are not carried out. It is rare for the virus to spread to humans; however, genetic reassortment can lead to susceptibility among humans. Due to direct contact with infected animals or a contaminated environment, swine influenza strains can be transmitted to human populations. In cases such as the 2009 flu pandemic , the virus was transmitted from swine to humans and caused a global pandemic which led to the deaths of approximately 12,000 people in the United States alone. For this reason, people who work or spend any time in close proximity with pigs are at risk for infection and must follow specific precautions to prevent the spread of swine influenza.Certain populations at agricultural fairs are at increased risk of developing serious complications after swine influenza exposure. For instance, pregnant women are more susceptible to swine influenza and have been shown to have increased rates of swine influenza mortality relative to the general population. Similarly, adolescents , infants , and those with serious medical comorbid conditions have disproportionately high rates of mortality with swine influenza. This is concerning as over 3.5 million children in the United States participate in youth agricultural programs every year. Agricultural fairs can readily lead to swine influenza infection in vulnerable populations because agricultural fairs are frequently visited by entire families, including children and pregnant women. Swine influenza variant viruses have been responsible for several recent outbreaks in the United States associated with contact with pigs at agricultural fairs. The three main Influenza A viruses responsible for these outbreaks are variants of the Influenza A viruses H1N1, H1N2, and H3N2. Recent swine influenza variant outbreaks associated with agriculture fairs in the United States:In the United States, agricultural fairs are a significant exposure source for swine influenza. Certain strains of swine influenza can be transmitted from pig to pig, pig to human, and human to human; swine influenza infection does not always show signs of illness. There are a variety of safety precautions that should be taken at agricultural fairs to prevent the spread of swine influenza. Vulnerable communities including children, people aged 65 years and older, pregnant women, and those suffering from long-term health conditions are groups who should avoid swine exposure due to their high-risk status. The CDC specifically recommends that high-risk individuals with known medical complications avoid interaction with swine at agricultural fairs. It is advised that anyone who develops flu symptoms after swine exposure at agricultural fairs contact their physician for appropriate medical consultation. There are other recommended prevention strategies to reduce the spread of swine influenza at agricultural fairs. It is suggested that people do not bring food into pig areas, do not take any items such as toys, pacifiers or similar items near the pig areas, avoid close contact with any pigs, and wash hands before and after handling pigs. Given the severity of the disease, it is prudent to adopt safety precautions to limit the spread of the swine flu.Incomplete list of shows in Australia: Ballarat Show Beaudesert Show Bendigo Show Boonah Show Bream Creek Show Camden Show Esk Show Gold Coast Show Gympie District Show Hawkesbury Show Huon Show Kangaroo Valley Show Kalbar Show Kingaroy Show Korumburra Show Mareeba Rodeo and Agricultural Show Melbourne Royal Show Mildura Show Moss Vale Show Mudgeeraba Show Nanango Show Newcastle Regional Show Nowra Show Robertson Show Royal Adelaide Show Royal Bathurst Show Royal Brisbane Show, the Ekka Royal Canberra Show Royal Darwin Show Royal Geelong Show Royal Hobart Show Royal Launceston Show Royal Norfolk Island Show Royal Perth Show Royal Toowoomba Show Royal Queensland Show (Ekka) Sydney Royal Easter Show Wanneroo Agricultural Show Warragul Show Warrnambool Show Gawler ShowIncomplete list of shows in Australia: Ballarat Show Beaudesert Show Bendigo Show Boonah Show Bream Creek Show Camden Show Esk Show Gold Coast Show Gympie District Show Hawkesbury Show Huon Show Kangaroo Valley Show Kalbar Show Kingaroy Show Korumburra Show Mareeba Rodeo and Agricultural Show Melbourne Royal Show Mildura Show Moss Vale Show Mudgeeraba Show Nanango Show Newcastle Regional Show Nowra Show Robertson Show Royal Adelaide Show Royal Bathurst Show Royal Brisbane Show, the Ekka Royal Canberra Show Royal Darwin Show Royal Geelong Show Royal Hobart Show Royal Launceston Show Royal Norfolk Island Show Royal Perth Show Royal Toowoomba Show Royal Queensland Show (Ekka) Sydney Royal Easter Show Wanneroo Agricultural Show Warragul Show Warrnambool Show Gawler ShowIncomplete list of shows in Australia: Ballarat Show Beaudesert Show Bendigo Show Boonah Show Bream Creek Show Camden Show Esk Show Gold Coast Show Gympie District Show Hawkesbury Show Huon Show Kangaroo Valley Show Kalbar Show Kingaroy Show Korumburra Show Mareeba Rodeo and Agricultural Show Melbourne Royal Show Mildura Show Moss Vale Show Mudgeeraba Show Nanango Show Newcastle Regional Show Nowra Show Robertson Show Royal Adelaide Show Royal Bathurst Show Royal Brisbane Show, the Ekka Royal Canberra Show Royal Darwin Show Royal Geelong Show Royal Hobart Show Royal Launceston Show Royal Norfolk Island Show Royal Perth Show Royal Toowoomba Show Royal Queensland Show (Ekka) Sydney Royal Easter Show Wanneroo Agricultural Show Warragul Show Warrnambool Show Gawler Show

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Rhinovirus

Rhinovirus A Rhinovirus B Rhinovirus C Enterovirus A Enterovirus B Enterovirus C Enterovirus D Enterovirus E Enterovirus F Enterovirus G Enterovirus H Enterovirus I Enterovirus J Enterovirus K Enterovirus L The rhinovirus (from the Ancient Greek : ῥίς , romanized : rhis "nose", gen ῥινός , romanized: rhinos "of the nose", and the Latin : vīrus ) is a positive-sense, single-stranded RNA virus belonging to the genus Enterovirus in the family Picornaviridae . Rhinovirus is the most common viral infectious agent in humans and is the predominant cause of the common cold . The three species of rhinovirus (A, B, and C) include at least 165 recognized types that differ according to their surface antigens or genetics. They are among the smallest viruses, with diameters of about 30 nanometers. By comparison, other viruses, such as smallpox and vaccinia , are around ten times larger at about 300 nanometers , while influenza viruses are around 80–120 nm. Rhinoviruses are transmitted through aerosols , respiratory droplets, fomites , and direct person-to-person contact. They primarily infect nasal epithelial cells in the airway and cause mild symptoms such as sore throat, cough, and nasal congestion. However, rhinovirus infection can cause more severe disease in infants, the elderly, and the immunocompromised. Rhinoviruses are also recognized as a major cause of asthma exacerbations. As of April 2024, there are no FDA-approved vaccines or antiviral treatments for rhinovirus infection. In 1953, when a cluster of nurses developed a mild respiratory illness, Winston Price , from the Johns Hopkins University , took nasal passage samples and isolated the first rhinovirus, which he called the JH virus, named after Johns Hopkins. His findings were published in 1956. In 2006, advancements in molecular testing techniques for identifying rhinoviruses in clinical specimens led to the discovery of rhinovirus C species in samples from Queensland, Australia and New York City, United States. The ICTV formally designated RV-C as a separate species in 2009. Rhinoviruses may be spread via airborne aerosols , respiratory droplets and from fomites (contaminated surfaces), including direct person-to-person contact. Rhinoviruses can survive on surfaces such as stainless steel or plastic for several hours. Airborne precautions are likely effective in reducing transmission, while other precautions such as hand-washing or cleaning surfaces with disinfectants are known effective in preventing rhinovirus transmission. Rhinoviruses are the primary cause of the common cold . Symptoms include sore throat , runny nose , nasal congestion , sneezing and cough ; sometimes accompanied by muscle aches , fatigue , malaise , headache , muscle weakness , or loss of appetite . Fever and extreme exhaustion are less common in rhinovirus infection compared to influenza .Rhinoviruses can be detected year-round; however, the incidence of rhinovirus is higher in the autumn and winter, with most infections occurring between September and April. The seasonality may be due to the start of the school year and to people spending more time indoors thereby increasing the chance of transmission of the virus. Lower ambient temperatures, especially outdoors, may also be a factor given that rhinoviruses preferentially replicate at 33 °C (91.4 °F) as opposed to 37 °C (98.6 °F). Other climate factors such as humidity may influence rhinovirus seasonality. Young children (<5 years old) experience a high rate of infection which can be detected in community surveillance studies of children up to 34% of the year. Those most affected by rhinoviruses are infants, the elderly, and immunocompromised people. The primary route of entry for human rhinoviruses is the upper respiratory tract (mouth and nose). Rhinovirus A and B use "major" ICAM-1 (Inter-Cellular Adhesion Molecule 1), also known as CD54 (Cluster of Differentiation 54), on respiratory epithelial cells, as receptors to bind to. Some subgroups under A and B uses the "minor" LDL receptor instead. Rhinovirus C uses cadherin-related family member 3 (CDHR3) to mediate cellular entry. As the virus replicates and spreads, infected cells release distress signals known as chemokines and cytokines (which in turn activate inflammatory mediators). Infection occurs rapidly, with the virus adhering to surface receptors within 15 minutes of entering the respiratory tract. Just over 50% of individuals will experience symptoms within 2 days of infection. Only about 5% of cases will have an incubation period of less than 20 hours, and, at the other extreme, it is expected that 5% of cases would have an incubation period of greater than four and a half days. Human rhinoviruses preferentially grow at 33 °C (91.4 °F), notably colder than the average human body temperature of 37 °C (98.6 °F), hence the virus's tendency to infect the upper respiratory tract , where respiratory airflow is in continual contact with the (colder) extrasomatic environment. Rhinovirus A and C species viruses are more strongly associated with significant illness and wheezing, while rhinovirus B species are more commonly mild or asymptomatic. Rhinovirus was formerly classified as a genus of the family Picornaviridae . The 39th Executive Committee (EC39) of the International Committee on Taxonomy of Viruses (ICTV) met in Canada during June 2007 with new taxonomic proposals. In April 2008, the International Committee on Taxonomy of Viruses voted and ratified the following changes: 2005.264V.04 To remove the following species from the existing genus Rhinovirus in the family Picornaviridae : Human rhinovirus A Human rhinovirus B 2005.265V.04 To assign the following species to the genus Enterovirus in the family Picornaviridae : Human rhinovirus A Human rhinovirus B 2005.266V.04 To remove the existing genus Rhinovirus from the family Picornaviridae . Note: The genus Rhinovirus hereby disappears. Human rhinovirus A Human rhinovirus B Human rhinovirus A Human rhinovirus B The merge is based on the grounds that the two "genera" of viruses are not significantly different in a virological sense. They have identical genome organizations and particle structures, and the phylogeny is not always monophyletic. In July 2009, the ICTV voted and ratified a proposal to add a third species, Human rhinovirus C to the genus Enterovirus . 2008.084V.A.HRV-C-Sp 2008.084V To create a new species named Human rhinovirus C in the genus Enterovirus , family Picornaviridae . There have been a total of 215 taxonomic proposals, which have been approved and ratified since the 8th ICTV Report of 2005. Prior to 2020, enteroviruses (including all rhinoviruses) were categorized according to their serotype . In 2020 the ICTV ratified a proposal to classify all new types based on the genetic diversity of their VP1 gene. Human rhinovirus type names are of the form RV- Xn where X is the rhinovirus species (A, B, or C) and n is an index number. Species A and B have used the same index up to number 100, while species C has always used a separate index. Valid index numbers are as follows: Rhinovirus A: 1, 1B, 2, 7–13, 15, 16, 18–25, 28–34, 36, 38–41, 43–47, 49–51, 53–68, 71, 73–78, 80–82, 85, 88–90, 94–96, 100–108 Rhinovirus B: 3–6, 14, 17, 26, 27, 35, 37, 42, 48, 52, 69, 70, 72, 79, 83, 84, 86, 91–93, 97, 99, 100-104 Rhinovirus C: 1–57Prior to 2020, enteroviruses (including all rhinoviruses) were categorized according to their serotype . In 2020 the ICTV ratified a proposal to classify all new types based on the genetic diversity of their VP1 gene. Human rhinovirus type names are of the form RV- Xn where X is the rhinovirus species (A, B, or C) and n is an index number. Species A and B have used the same index up to number 100, while species C has always used a separate index. Valid index numbers are as follows: Rhinovirus A: 1, 1B, 2, 7–13, 15, 16, 18–25, 28–34, 36, 38–41, 43–47, 49–51, 53–68, 71, 73–78, 80–82, 85, 88–90, 94–96, 100–108 Rhinovirus B: 3–6, 14, 17, 26, 27, 35, 37, 42, 48, 52, 69, 70, 72, 79, 83, 84, 86, 91–93, 97, 99, 100-104 Rhinovirus C: 1–57Rhinoviruses have single-stranded positive sense RNA genomes of between 7200 and 8500 nucleotides in length. At the 5' end of the genome is a virus-encoded protein and, as in mammalian mRNA, there is a 3' poly-A tail . Structural proteins are encoded in the 5' region of the genome and non structural at the 3' end. This is the same for all picornaviruses . The viral particles themselves are not enveloped and are dodecahedral in structure. The viral proteins are translated as a single long polypeptide, which is cleaved into the structural and nonstructural viral proteins. The structure of the virus was determined in 1985 using x-ray crystallography by researcher at Purdue University and the University of Wisconsin led by Michael Rossmann . The virus was crystallized forming cubic crystals with four virus particles in each unit cell ( space group P 2 1 3, no. 198), similar to a cubic close-packed arrangement. Human rhinoviruses are composed of a capsid that contains four viral proteins , VP1, VP2, VP3 and VP4. VP1, VP2, and VP3 form the major part of the protein capsid. The much smaller VP4 protein has a more extended structure, and lies at the interface between the capsid and the RNA genome. There are 60 copies of each of these proteins assembled as an icosahedron . Antibodies are a major defense against infection with the epitopes lying on the exterior regions of VP1-VP3.There are currently no FDA-approved antiviral drugs to treat rhinovirus infections. Several novel antiviral compounds have been tested in clinical trials without sufficient efficacy to progress to FDA approval. Compounds specifically targeted for rhinoviruses, or more broadly, picornaviruses, include the following: Other treatments aiming to reduce rhinovirus infection symptoms include immunomodulatory agents. These may promote beneficial antiviral responses or reduce inflammatory responses associated with symptoms. Interferon-alpha used intranasally was shown to be effective against human rhinovirus infections. However, volunteers treated with this drug experienced some side effects, such as nasal bleeding and began developing tolerance to the drug. Subsequently, research into the treatment was abandoned. Inhaled budesonide has been shown to reduce viral load and pro-inflammatory IL-1β in mice. Omalizumab , which was developed for treatment of severe allergic asthma, has shown evidence in reducing symptom severity of asthma patients infected with rhinovirus. There are no vaccines against these viruses as there is little-to-no cross-protection between serotypes . At least 165 types of human rhinoviruses are known. However, a study of the VP4 protein has shown it to be highly conserved among many serotypes of human rhinovirus, opening up the potential for a future pan-serotype human rhinovirus vaccine. A similar result was obtained with the VP1 protein. Like VP4, VP1 also occasionally "pokes" out of the viral particle, making it available to neutralizing antibodies. Both peptides have been tested on rabbits, resulting in successful generation of cross-serotype antibodies. Rhinovirus genome has a high rate of variability in human circulation, even occurring with genomic sequences that differ up to 30%. Recent studies have identified conserved regions of the rhinovirus genome; this, along with an adjuvanted polyvalent rhinovirus vaccine, shows potential for future development in vaccine treatment. Human rhinovirus can remain infectious for up to three hours outside of a human host. Once the virus is contracted, a person is most contagious within the first three days. Preventative measures such as regular vigorous handwashing with soap and water may aid in avoiding infection. Avoiding touching the mouth, eyes, and nose (the most common entry points for rhinovirus) may also assist prevention. Droplet precautions, which take the form of a surgical mask and gloves, are the method used in major hospitals. As with all respiratory pathogens once presumed to transmit via respiratory droplets, it is highly likely to be carried by the aerosols generated during routine breathing, talking, and even singing. In order to prevent airborne transmission, droplet precautions are insufficient, and routine airborne precautions are necessary.

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List of mammals that can get H5N1

Although a wide variety of bird species have been shown to contract and spread Influenza A virus subtype H5N1 , from waterfowl to poultry and birds of prey , mammalian infections have been of particular interest to researchers due to their potential to develop mutations that increase the risk of mammal-to-mammal spread and transmission to and among humans. Other influenza strains are common among mammals, including humans, but this list only shows those who have been proven to carry H5N1. In October 2022, mink became the first detected mammal able to engage in mammal-to-mammal spread of H5N1 .

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H5N1 genetic structure

H5N1 genetic structure is the molecular structure of the H5N1 virus's RNA . H5N1 is an Influenza A virus subtype. Experts believe it might mutate into a form that transmits easily from person to person. If such a mutation occurs, it might remain an H5N1 subtype or could shift subtypes as did H2N2 when it evolved into the Hong Kong Flu strain of H3N2 . H5N1 has mutated through antigenic drift into dozens of highly pathogenic varieties, but all currently belonging to genotype Z of avian influenza virus H5N1. Genotype Z emerged through reassortment in 2002 from earlier highly pathogenic genotypes of H5N1 that first appeared in China in 1996 in birds and in Hong Kong in 1997 in humans . The "H5N1 viruses from human infections and the closely related avian viruses isolated in 2004 and 2005 belong to a single genotype, often referred to as genotype Z." This infection of humans coincided with an epizootic (an epidemic in nonhumans) of H5N1 influenza in Hong Kong's poultry population. This panzootic (a disease affecting animals of many species especially over a wide area) outbreak was stopped by the killing of the entire domestic poultry population within the territory. The name H5N1 refers to the subtypes of surface antigens present on the virus : hemagglutinin type 5 and neuraminidase type 1. Genotype Z of H5N1 is now the dominant genotype of H5N1. Genotype Z is endemic in birds in southeast Asia and represents a long term pandemic threat. Influenza A viruses have 11 genes on eight separate RNA molecules Orthomyxoviruses : Two of the most important RNA molecules are HA and PB1. HA creates a surface antigen that is especially important in transmissibility . PB1 creates a viral polymerase molecule that is especially important in virulence . The HA RNA molecule contains the HA gene, which codes for hemagglutinin , which is an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. Hemagglutinin forms spikes at the surface of flu viruses that function to attach viruses to cells . This attachment is required for efficient transfer of flu virus genes into cells, a process that can be blocked by antibodies that bind to the hemagglutinin proteins. One genetic factor in distinguishing between human flu viruses and avian flu viruses is that avian influenza HA bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. Swine influenza viruses have the ability to bind both types of sialic acid receptors. Humans have avian-type receptors at very low densities and chickens have human-type receptors at very low densities. Some isolates taken from H5N1-infected human have been observed to have HA mutations at positions 182, 192, 223, 226, or 228 and these mutations have been shown to influence the selective binding of the virus to those previously mentioned sialic acid avian and/or human cell surface receptors. These are the types of mutations that can change a bird flu virus into a flu pandemic virus. A 2008 virulence study that mated in a laboratory an avian flu H5N1 virus that circulated in Thailand in 2004 and a human flu H3N2 virus recovered in Wyoming in 2003 produced 63 viruses representing various potential combinations of human and avian influenza A virus genes. One in five were lethal to mice at low doses. The virus that most closely matched H5N1 for virulence was one with the hemagglutinin (HA), the neuraminidase (NA) and the PB1 avian flu virus RNA molecules with their genes combined with the remaining five RNA molecules (PB2, PA, NP, M, and NS) with their genes from the human flu virus. Both the viruses from the 1957 pandemic and 1968 pandemic carried an avian flu virus PB1 gene. The authors suggest that picking up an avian flu virus PB1 gene may be a critical step in a potential flu pandemic virus arising through reassortment ." PB1 codes for the PB1 protein and the PB1-F2 protein. The PB1 protein is a critical component of the viral polymerase . The PB1-F2 protein is encoded by an alternative open reading frame of the PB1 RNA segment and "interacts with 2 components of the mitochondrial permeability transition pore complex, ANT3 and VDCA1, [sensitizing] cells to apoptosis . [...] PB1-F2 likely contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza." This was discovered by Chen et al. and reported in Nature . "After comparing viruses from the Hong Kong 1997 H5N1 outbreak, one amino acid change (N66S) was found in the PB1-F2 sequence at position 66 that correlated with pathogenicity. This same amino acid change (N66S) was also found in the PB1-F2 protein of the 1918 pandemic A/Brevig Mission/18 virus." The Orthomyxovirus family consists of 7 genera: The "RNA viruses" include the "negative-sense ssRNA viruses" which include the Family "Orthomyxoviridae" which contains five genera, classified by variations in nucleoprotein (NP and M) antigens. One of these is the Genus "Influenzavirus A" which consists of a single species called " Influenza A virus "; one of its subtypes is H5N1 . H5N1 (like the other avian flu viruses) has strains called "highly pathogenic" (HP) and "low-pathogenic" (LP). Avian influenza viruses that cause HPAI are highly virulent , and mortality rates in infected flocks often approach 100%. LPAI viruses are generally of lower virulence, but these viruses can serve as progenitors to HPAI viruses. The current strain of H5N1 responsible for die-offs of domestic birds in Asia is an HPAI strain; other strains of H5N1 occurring elsewhere in the world are less virulent and, therefore, are classified as LPAI strains. All HPAI strains identified to date have involved H5 and H7 subtypes. The distinction concerns pathogenicity in poultry, not humans. Normally a highly pathogenic avian virus is not highly pathogenic to either humans or non-poultry birds. This current strain of H5N1 is unusual in being deadly to so many species. Both "influenza" (meaning flu) and "A" (meaning species type A) can be used as adjectives of the noun "virus" resulting in the noun phrase "influenza A virus"; which when capitalized is the proper noun Influenza A virus which is the name of the species the noun phrase also refers to.A virus is one type of microscopic parasite that infects cells in biological organisms. The Orthomyxoviridae are a family of RNA viruses which infect vertebrates. It includes those viruses which cause influenza . Viruses of this family contain 7 to 8 segments of linear negative-sense single-stranded RNA . "Influenza virus" refers to a subset of Orthomyxoviridae that create influenza . This taxonomic category is not based on phylogenetics . Influenza A viruses have 10 genes on eight separate RNA molecules, which, for the reasons mentioned above, are named PB2, PB1, PA, HA, NP, NA, M, and NS. HA, NA, and M specify the structure of proteins that are most medically relevant as targets for antiviral drugs and antibodies . (An eleventh recently discovered gene called PB1-F2 sometimes creates a protein but is absent from some influenza virus isolates. ) This segmentation of the influenza genome facilitates genetic recombination by segment reassortment in hosts who are infected with two different influenza viruses at the same time. Influenza A virus is the only species in the Influenzavirus A genus of the family Orthomyxoviridae and are negative sense, single-stranded, segmented RNA viruses . "The influenza virus RNA polymerase is a multifunctional complex composed of the three viral proteins PB1, PB2 and PA, which, together with the viral nucleoprotein NP, form the minimum complement required for viral mRNA synthesis and replication." HA codes for hemagglutinin , which is an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. Hemagglutinin forms spikes at the surface of flu viruses that function to attach viruses to cells . This attachment is required for efficient transfer of flu virus genes into cells, a process that can be blocked by antibodies that bind to the hemagglutinin proteins. One genetic factor in distinguishing between human flu viruses and avian flu viruses is that "avian influenza HA bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. Swine influenza viruses have the ability to bind both types of sialic acid receptors." A mutation found in Turkey in 2006 "involves a substitution in one sample of an amino acid at position 223 of the haemoagglutinin receptor protein. This protein allows the flu virus to bind to the receptors on the surface of its host's cells. This mutation has been observed twice before — in a father and son in Hong Kong in 2003, and in one fatal case in Vietnam last year. It increases the virus's ability to bind to human receptors, and decreases its affinity for poultry receptors, making strains with this mutation better adapted to infecting humans." [ according to whom? ] Another mutation in the same sample at position 153 has as yet unknown effects. "Amino acid residues at positions 226 and 228 of the receptor binding pocket of HA appear to determine binding affinity to cell surface receptors and to influence the selective binding of the virus to avian (sialic acid -2,3-NeuAcGal) or human (sialic acid -2,6-NeuAcGal) cell surface receptors. The human A/HK/212/03 and A/HK/213/03 isolates retain the signature associated with avian receptor binding, but they have a unique amino acid substitution (Ser227Ile) within the receptor binding pocket that was not present even in the closely related A/Gs/HK/739.2/02 (genotype Z+) virus." Recent research reveals that humans have avian type receptors at very low densities and chickens have human type receptors at very low densities. Researchers "found that the mutations at two places in the gene, identified as 182 and 192, allow the virus to bind to both bird and human receptors." See research articles Host Range Restriction and Pathogenicity in the Context of Influenza Pandemic (Centers for Disease Control and Prevention, 2006) (by Gabriele Neumann and Yoshihiro Kawaoka) and Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus (American Association for the Advancement of Science, 2006) (by James Stevens, Ola Blixt, Terrence M. Tumpey, Jeffery K. Taubenberger, James C. Paulson , Ian A. Wilson) for further details. NA codes for neuraminidase which is an antigenic glycoprotein enzyme found on the surface of the influenza viruses . It helps the release of progeny viruses from infected cells. Flu drugs Tamiflu and Relenza work by inhibiting some strains of neuraminidase . They were developed based on N2 and N9. "In the N1 form of the protein, a small segment called the 150-loop is inverted, creating a hollow pocket that does not exist in the N2 and N9 proteins. [...] When the researchers looked at how existing drugs interacted with the N1 protein, they found that, in the presence of neuraminidase inhibitors, the loop changed its conformation to one similar to that in the N2 and N9 proteins." HA codes for hemagglutinin , which is an antigenic glycoprotein found on the surface of the influenza viruses and is responsible for binding the virus to the cell that is being infected. Hemagglutinin forms spikes at the surface of flu viruses that function to attach viruses to cells . This attachment is required for efficient transfer of flu virus genes into cells, a process that can be blocked by antibodies that bind to the hemagglutinin proteins. One genetic factor in distinguishing between human flu viruses and avian flu viruses is that "avian influenza HA bind alpha 2-3 sialic acid receptors while human influenza HA bind alpha 2-6 sialic acid receptors. Swine influenza viruses have the ability to bind both types of sialic acid receptors." A mutation found in Turkey in 2006 "involves a substitution in one sample of an amino acid at position 223 of the haemoagglutinin receptor protein. This protein allows the flu virus to bind to the receptors on the surface of its host's cells. This mutation has been observed twice before — in a father and son in Hong Kong in 2003, and in one fatal case in Vietnam last year. It increases the virus's ability to bind to human receptors, and decreases its affinity for poultry receptors, making strains with this mutation better adapted to infecting humans." [ according to whom? ] Another mutation in the same sample at position 153 has as yet unknown effects. "Amino acid residues at positions 226 and 228 of the receptor binding pocket of HA appear to determine binding affinity to cell surface receptors and to influence the selective binding of the virus to avian (sialic acid -2,3-NeuAcGal) or human (sialic acid -2,6-NeuAcGal) cell surface receptors. The human A/HK/212/03 and A/HK/213/03 isolates retain the signature associated with avian receptor binding, but they have a unique amino acid substitution (Ser227Ile) within the receptor binding pocket that was not present even in the closely related A/Gs/HK/739.2/02 (genotype Z+) virus." Recent research reveals that humans have avian type receptors at very low densities and chickens have human type receptors at very low densities. Researchers "found that the mutations at two places in the gene, identified as 182 and 192, allow the virus to bind to both bird and human receptors." See research articles Host Range Restriction and Pathogenicity in the Context of Influenza Pandemic (Centers for Disease Control and Prevention, 2006) (by Gabriele Neumann and Yoshihiro Kawaoka) and Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus (American Association for the Advancement of Science, 2006) (by James Stevens, Ola Blixt, Terrence M. Tumpey, Jeffery K. Taubenberger, James C. Paulson , Ian A. Wilson) for further details.NA codes for neuraminidase which is an antigenic glycoprotein enzyme found on the surface of the influenza viruses . It helps the release of progeny viruses from infected cells. Flu drugs Tamiflu and Relenza work by inhibiting some strains of neuraminidase . They were developed based on N2 and N9. "In the N1 form of the protein, a small segment called the 150-loop is inverted, creating a hollow pocket that does not exist in the N2 and N9 proteins. [...] When the researchers looked at how existing drugs interacted with the N1 protein, they found that, in the presence of neuraminidase inhibitors, the loop changed its conformation to one similar to that in the N2 and N9 proteins." Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses . The segmentation of the influenza genome facilitates genetic recombination by segment reassortment in hosts who are infected with two different influenza viruses at the same time. H5N1 viruses can reassort genes with other strains that co-infect a host organism, such as a pig, bird, or human, and mutate into a form that can pass easily among humans. This is one of many possible paths to a pandemic. The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types. This doesn't mean that one amino acid substitution can cause a pandemic, but it does mean that one amino acid substitution can cause an avian flu virus that is not pathogenic in humans to become pathogenic in humans. H3N2 (" swine flu ") is endemic in pigs in China, and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains. The dominant strain of annual flu virus in January 2006 was H3N2 , which is now resistant to the standard antiviral drugs amantadine and rimantadine . The possibility of H5N1 and H3N2 exchanging genes through reassortment is a major concern. If a reassortment in H5N1 occurs, it might remain an H5N1 subtype, or it could shift subtypes, as H2N2 did when it evolved into the Hong Kong Flu strain of H3N2 . Both the H2N2 and H3N2 pandemic strains contained avian influenza virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish flu' in 1918 appears to be entirely derived from an avian source". In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute , Harbin , China and Professor Robert G. Webster of the St. Jude Children's Research Hospital , Memphis, Tennessee , reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity". Results reported by Dr. Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks. Asian lineage HPAI A(H5N1) is divided into two antigenic clades. "Clade 1 includes human and bird isolates from Vietnam , Thailand , and Cambodia and bird isolates from Laos and Malaysia . Clade 2 viruses were first identified in bird isolates from China , Indonesia , Japan , and South Korea before spreading westward to the Middle East , Europe , and Africa . The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO. Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections: Map A 2007 study focused on the EMA subclade has shed further light on the EMA mutations. "The 36 new isolates reported here greatly expand the amount of whole-genome sequence data available from recent avian influenza (H5N1) isolates. Before our project, GenBank contained only 5 other complete genomes from Europe for the 2004–2006 period, and it contained no whole genomes from the Middle East or northern Africa. Our analysis showed several new findings. First, all European, Middle Eastern, and African samples fall into a clade that is distinct from other contemporary Asian clades, all of which share common ancestry with the original 1997 Hong Kong strain. Phylogenetic trees built on each of the 8 segments show a consistent picture of 3 lineages, as illustrated by the HA tree shown in Figure 1. Two of the clades contain exclusively Vietnamese isolates; the smaller of these, with 5 isolates, we label V1; the larger clade, with 9 isolates, is V2. The remaining 22 isolates all fall into a third, clearly distinct clade, labeled EMA, which comprises samples from Europe, the Middle East, and Africa. Trees for the other 7 segments display a similar topology, with clades V1, V2, and EMA clearly separated in each case. Analyses of all available complete influenza (H5N1) genomes and of 589 HA sequences placed the EMA clade as distinct from the major clades circulating in People's Republic of China, Indonesia, and Southeast Asia." See https://web.archive.org/web/20090709040039/http://who.int/csr/disease/avian_influenza/H5CompleteTree.pdf for a Genetic Tree of 1,342 H5N1 viruses based on their HA gene, showing their clade designations.

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Human mortality from H5N1

The thin line represents average mortality of recent cases. The thicker line represents mortality averaged over all cases. According to WHO: " Assessment of mortality rates and the time intervals between symptom onset and hospitalization and between symptom onset and death suggests that the illness pattern has not changed substantially during the three years. " Human mortality from H5N1 or the human fatality ratio from H5N1 or the case-fatality rate of H5N1 is the ratio of the number of confirmed human deaths resulting from confirmed cases of transmission and infection of H5N1 to the number of those confirmed cases. For example, if there are 100 confirmed cases of humans infected with H5N1 and 50 die, then there is a 50% human fatality ratio (or mortality rate). H5N1 flu is a concern due to the global spread of H5N1 that constitutes a pandemic threat. The majority of H5N1 flu cases have been reported in southeast and east Asia. The case-fatality rate is central to pandemic planning. Estimates of case-fatality (CF) rates for past influenza pandemics have ranged from to 2-3% for the 1918 pandemic to about 0.6% for the 1957 pandemic to 0.2% for the 1968 pandemic . As of 2008, the official World Health Organization estimate for the case-fatality rate for the outbreak of H5N1 avian influenza was approximately 60%. Public health officials in Ontario, Canada argue that the true case-fatality rate could be lower, pointing to studies suggesting it could be 14-33%, and warned that it was unlikely to be as low as the 0.1–0.4% rate that was built into many pandemic plans. H5N1 infections in humans are generally caused by bird to human transmission of the virus. Until May 2006, the WHO estimate of the number of human to human transmissions had been "two or three cases". On May 24, 2006, Dr. Julie L. Gerberding, director of the United States Centers for Disease Control and Prevention in Atlanta , estimated that there had been "at least three." On May 30, Maria Cheng, a WHO spokeswoman, said there were "probably about half a dozen," but that no one "has got a solid number." The cases of suspected human to human transmission that continue to be found have been isolated and contained, and include transmission among members of a family in Sumatra, Indonesia in June 2006 as well as earlier and later instances arising in other countries. However, no pandemic strain of H5N1 has yet been found. The key point is that, at present, "the virus is not spreading efficiently or sustainably among humans." H5N1 vaccines for chickens exist and are sometimes used, although there are many difficulties that make it especially difficult to decide whether vaccination will do more harm than good. In the U.S. H5N1 pre-pandemic vaccines exist in quantities sufficient to inoculate a few million people and might be useful for priming to "boost the immune response to a different H5N1 vaccine tailor-made years later to thwart an emerging pandemic". Japan has inoculated 6,000 health care workers with a pre-pandemic vaccine, and is planning how to proceed with widespread vaccinations, particularly workers who would provide utilities during an outbreak. Switzerland is also considering preemptive vaccination to protect the general public. H5N1 pandemic vaccines and the technologies to rapidly create them are in the H5N1 clinical trials stage but cannot be verified as useful until after a pandemic strain emerges. Efforts to identify the changes that might result in a human-communicable strain have resulted in laboratory-generated H5N1 with substantially greater affinity for human cellular receptors after a change of just two of the H5 surface proteins. Significantly, mouse antibodies were 10 times less potent against the mutants than against the pre-mutated viruses. A graphic exhibiting total cases and mortality incidence is kept current by the WHO at https://web.archive.org/web/20080827215244/http://www.wpro.who.int/NR/rdonlyres/7549914F-5C83-4418-8C20-007ADCC07C61/0/s3.jpg and complements the country-specific information shown below. Country-specific totals of cases and deaths kept current by the WHO may be viewed by clicking through the links provided at Global influenza virological surveillance and the map links provided here Map Gallery Search Results Global influenza virological surveillance (in the Global Health Observatory)A strain of H5N1 killed chickens in 1959 in Scotland and turkeys in 1991 in England . This strain was "highly pathogenic" (deadly to birds) but caused neither illness nor death in humans. "The precursor of the H5N1 influenza virus that spread to humans in 1997 was first detected in Guangdong , China , in 1996, when it caused a moderate number of deaths in geese and attracted very little attention." In 1997, in Hong Kong , 18 humans were infected and 6 died in the first known case of H5N1 infecting humans. H5N1 had evolved from a zero mortality rate to a 33% mortality rate. The first report, in the current wave of HPAI A(H5N1) outbreaks, was of an outbreak that began December 10, 2003 in the Republic of Korea and continued for fourteen weeks. This strain caused asymptomatic infections in humans and may have died out, like the 1959 strain, so that its low mortality level would have little value for predicting the mortality rate of a pandemic evolving from existing HPAI A(H5N1) strains. The apparently extinct strain that caused human deaths from H5N1 in the Northern part of Vietnam in 2003, 2004 and 2005 also had a much lower case mortality rate than the currently existing strains. Changes are occurring in H5N1 that are increasing its pathogenicity in mammals. From inception through 2007, the total number of WHO -confirmed cases was 349, with 216 of those fatalities (as reported by the U.N. on January 15, 2008, confirming earlier deaths) reflecting a 62% fatality rate among WHO -confirmed cases through 2007. These overall figures fail to bring forward fluctuations that have appeared from year to year and in particular geographic areas. In 2005, when a markedly less-lethal strain in Northern Vietnam was responsible for most of the cases reported worldwide, only 42 of 97 people confirmed by the WHO to be infected with H5N1 died — a 43% fatality rate. In 2006, the case fatality ratio was higher among the WHO -confirmed cases, with 79 deaths among 114 confirmed cases. — or 69%. In 2007, 59 of the 86 WHO-confirmed cases ended in death, again a 69% fatality rate. And 24 of the first 31 cases of 2008 (to April 30, 2008) have been fatal, or 77%. The higher total case fatality ratio after the end of 2005 may reflect the widespread circulation in Vietnam of a less-lethal clade of H5N1 in 2005, which was subsequently brought under control. The change was nonetheless interpreted by some as indicating that the virus itself was becoming more deadly over time. In fact, when less-virulent strains die off, the surviving strains are the more virulent. Such difficulties in interpretation underscore that the global case fatality ratio can serve as but a crude and imperfect summary of the current complex situation with its many contributing factors, and not a clear or reliable predictive tool. If and when an influenza pandemic arises from one of the currently circulating pre-pandemic strains of Asian lineage HPAI A(H5N1) , the mortality rates for the resulting human adapted pandemic strain cannot be predicted with any confidence. [ citation needed ]The global case fatality ratio looks only to the official tally of cases confirmed by the WHO . It takes no account of other cases, such as those appearing in press reports. Nor does it reflect any estimate of the global extent of mild, asymptomatic, or other cases which are undiagnosed, unreported by national governments to the WHO , or for any reason cannot be confirmed by the WHO . While the WHO 's case count is clearly the most authoritative, these unavoidable limitations result in an unknown number of cases being omitted from it. The problem of overlooked but genuine cases is emphasized by occasional reports in which later serology reveals antibodies to the H5N1 infection in the blood of persons who were never known to have bird flu, and who then are confirmed by the WHO only retroactively as "cases." Press reports of such cases, often poultry handlers, have appeared in various countries. The largest number of asymptomatic cases was confirmed in 2006 among Korean workers who had assisted in massive culls of H5N1-infected poultry. This relatively benign Korean strain of H5N1 has died out, and the remaining strains of H5N1 have a higher case fatality rate in humans. Unconfirmed cases have a potentially huge impact on the case fatality ratio. This mathematical impact is well understood by epidemiologists, and is easy to see in theory. For example, if for each confirmed case reported by the WHO we assume that there has been another mild and unreported case, the actual global number of cases would be double the current number of WHO -confirmed cases. The fatality ratio for H5N1 infections would then be calculated as the same number of deaths, but divided by a doubled number for total cases, resulting in a hypothetical death ratio of half the currently reported fatality ratio. Such a result would indicate to epidemiologists that the world was confronting an H5N1 virus that is less-lethal than currently assumed, although possibly one that was more contagious and difficult to track. A case-fatality ratio based on an accurate and all-inclusive count of cases would be invaluable, but unfortunately it is impossible to attain. The ability to diagnose every case of H5N1 as it arises does not exist. A few small reported studies have attempted to gather preliminary data on this crucial statistic, by carrying out systematic blood testing of neighbors and contacts of fatal cases in villages where there had been confirmed H5N1 fatalities. In most cases, this testing failed to turn up any overlooked mild cases, though in at least one study mild overlooked cases were identified. These methodical studies of contacts provide significant evidence that the high death rate among confirmed cases in the villages where these studies were carried out cannot be simply attributed to a wholesale failure to detect mild cases. Unfortunately, these studies are likely to remain too few and sketchy to define the complex situation worldwide regarding the lethality of the varying H5N1 clades. The testing and reporting necessary for mass serology studies to determine the incidence of overlooked cases for each existing clade and strain of H5N1 worldwide would be prohibitively costly. [ citation needed ] Hence the precise allocation of infections by the various H5N1 clades across the spectrum including lethal, serious, mild, and asymptomatic cases is likely to remain unknown in both humans and the hundreds of other species it can infect. Scientists are very concerned about what we do know about H5N1 ; but even more concerned about the vast amount of important data that we don't know about H5N1 and its future mutations. [ citation needed ]Review of patient ages and outcomes reveals that H5N1 attacks are especially lethal in pre-adults and young adults, while older victims tend to have milder attacks and to survive. This is consistent with the frequent development of a cytokine storm in the affected. Few persons over 50 years of age seem to have become infected by H5N1, and very few have died following an H5N1 attack. Instead, the age-fatality curve of H5N1 influenza attacks in humans resembles that of the 1918 Spanish pandemic flu, and is the opposite of the mortality curve of seasonal flu strains, since seasonal influenza preferentially kills the elderly and does not kill by cytokine storm . An additional factor which may be active is that H1N1 was the predominant human flu circulating from 1918 until 1957 when the H2N2 strain emerged. Hence those over 50 years old have had the opportunity to be exposed to H1N1, and to develop some immune response to the N1 group contained in that human form of flu. Likewise, annual flu vaccination includes inoculation against a type-A human H1N1 flu, leading to the possibility that the annual flu shot or Flumist inoculation might confer some immunity against H5N1 bird flu infection, and indeed testing the blood of volunteers to look for immune response to H5N1 found that some blood samples showed immunity, but more of the blood samples of persons who had received the flu shot showed an immune response. Another factor complicating any attempt to predict lethality of an eventual pandemic strain is the variability of the resistance of human victims to the pathogen. Many people with the current H5N1 influenza have been blood relatives (but rarely spouses) of other victims. Though this observation seemed to suggest that a familial genetic susceptibility might have played a role in human infection, a study by researchers at the Harvard School of public health noted no significant familial pattern of infection. Clearly, those whose immune systems are best able to fight off the virus are the most likely to survive a pandemic. Those with impairment of the needed immune function, whether from familial genetics or from AIDS, have poorer chances. Moreover, the health care system is generally expected to be overwhelmed throughout a pandemic. Persons needing access to medical care, whether for influenza or for unrelated serious maladies, are unlikely to receive the accustomed care, and without it their survival chances will be reduced. [ citation needed ]Although the actual rate of mortality during a pandemic is unknowable in advance, it is pressing to predict the possible ranges for that lethality responsibly in advance. The pre-pandemic case fatality ratio of over 50% provides a grim backdrop for the fact that the currently circulating H5N1 strains have certain genetic similarities with the Spanish Influenza pandemic virus. In that pandemic, 50 million to 100 million people worldwide were killed during about a year in 1918 and 1919. The highly lethal second and third waves of the 1918 Spanish flu evolved through time into a less virulent and more transmissible human form. Although the overall fatality rate for the Spanish flu is estimated to have been 10% to 20% of the population, [ citation needed ] the lethal waves of the Spanish flu are not reported to have emerged with anything like the over-50% case fatality ratio observed to date in human H5N1 infection. Studies indicating that an H5N1 pandemic may be more pathogenic than was the Spanish flu include a mouse study in which the H5N1 virus elicited significantly higher levels of pro-inflammatory cytokines in the lungs. A human H5N1 pandemic might emerge with initial lethality resembling that over-50% case fatality now observed in pre-pandemic H5N1 human cases, rather than with the still-high 1-2% seen with the Spanish flu or with the lower rates seen in the two more recent influenza pandemics. As a WHO working group noted, Determinants of virulence and transmissibility. The U.S. CDC presents a similarly sobering conclusion authored by Robert G. Webster et al.: Although some mammalian adaptations have been noted, H5N1 remains better adapted for infecting birds than mammalian hosts, which is why the disease it causes is called a bird flu . No pandemic strain of H5N1 has yet been found. The precise nature and extent of the genetic alterations that might change one of the currently circulating avian influenza strains into a human flu strain cannot be known in advance. While many of the current H5N1 strains circulating in birds can generate a dangerous cytokine storm in healthy adult humans, the ultimate pandemic strain might arise from a less-lethal strain, or its current level of lethality might be lost in the adaptation to a human host. If H5N1 mutates so that it can jump from human to human, while maintaining a relatively high level of mortality, how many people could die? Risk communication analysts Peter M. Sandman and Jody Lanard give a round-up of the various estimates: Worldwide mortality estimates range all the way from 2-7.4 million deaths (the "conservatively low" pandemic influenza calculation of a flu modeling expert at the U.S. Centers for Disease Control and Prevention) to 1000 million deaths (the bird flu pandemic prediction of one Russian virologist). The estimates of most H5N1 experts range less widely but still widely. In an H5N1 pandemic, the experts guess that somewhere between a quarter of us and half of us would get sick, and somewhere between one percent and five percent of those who got sick would die — the young and hale as well as the old and frail. If it's a quarter and one percent, that's 16 million dead; if it's a half and five percent, it's 160 million dead. Either way it's a big number. The renowned virus expert Robert G. Webster provided perhaps the most extreme estimate when he acknowledged in March 2006 that H5N1 has the theoretical capacity to mutate into a form that could kill one half of the human population, stating, "Society just can't accept the idea that 50 percent of the population could die. And I think we have to face that possibility". H5N1 may cause more than one influenza pandemic as it is expected to continue mutating in birds regardless of whether humans develop herd immunity to a future pandemic strain. Influenza pandemics from its genetic offspring may include influenza A virus subtypes other than H5N1. While genetic analysis of the H5N1 virus shows that influenza pandemics from its genetic offspring can easily be far more lethal than the Spanish flu pandemic, planning for a future influenza pandemic is based on what can be done and there is no higher Pandemic Severity Index level than a Category 5 pandemic which, roughly speaking, is any pandemic as bad the Spanish flu or worse; and for which all intervention measures are to be used. There "is evidence of at least three independent virulence factors connected with three different genes . It is highly unlikely that all of the high-virulence alleles will simultaneously mutate and disappear if and when the haemagglutinin gene changes so as to make the haemagglutinin molecule better adapted for the human-type (alpha-2,6-linked) receptor (which is a necessary prerequisite in order that a pandemic with H5N1 virus may start). It is more probable that evolutionary adaptation of the haemagglutinin of H5N1 viruses to the human-type receptor will happen without any simultaneous change in those other genetic properties that now are important for explaining the exceptionally high virulence of certain strains of avian-adapted H5N1 influenza virus. The change of the haemagglutinin molecule from avian adaptation to human adaptation must be expected to act as an additional virulence factor because it will enhance the total number of cells that can be infected (per host organism), increase the total rate of virus replication and potentiate the effects of the other virulence factors already present." The H5N1 genes work together in ways we don't yet understand. Influenza research is continuing. The genetic factors that make H5N1 so deadly are only partly understood. Known factors involve the surface antigen encoding gene segments H ( hemagglutinin ) and N ( neuraminidase ) genes (causing it to be H5N1 for example), as well as the matrix M2 gene, and the polymerase genes. A change of just two genes identified in laboratory testing appears to substantially increase the affinity of H5N1 for binding with human cell surface receptors. Neuraminidase is an antigenic glycoprotein enzyme found on the surface of the influenza viruses . It helps the release of progeny viruses from infected cells. Flu drugs Tamiflu and Relenza work by inhibiting some strains of neuraminidase . They were developed based on N2 and N9. "In the N1 form of the protein, a small segment called the 150-loop is inverted, creating a hollow pocket that does not exist in the N2 and N9 proteins. [...] When the researchers looked at how existing drugs interacted with the N1 protein, they found that, in the presence of neuraminidase inhibitors, the loop changed its conformation to one similar to that in the N2 and N9 proteins." The amino acid substitution (Ser31Asn) in the M2 gene in some H5N1 genotypes is associated with amantadine resistance which increases lethality. However the pathogenicity of H5N1/97 was related to the nonstructural (NS) gene. NS codes for two nonstructural proteins (NS1 and NEP). The NS1 gene of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia is believed to be responsible for an enhanced proinflammatory cytokine response (especially TNFa) induced by these viruses in human macrophages. H5N1 NS1 is characterized by a single amino acid change at position 92. By changing the amino acid from glutamic acid to aspartic acid, researchers were able to abrogate the effect of the H5N1 NS1. This single amino acid change in the NS1 gene greatly increased the pathogenicity of the H5N1 influenza virus. This is one genetic factor in why H5N1 is so deadly. [ citation needed ] Polymerase encoding gene segments are also implicated in why H5N1 is so deadly. PA genes code for the PA protein, which is a critical component of the viral polymerase. The PB1 gene codes for the PB1 protein and the PB1-F2 protein. The PB1-F2 protein probably contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza. Until H5N1, all known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a lysine. Recently, some 75% of H5N1 human virus isolates identified in Vietnam had a mutation consisting of Lysine at residue 627 in the PB2 protein; a change believed associated with high levels of virulence. Areas of research to identify the likelihood of rapid or slow evolution to human contagion, or for predicting the greater or lesser likelihood of a rather lethal human-adapted influenza include: [ citation needed ] bird species susceptibility bird migration paths cell-based vaccine development adjuvant testing human vaccine clinical trials bird vaccine testing and use computer simulations of pandemic spread patterns (e.g. will grounding flights help?) detailed shape and gene code analysis of each of the RNA strands for as many flu virus strains as possible and making them available on a database for study wild bird testing for flu viruses testing humans for asymptomatic H5N1 infection training exercises in case of a pandemic Computer simulations and direct gene manipulation have yielded inconclusive results. Scientific advances may attenuate probable lethality. The genetic lethality potential of the initial flu pandemic strain is only one important factor in determining the ultimate outcome in number of human lives lost. Another factor that grows potentially more important with the passage of time is human preparation. For example, no influenza vaccine specific to H5N1 could be produced when it emerged in Hong Kong in 1997, because it was lethal to eggs. Reverse DNA techniques have since made a vaccine possible, and several H5N1 vaccines have been tested and are in production in at least limited quantities. Vaccine development and production facilities are being ramped up, and possible pre-pandemic vaccines are being produced and studied. If a human pandemic does not emerge in the next few years, its eventual emergence may become almost a non-event if a very-effective pre-pandemic vaccine has prepared the population with sufficient herd immunity to blunt its lethality. Indeed, if there is sufficient immunity to stop it at the source, it will not become pandemic. [ citation needed ] As long as the likelihood of protecting the population continues to rise with the passage of time, that likelihood becomes an increasingly important factor in predicting the loss of lives and the amount of economic dislocation that will ultimately occur. In light of human potential to develop herd immunity via vaccination in advance of a pandemic strain, the time that it allows us to do so before it evolves may become as crucial or more crucial to the measure of damage it causes than its own lethality and contagiousness. [ citation needed ] Among the more attractive alternatives available for reducing mortality is vaccine stockpiling and prepandemic vaccination. "Human H5N1 vaccines are currently available and can induce heterotypic immunity. WHO and governments should give urgent consideration to the use of these vaccines for the priming of individuals or communities who would be at greatest risk of infection if an H5N1 influenza pandemic were to emerge." Death associated with influenza A viruses "is usually mediated by superinfection with bacteria, mainly Streptococcus pneumoniae.", suggesting that lethality may be reduced by vaccination against pneumonia. Among others, the Secretary of the United States Department of Health and Human Services (HHS) has repeatedly pointed out the key role of preparation in reducing pandemic mortality, including as examples research in cell- and DNA-based vaccines, as well as stockpiling available vaccines and antivirals and increasing vaccine manufacturing capacity. H5N1 may cause more than one influenza pandemic as it is expected to continue mutating in birds regardless of whether humans develop herd immunity to a future pandemic strain. Influenza pandemics from its genetic offspring may include influenza A virus subtypes other than H5N1. While genetic analysis of the H5N1 virus shows that influenza pandemics from its genetic offspring can easily be far more lethal than the Spanish flu pandemic, planning for a future influenza pandemic is based on what can be done and there is no higher Pandemic Severity Index level than a Category 5 pandemic which, roughly speaking, is any pandemic as bad the Spanish flu or worse; and for which all intervention measures are to be used. There "is evidence of at least three independent virulence factors connected with three different genes . It is highly unlikely that all of the high-virulence alleles will simultaneously mutate and disappear if and when the haemagglutinin gene changes so as to make the haemagglutinin molecule better adapted for the human-type (alpha-2,6-linked) receptor (which is a necessary prerequisite in order that a pandemic with H5N1 virus may start). It is more probable that evolutionary adaptation of the haemagglutinin of H5N1 viruses to the human-type receptor will happen without any simultaneous change in those other genetic properties that now are important for explaining the exceptionally high virulence of certain strains of avian-adapted H5N1 influenza virus. The change of the haemagglutinin molecule from avian adaptation to human adaptation must be expected to act as an additional virulence factor because it will enhance the total number of cells that can be infected (per host organism), increase the total rate of virus replication and potentiate the effects of the other virulence factors already present." The H5N1 genes work together in ways we don't yet understand. Influenza research is continuing. The genetic factors that make H5N1 so deadly are only partly understood. Known factors involve the surface antigen encoding gene segments H ( hemagglutinin ) and N ( neuraminidase ) genes (causing it to be H5N1 for example), as well as the matrix M2 gene, and the polymerase genes. A change of just two genes identified in laboratory testing appears to substantially increase the affinity of H5N1 for binding with human cell surface receptors. Neuraminidase is an antigenic glycoprotein enzyme found on the surface of the influenza viruses . It helps the release of progeny viruses from infected cells. Flu drugs Tamiflu and Relenza work by inhibiting some strains of neuraminidase . They were developed based on N2 and N9. "In the N1 form of the protein, a small segment called the 150-loop is inverted, creating a hollow pocket that does not exist in the N2 and N9 proteins. [...] When the researchers looked at how existing drugs interacted with the N1 protein, they found that, in the presence of neuraminidase inhibitors, the loop changed its conformation to one similar to that in the N2 and N9 proteins." The amino acid substitution (Ser31Asn) in the M2 gene in some H5N1 genotypes is associated with amantadine resistance which increases lethality. However the pathogenicity of H5N1/97 was related to the nonstructural (NS) gene. NS codes for two nonstructural proteins (NS1 and NEP). The NS1 gene of the highly pathogenic avian H5N1 viruses circulating in poultry and waterfowl in Southeast Asia is believed to be responsible for an enhanced proinflammatory cytokine response (especially TNFa) induced by these viruses in human macrophages. H5N1 NS1 is characterized by a single amino acid change at position 92. By changing the amino acid from glutamic acid to aspartic acid, researchers were able to abrogate the effect of the H5N1 NS1. This single amino acid change in the NS1 gene greatly increased the pathogenicity of the H5N1 influenza virus. This is one genetic factor in why H5N1 is so deadly. [ citation needed ] Polymerase encoding gene segments are also implicated in why H5N1 is so deadly. PA genes code for the PA protein, which is a critical component of the viral polymerase. The PB1 gene codes for the PB1 protein and the PB1-F2 protein. The PB1-F2 protein probably contributes to viral pathogenicity and might have an important role in determining the severity of pandemic influenza. Until H5N1, all known avian influenza viruses had a Glu at position 627, while all human influenza viruses had a lysine. Recently, some 75% of H5N1 human virus isolates identified in Vietnam had a mutation consisting of Lysine at residue 627 in the PB2 protein; a change believed associated with high levels of virulence.Areas of research to identify the likelihood of rapid or slow evolution to human contagion, or for predicting the greater or lesser likelihood of a rather lethal human-adapted influenza include: [ citation needed ] bird species susceptibility bird migration paths cell-based vaccine development adjuvant testing human vaccine clinical trials bird vaccine testing and use computer simulations of pandemic spread patterns (e.g. will grounding flights help?) detailed shape and gene code analysis of each of the RNA strands for as many flu virus strains as possible and making them available on a database for study wild bird testing for flu viruses testing humans for asymptomatic H5N1 infection training exercises in case of a pandemic Computer simulations and direct gene manipulation have yielded inconclusive results.Scientific advances may attenuate probable lethality. The genetic lethality potential of the initial flu pandemic strain is only one important factor in determining the ultimate outcome in number of human lives lost. Another factor that grows potentially more important with the passage of time is human preparation. For example, no influenza vaccine specific to H5N1 could be produced when it emerged in Hong Kong in 1997, because it was lethal to eggs. Reverse DNA techniques have since made a vaccine possible, and several H5N1 vaccines have been tested and are in production in at least limited quantities. Vaccine development and production facilities are being ramped up, and possible pre-pandemic vaccines are being produced and studied. If a human pandemic does not emerge in the next few years, its eventual emergence may become almost a non-event if a very-effective pre-pandemic vaccine has prepared the population with sufficient herd immunity to blunt its lethality. Indeed, if there is sufficient immunity to stop it at the source, it will not become pandemic. [ citation needed ] As long as the likelihood of protecting the population continues to rise with the passage of time, that likelihood becomes an increasingly important factor in predicting the loss of lives and the amount of economic dislocation that will ultimately occur. In light of human potential to develop herd immunity via vaccination in advance of a pandemic strain, the time that it allows us to do so before it evolves may become as crucial or more crucial to the measure of damage it causes than its own lethality and contagiousness. [ citation needed ] Among the more attractive alternatives available for reducing mortality is vaccine stockpiling and prepandemic vaccination. "Human H5N1 vaccines are currently available and can induce heterotypic immunity. WHO and governments should give urgent consideration to the use of these vaccines for the priming of individuals or communities who would be at greatest risk of infection if an H5N1 influenza pandemic were to emerge." Death associated with influenza A viruses "is usually mediated by superinfection with bacteria, mainly Streptococcus pneumoniae.", suggesting that lethality may be reduced by vaccination against pneumonia.Among others, the Secretary of the United States Department of Health and Human Services (HHS) has repeatedly pointed out the key role of preparation in reducing pandemic mortality, including as examples research in cell- and DNA-based vaccines, as well as stockpiling available vaccines and antivirals and increasing vaccine manufacturing capacity. Governments and other organizations at many levels and in many places have produced "planning" reports that, among other things, have offered speculation on the mortality rate of an eventual H5N1 pandemic. That speculation has varied widely. One such report stated that "over half a million Americans could die and over 2.3 million could be hospitalized if a moderately severe strain of a pandemic flu virus hits the U.S.". No one knew if "moderately severe" was an accurate guess or not. A report entitled A Killer Flu? projected that, with an assumed (guessed) contraction rate of just 25%, and with a severity rate as low as that of the two lowest severity flu pandemics of the 1900s, a modern influenza A pandemic would cause 180 thousand deaths in the US, while a pandemic equaling the 1918 Spanish flu in level of lethality would cause one million deaths in the US. Again, the report offered no evidence that an emerging H5N1 flu pandemic would be between these figures. The current avian flu, in humans, is fatal in over 50% of confirmed cases. Yet early projections like those above have assumed that such a lethal avian strain would surely lose genes contributing to its lethality in humans as it made the adaptations necessary for ready transmission in the human population. This optimistic assumption cannot be relied on. As the WHO reported in November 2006, initial outbreaks of an H5N1 pandemic could rival the current lethality of over 50%. Further information necessary to make an accurate projection of initial lethality of an H5N1 pandemic does not exist, as no data was collected that could show the pre-pandemic virulence in any potential flu strain until after the last pandemic of the 20th Century. There is no basis for assuming that an H5N1 pandemic will emerge with only the far lower 1-2% lethality rate of the Spanish flu, once assumed to be a worst-case scenario. There exists no reliable prediction of the mortality rate of an H5N1 pandemic, and it would be irresponsible to confine planning to only optimistic assumptions out of step with the currently observed case fatality ratio. [ citation needed ] Although marred by unrealistically low ranges of assumed mortality, the earlier planning reports nevertheless show convincingly that we are not prepared even for a pandemic as severe as the milder pandemics of the past century., let alone the much higher case fatality ratios seen more recently.

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Pandemic

A pandemic ( / p æ n ˈ d ɛ m ɪ k / pan-DEM-ik ) is an epidemic of an infectious disease that has spread across a large region, for instance multiple continents or worldwide, affecting a substantial number of individuals. Widespread endemic diseases with a stable number of infected individuals such as recurrences of seasonal influenza are generally excluded as they occur simultaneously in large regions of the globe rather than being spread worldwide. Throughout human history , there have been a number of pandemics of diseases such as smallpox . The Black Death , caused by the Plague , wiped out up to half of the population of Europe in the 14th century. The term pandemic had not been used then, but was used for later epidemics, including the 1918 H1N1 influenza A pandemic—more commonly known as the Spanish flu —which is the deadliest pandemic in history . The most recent pandemics include the HIV/AIDS pandemic , [lower-alpha 1] the 2009 swine flu pandemic and the COVID-19 pandemic . Almost all these diseases still circulate among humans though their impact now is often far less. In response to the COVID-19 pandemic, 194 member states of the World Health Organization began negotiations on an International Treaty on Pandemic Prevention, Preparedness and Response , with a requirement to submit a draft of this treaty to the 77th World Health Assembly during its 2024 convention. A medical dictionary definition of pandemic is " an epidemic occurring on a scale that crosses international boundaries, usually affecting people on a worldwide scale ". A disease or condition is not a pandemic merely because it is widespread or kills many people; it must also be infectious. For instance, cancer is responsible for many deaths but is not considered a pandemic because the disease is not contagious —i.e. easily transmissible—and not even simply infectious . This definition differs from colloquial usage in that it encompasses outbreaks of relatively mild diseases. The World Health Organization (WHO) has a category of Public Health Emergency of International Concern , defined as " an extraordinary event which is determined to constitute a public health risk to other States through the international spread of disease and to potentially require a coordinated international response ". There is a rigorous process underlying this categorization and a clearly defined trajectory of responses. A WHO-sponsored international body, tasked with preparing an international agreement on pandemic prevention, preparedness and response has defined a pandemic as " the global spread of a pathogen or variant that infects human populations with limited or no immunity through sustained and high transmissibility from person to person, overwhelming health systems with severe morbidity and high mortality, and causing social and economic disruptions, all of which require effective national and global collaboration and coordination for its control ". The word comes from the Greek παν- pan- meaning "all", or "every" and δῆμος demos "people". A common early characteristic of a pandemic is a rapid, sometimes exponential , growth in the number of infections, coupled with a widening geographical spread. WHO utilises different criteria to declare a Public Health Emergency of International Concern (PHEIC), its nearest equivalent to the term pandemic. The potential consequences of an incident are considered, rather than its current status. For example, polio was declared a PHEIC in 2014 even though only 482 cases were reported globally in the previous year; this was justified by concerns that polio might break out of its endemic areas and again become a significant health threat globally. The PHEIC status of polio is reviewed regularly and is ongoing, despite the small number of cases annually. [lower-alpha 2] The end of a pandemic is more difficult to delineate. Generally, past epidemics & pandemics have faded out as the diseases become accepted into people's daily lives and routines, becoming endemic . The transition from pandemic to endemic may be defined based on: - a high proportion of the global population having immunity (through either natural infection or vaccination) fewer deaths health systems step down from emergency status perceived personal risk is lessened restrictive measures such as travel restrictions removed less coverage in public media. An endemic disease is always present in a population, but at a relatively low and predictable level. There may be periodic spikes of infections or seasonality, (e.g. influenza ) but generally the burden on health systems is manageable. A common early characteristic of a pandemic is a rapid, sometimes exponential , growth in the number of infections, coupled with a widening geographical spread. WHO utilises different criteria to declare a Public Health Emergency of International Concern (PHEIC), its nearest equivalent to the term pandemic. The potential consequences of an incident are considered, rather than its current status. For example, polio was declared a PHEIC in 2014 even though only 482 cases were reported globally in the previous year; this was justified by concerns that polio might break out of its endemic areas and again become a significant health threat globally. The PHEIC status of polio is reviewed regularly and is ongoing, despite the small number of cases annually. [lower-alpha 2] The end of a pandemic is more difficult to delineate. Generally, past epidemics & pandemics have faded out as the diseases become accepted into people's daily lives and routines, becoming endemic . The transition from pandemic to endemic may be defined based on: - a high proportion of the global population having immunity (through either natural infection or vaccination) fewer deaths health systems step down from emergency status perceived personal risk is lessened restrictive measures such as travel restrictions removed less coverage in public media. An endemic disease is always present in a population, but at a relatively low and predictable level. There may be periodic spikes of infections or seasonality, (e.g. influenza ) but generally the burden on health systems is manageable. Pandemic prevention comprises activities such as anticipatory research and development of therapies and vaccines, as well as monitoring for pathogens and disease outbreaks which may have pandemic potential. Routine vaccination programs are a type of prevention strategy, holding back diseases such as influenza and polio which have caused pandemics in the past, and could do so again if not controlled. Prevention overlaps with preparedness which aims to curtail an outbreak and prevent it getting out of control - it involves strategic planning, data collection and modelling to measure the spread, stockpiling of therapies, vaccines, and medical equipment, as well as public health awareness campaigning. By definition, a pandemic involves many countries so international cooperation, data sharing, and collaboration are essential; as is universal access to tests and therapies. Collaboration - In response to the COVID-19 pandemic, WHO established a Pandemic Hub in September 2021 in Berlin, aiming to address weaknesses around the world in how countries detect, monitor and manage public health threats. The Hub's initiatives include using artificial intelligence to analyse more than 35,000 data feeds for indications of emerging health threats, as well as improving facilities and coordination between academic institutions and WHO member countries. Detection - In May 2023, WHO launched the International Pathogen Surveillance Network (IPSN) (hosted by the Pandemic Hub) aiming to detect and respond to disease threats before they become epidemics and pandemics, and to optimize routine disease surveillance. The network provides a platform to connect countries, improving systems for collecting and analysing samples of potentially harmful pathogens . Therapies and Vaccines - The Coalition for Epidemic Preparedness Innovations (CEPI) is developing a program to condense new vaccine development timelines to 100 days, a third of the time it took to develop a COVID-19 vaccine. CEPI aims to reduce global epidemic and pandemic risk by developing vaccines against known pathogens as well as enabling rapid response to Disease X . In the US, the National Institute of Allergy and Infectious Diseases (NIAID) has developed a Pandemic Preparedness Plan which focuses on identifying viruses of concern and developing diagnostics and therapies (including prototype vaccines) to combat them. Modeling is important to inform policy decisions. It helps to predict the burden of disease on healthcare facilities, the effectiveness of control measures, projected geographical spread, and timing and extent of future pandemic waves. Public Awareness involves disseminating reliable information, ensuring consistency on message, transparency, and steps to discredit misinformation . Stockpiling involves maintaining strategic stockpiles of emergency supplies such as personal protective equipment, drugs and vaccines, and equipment such as respirators. Many of these items have limited shelf life , so they require stock rotation even though they may be rarely used. The COVID-19 pandemic highlighted a number of ethical and political issues which must be considered during a pandemic. These included decisions about who should be prioritised for treatment while resources are scarce; whether or not to make vaccination compulsory; the timing and extent of constraints on individual liberty, how to sanction individuals who do not comply with emergency regulations, and the extent of international collaboration and resource sharing. The COVID-19 pandemic highlighted a number of ethical and political issues which must be considered during a pandemic. These included decisions about who should be prioritised for treatment while resources are scarce; whether or not to make vaccination compulsory; the timing and extent of constraints on individual liberty, how to sanction individuals who do not comply with emergency regulations, and the extent of international collaboration and resource sharing. The basic strategies in the control of an outbreak are containment and mitigation . Containment may be undertaken in the early stages of the outbreak, including contact tracing and isolating infected individuals to stop the disease from spreading to the rest of the population, other public health interventions on infection control, and therapeutic countermeasures such as vaccinations which may be effective if available. When it becomes apparent that it is no longer possible to contain the spread of the disease, management will then move on to the mitigation stage, in which measures are taken to slow the spread of the disease and mitigate its effects on society and the healthcare system. In reality, containment and mitigation measures may be undertaken simultaneously. A key part of managing an infectious disease outbreak is trying to decrease the epidemic peak, known as " flattening the curve ". This helps decrease the risk of health services being overwhelmed and provides more time for a vaccine and treatment to be developed. A broad group of non-pharmaceutical interventions may be taken to manage the outbreak. In a flu pandemic, these actions may include personal preventive measures such as hand hygiene, wearing face-masks, and self-quarantine; community measures aimed at social distancing such as closing schools and canceling mass gatherings; community engagement to encourage acceptance and participation in such interventions; and environmental measures such as cleaning of surfaces. Another strategy, suppression , requires more extreme long-term non-pharmaceutical interventions to reverse the pandemic by reducing the basic reproduction number to less than 1. The suppression strategy, which includes stringent population-wide social distancing, home isolation of cases, and household quarantine, was undertaken by China during the COVID-19 pandemic where entire cities were placed under lockdown; such a strategy may carry with it considerable social and economic costs. For a novel influenza virus , WHO previously applied a six-stage classification to delineate the process by which the virus moves from the first few infections in humans through to a pandemic. Starting with phase 1 (infections identified in animals only), it moves through phases of increasing infection and spread to phase 6 (pandemic). In February 2020, a WHO spokesperson clarified that the system is no longer in use. In 2014, the United States Centers for Disease Control and Prevention (CDC) introduced a framework for characterising the progress of an influenza pandemic titled the Pandemic Intervals Framework . The six intervals of the framework are as follows: investigation of cases of novel influenza, recognition of increased potential for ongoing transmission, initiation of a pandemic wave, acceleration of a pandemic wave, deceleration of a pandemic wave, and preparation for future pandemic waves. At the same time, the CDC adopted the Pandemic Severity Assessment Framework (PSAF) to assess the severity of influenza pandemics. The PSAF rates the severity of an influenza outbreak on two dimensions: clinical severity of illness in infected persons; and the transmissibility of the infection in the population. This tool was not applied during the COVID-19 pandemic. For a novel influenza virus , WHO previously applied a six-stage classification to delineate the process by which the virus moves from the first few infections in humans through to a pandemic. Starting with phase 1 (infections identified in animals only), it moves through phases of increasing infection and spread to phase 6 (pandemic). In February 2020, a WHO spokesperson clarified that the system is no longer in use. In 2014, the United States Centers for Disease Control and Prevention (CDC) introduced a framework for characterising the progress of an influenza pandemic titled the Pandemic Intervals Framework . The six intervals of the framework are as follows: investigation of cases of novel influenza, recognition of increased potential for ongoing transmission, initiation of a pandemic wave, acceleration of a pandemic wave, deceleration of a pandemic wave, and preparation for future pandemic waves. At the same time, the CDC adopted the Pandemic Severity Assessment Framework (PSAF) to assess the severity of influenza pandemics. The PSAF rates the severity of an influenza outbreak on two dimensions: clinical severity of illness in infected persons; and the transmissibility of the infection in the population. This tool was not applied during the COVID-19 pandemic. SARS-CoV-2 , a new strain of coronavirus , was first detected in the city of Wuhan, Hubei Province , China, in December 2019. The outbreak was characterized as a Public Health Emergency of International Concern (PHEIC) between January 2020 and May 2023 by WHO. The number of people infected with COVID-19 has reached more than 767 million worldwide, with a death toll of 6.9 million. [lower-alpha 3] It is considered likely that the virus will eventually become endemic and, like the common cold, cause less severe disease for most people. HIV/AIDS was first identified as a disease in 1981, and is an ongoing worldwide public health issue. Since then, HIV/AIDS has killed an estimated 40 million people with a further 630,000 deaths annually; 39 million people are currently living with HIV infection. [lower-alpha 4] HIV has a zoonotic origin, having originated in nonhuman primates in Central Africa and transferred to humans in the early 20th century. The most frequent mode of transmission of HIV is through sexual contact with an infected person. There may be a short period of mild, nonspecific symptoms followed by an asymptomatic (but nevertheless infectious) stage called clinical latency - without treatment, this stage can last between 3 and 20 years. The only way to detect infection is by means of a HIV test. There is no vaccine to prevent HIV infection, but the disease can be held in check by means of antiretroviral therapy . Historical accounts of epidemics are often vague or contradictory in describing how victims were affected. A rash accompanied by a fever might be smallpox, measles, scarlet fever, or varicella , and it is possible that epidemics overlapped, with multiple infections striking the same population at once. It is often impossible to know the exact causes of mortality, although ancient DNA studies can sometimes detect residues of certain pathogens. It is assumed that, prior to the neolithic revolution around 10,000 BC, disease outbreaks were limited to a single family or clan, and did not spread widely before dying out. The domestication of animals increased human-animal contact, increasing the possibility of zoonotic infections. The advent of agriculture, and trade between settled groups, made it possible for pathogens to spread widely. As population increased, contact between groups became more frequent. A history of epidemics maintained by the Chinese Empire from 243 B.C. to 1911 A.C. shows an approximate correlation between the frequency of epidemics and the growth of the population. Here is an incomplete list of known epidemics which spread widely enough to merit the title "pandemic". Beginning from the Middle Ages, encounters between European settlers and native populations in the rest of the world often introduced epidemics of extraordinary virulence. Settlers introduced novel diseases which were endemic in Europe, such as smallpox , measles , pertussis .and influenza , to which the indigenous peoples had no immunity. The Europeans infected with such diseases typically carried them in a dormant state , were actively infected but asymptomatic , or had only mild symptoms. Smallpox was the most destructive disease that was brought by Europeans to the Native Americans, both in terms of morbidity and mortality. The first well-documented smallpox epidemic in the Americas began in Hispaniola in late 1518 and soon spread to Mexico. Estimates of mortality range from one-quarter to one-half of the population of central Mexico. It is estimated that over the 100 years after European arrival in 1492, the indigenous population of the Americas dropped from 60 million to only 6 million, due to a combination of disease, war, and famine. The majority these deaths are attributed to successive waves of introduced diseases such as smallpox, measles, and typhoid fever. In Australia , smallpox was introduced by European settlers in 1789 devastating the Australian Aboriginal population, killing an estimated 50% of those infected with the disease during the first decades of colonisation. In the early 1800s, measles, smallpox and intertribal warfare killed an estimated 20,000 New Zealand Māori . In 1848–49, as many as 40,000 out of 150,000 Hawaiians are estimated to have died of measles , whooping cough and influenza . Measles killed more than 40,000 Fijians , approximately one-third of the population, in 1875, and in the early 19th century devastated the Great Andamanese population. In Hokkaido , an epidemic of smallpox introduced by Japanese settlers is estimated to have killed 34% of the native Ainu population in 1845. SARS-CoV-2 , a new strain of coronavirus , was first detected in the city of Wuhan, Hubei Province , China, in December 2019. The outbreak was characterized as a Public Health Emergency of International Concern (PHEIC) between January 2020 and May 2023 by WHO. The number of people infected with COVID-19 has reached more than 767 million worldwide, with a death toll of 6.9 million. [lower-alpha 3] It is considered likely that the virus will eventually become endemic and, like the common cold, cause less severe disease for most people. HIV/AIDS was first identified as a disease in 1981, and is an ongoing worldwide public health issue. Since then, HIV/AIDS has killed an estimated 40 million people with a further 630,000 deaths annually; 39 million people are currently living with HIV infection. [lower-alpha 4] HIV has a zoonotic origin, having originated in nonhuman primates in Central Africa and transferred to humans in the early 20th century. The most frequent mode of transmission of HIV is through sexual contact with an infected person. There may be a short period of mild, nonspecific symptoms followed by an asymptomatic (but nevertheless infectious) stage called clinical latency - without treatment, this stage can last between 3 and 20 years. The only way to detect infection is by means of a HIV test. There is no vaccine to prevent HIV infection, but the disease can be held in check by means of antiretroviral therapy . SARS-CoV-2 , a new strain of coronavirus , was first detected in the city of Wuhan, Hubei Province , China, in December 2019. The outbreak was characterized as a Public Health Emergency of International Concern (PHEIC) between January 2020 and May 2023 by WHO. The number of people infected with COVID-19 has reached more than 767 million worldwide, with a death toll of 6.9 million. [lower-alpha 3] It is considered likely that the virus will eventually become endemic and, like the common cold, cause less severe disease for most people. HIV/AIDS was first identified as a disease in 1981, and is an ongoing worldwide public health issue. Since then, HIV/AIDS has killed an estimated 40 million people with a further 630,000 deaths annually; 39 million people are currently living with HIV infection. [lower-alpha 4] HIV has a zoonotic origin, having originated in nonhuman primates in Central Africa and transferred to humans in the early 20th century. The most frequent mode of transmission of HIV is through sexual contact with an infected person. There may be a short period of mild, nonspecific symptoms followed by an asymptomatic (but nevertheless infectious) stage called clinical latency - without treatment, this stage can last between 3 and 20 years. The only way to detect infection is by means of a HIV test. There is no vaccine to prevent HIV infection, but the disease can be held in check by means of antiretroviral therapy . Historical accounts of epidemics are often vague or contradictory in describing how victims were affected. A rash accompanied by a fever might be smallpox, measles, scarlet fever, or varicella , and it is possible that epidemics overlapped, with multiple infections striking the same population at once. It is often impossible to know the exact causes of mortality, although ancient DNA studies can sometimes detect residues of certain pathogens. It is assumed that, prior to the neolithic revolution around 10,000 BC, disease outbreaks were limited to a single family or clan, and did not spread widely before dying out. The domestication of animals increased human-animal contact, increasing the possibility of zoonotic infections. The advent of agriculture, and trade between settled groups, made it possible for pathogens to spread widely. As population increased, contact between groups became more frequent. A history of epidemics maintained by the Chinese Empire from 243 B.C. to 1911 A.C. shows an approximate correlation between the frequency of epidemics and the growth of the population. Here is an incomplete list of known epidemics which spread widely enough to merit the title "pandemic".Beginning from the Middle Ages, encounters between European settlers and native populations in the rest of the world often introduced epidemics of extraordinary virulence. Settlers introduced novel diseases which were endemic in Europe, such as smallpox , measles , pertussis .and influenza , to which the indigenous peoples had no immunity. The Europeans infected with such diseases typically carried them in a dormant state , were actively infected but asymptomatic , or had only mild symptoms. Smallpox was the most destructive disease that was brought by Europeans to the Native Americans, both in terms of morbidity and mortality. The first well-documented smallpox epidemic in the Americas began in Hispaniola in late 1518 and soon spread to Mexico. Estimates of mortality range from one-quarter to one-half of the population of central Mexico. It is estimated that over the 100 years after European arrival in 1492, the indigenous population of the Americas dropped from 60 million to only 6 million, due to a combination of disease, war, and famine. The majority these deaths are attributed to successive waves of introduced diseases such as smallpox, measles, and typhoid fever. In Australia , smallpox was introduced by European settlers in 1789 devastating the Australian Aboriginal population, killing an estimated 50% of those infected with the disease during the first decades of colonisation. In the early 1800s, measles, smallpox and intertribal warfare killed an estimated 20,000 New Zealand Māori . In 1848–49, as many as 40,000 out of 150,000 Hawaiians are estimated to have died of measles , whooping cough and influenza . Measles killed more than 40,000 Fijians , approximately one-third of the population, in 1875, and in the early 19th century devastated the Great Andamanese population. In Hokkaido , an epidemic of smallpox introduced by Japanese settlers is estimated to have killed 34% of the native Ainu population in 1845. Prevention of future pandemics requires steps to identify future causes of pandemics and to take preventive measures before the disease moves uncontrollably into the human population. For example, influenza is a rapidly evolving disease which has caused pandemics in the past and has potential to cause future pandemics. WHO collates the findings of 144 national influenza centres worldwide which monitor emerging flu viruses. Virus variants which are assessed as likely to represent a significant risk are identified and can then be incorporated into the next seasonal influenza vaccine program. In a press conference on 28 December 2020, Mike Ryan, head of the WHO Emergencies Program, and other officials said the current COVID-19 pandemic is "not necessarily the big one" and "the next pandemic may be more severe." They called for preparation. WHO and the UN have warned the world must tackle the cause of pandemics and not just the health and economic symptoms. There is always a possibility that a disease which has caused epidemics in the past may return in the future. It is also possible that little known diseases may become more virulent; in order to encourage research, a number of organisations which monitor global health have drawn up lists of diseases which may have pandemic potential; see table below. [lower-alpha 5] Coronavirus diseases are a family of usually mild illnesses in humans, including those such as the common cold , that have resulted in outbreaks and pandemics such as the 1889-1890 pandemic , the 2002–2004 SARS outbreak , Middle East respiratory syndrome–related coronavirus and the COVID-19 pandemic . There is widespread concern that members of the coronavirus family, particularly SARS and MERS have the potential to cause future pandemics. Many human coronaviruses have zoonotic origin, their with natural reservoir in bats or rodents, leading to concerns for future spillover events. Following the end of the COVID-19 pandemic Public Health Emergency of International Concern deceleration by WHO, WHO Director General Tedros Ghebreyesus stated he would not hesitate to re-declare COVID-19 a PHEIC should the global situation worsen in the coming months or years. Influenza was first described by the Greek physician Hippocrates in 412 BC. Since the Middle Ages, influenza pandemics have been recorded every 10 to 30 years as the virus mutates to evade immunity. Influenza is an endemic disease , with a fairly constant number of cases which vary seasonally and can, to a certain extent, be predicted. In a typical year, 5–15% of the population contracts influenza. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. The 1889–1890 pandemic is estimated to have caused around a million fatalities, and the " Spanish flu " of 1918–1920 eventually infected about one-third of the world's population and caused an estimate 50 million fatalities. The Global Influenza Surveillance and Response System is a global network of laboratories that has for purpose to monitor the spread of influenza with the aim to provide WHO with influenza control information. More than two million respiratory specimens are tested by GISRS annually to monitor the spread and evolution of influenza viruses through a network of about 150 laboratories in 114 countries representing 91% of the world's population. Antibiotic-resistant microorganisms, which sometimes are referred to as " superbugs ", may contribute to the re-emergence of diseases with pandemic potential that are currently well controlled. For example, cases of tuberculosis that are resistant to traditionally effective treatments remain a cause of great concern to health professionals. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide. China and India have the highest rate of MDR-TB. WHO reports that approximately 50 million people worldwide are infected with MDR-TB, with 79 percent of those cases resistant to three or more antibiotics. Extensively drug-resistant tuberculosis ( XDR-TB ) was first identified in Africa in 2006 and subsequently discovered to exist in 49 countries. During 2021 there were estimated to be around 25,000 cases XDR-TB worldwide. In the past 20 years, other common bacteria including Staphylococcus aureus , Serratia marcescens and Enterococcus , have developed resistance to a wide range of antibiotics . Antibiotic-resistant organisms have become an important cause of healthcare-associated ( nosocomial ) infections. There are two groups of infectious disease that may be affected by climate change. The first group are vector-borne diseases which are transmitted via insects such as mosquitos or ticks. Some of these diseases, such as malaria , yellow fever , and dengue fever , can have potentially severe health consequences. Climate can affect the distribution of these diseases due to the changing geographic range of their vectors, with the potential to cause serious outbreaks in areas where the disease has not previously been known. The other group comprises water-borne diseases such as cholera, dysentery, and typhoid which may increase in prevalence due to changes in rainfall patterns. The October 2020 'era of pandemics' report by the United Nations ' Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services , written by 22 experts in a variety of fields, said the anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals—in particular birds and mammals —to humans. The "exponential rise" in consumption and trade of commodities such as meat , palm oil , and metals, largely facilitated by developed nations, and a growing human population , are the primary drivers of this destruction. According to Peter Daszak , the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic or any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." Proposed policy options from the report include taxing meat production and consumption, cracking down on the illegal wildlife trade, removing high-risk species from the legal wildlife trade, eliminating subsidies to businesses that are harmful to the natural world, and establishing a global surveillance network. In June 2021, a team of scientists assembled by the Harvard Medical School Center for Health and the Global Environment warned that the primary cause of pandemics so far, the anthropogenic destruction of the natural world through such activities including deforestation and hunting , is being ignored by world leaders. Permafrost covers a fifth of the northern hemisphere and is made up of soil that has been kept at temperatures below freezing for long periods. Viable samples of viruses have been recovered from thawing permafrost, after having been frozen for many years, sometimes for millennia. There is a remote possibility that a thawed pathogen could infect humans or animals. There is always a possibility that a disease which has caused epidemics in the past may return in the future. It is also possible that little known diseases may become more virulent; in order to encourage research, a number of organisations which monitor global health have drawn up lists of diseases which may have pandemic potential; see table below. [lower-alpha 5] Coronavirus diseases are a family of usually mild illnesses in humans, including those such as the common cold , that have resulted in outbreaks and pandemics such as the 1889-1890 pandemic , the 2002–2004 SARS outbreak , Middle East respiratory syndrome–related coronavirus and the COVID-19 pandemic . There is widespread concern that members of the coronavirus family, particularly SARS and MERS have the potential to cause future pandemics. Many human coronaviruses have zoonotic origin, their with natural reservoir in bats or rodents, leading to concerns for future spillover events. Following the end of the COVID-19 pandemic Public Health Emergency of International Concern deceleration by WHO, WHO Director General Tedros Ghebreyesus stated he would not hesitate to re-declare COVID-19 a PHEIC should the global situation worsen in the coming months or years. Influenza was first described by the Greek physician Hippocrates in 412 BC. Since the Middle Ages, influenza pandemics have been recorded every 10 to 30 years as the virus mutates to evade immunity. Influenza is an endemic disease , with a fairly constant number of cases which vary seasonally and can, to a certain extent, be predicted. In a typical year, 5–15% of the population contracts influenza. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. The 1889–1890 pandemic is estimated to have caused around a million fatalities, and the " Spanish flu " of 1918–1920 eventually infected about one-third of the world's population and caused an estimate 50 million fatalities. The Global Influenza Surveillance and Response System is a global network of laboratories that has for purpose to monitor the spread of influenza with the aim to provide WHO with influenza control information. More than two million respiratory specimens are tested by GISRS annually to monitor the spread and evolution of influenza viruses through a network of about 150 laboratories in 114 countries representing 91% of the world's population. Coronavirus diseases are a family of usually mild illnesses in humans, including those such as the common cold , that have resulted in outbreaks and pandemics such as the 1889-1890 pandemic , the 2002–2004 SARS outbreak , Middle East respiratory syndrome–related coronavirus and the COVID-19 pandemic . There is widespread concern that members of the coronavirus family, particularly SARS and MERS have the potential to cause future pandemics. Many human coronaviruses have zoonotic origin, their with natural reservoir in bats or rodents, leading to concerns for future spillover events. Following the end of the COVID-19 pandemic Public Health Emergency of International Concern deceleration by WHO, WHO Director General Tedros Ghebreyesus stated he would not hesitate to re-declare COVID-19 a PHEIC should the global situation worsen in the coming months or years.Influenza was first described by the Greek physician Hippocrates in 412 BC. Since the Middle Ages, influenza pandemics have been recorded every 10 to 30 years as the virus mutates to evade immunity. Influenza is an endemic disease , with a fairly constant number of cases which vary seasonally and can, to a certain extent, be predicted. In a typical year, 5–15% of the population contracts influenza. There are 3–5 million severe cases annually, with up to 650,000 respiratory-related deaths globally each year. The 1889–1890 pandemic is estimated to have caused around a million fatalities, and the " Spanish flu " of 1918–1920 eventually infected about one-third of the world's population and caused an estimate 50 million fatalities. The Global Influenza Surveillance and Response System is a global network of laboratories that has for purpose to monitor the spread of influenza with the aim to provide WHO with influenza control information. More than two million respiratory specimens are tested by GISRS annually to monitor the spread and evolution of influenza viruses through a network of about 150 laboratories in 114 countries representing 91% of the world's population. Antibiotic-resistant microorganisms, which sometimes are referred to as " superbugs ", may contribute to the re-emergence of diseases with pandemic potential that are currently well controlled. For example, cases of tuberculosis that are resistant to traditionally effective treatments remain a cause of great concern to health professionals. Every year, nearly half a million new cases of multidrug-resistant tuberculosis (MDR-TB) are estimated to occur worldwide. China and India have the highest rate of MDR-TB. WHO reports that approximately 50 million people worldwide are infected with MDR-TB, with 79 percent of those cases resistant to three or more antibiotics. Extensively drug-resistant tuberculosis ( XDR-TB ) was first identified in Africa in 2006 and subsequently discovered to exist in 49 countries. During 2021 there were estimated to be around 25,000 cases XDR-TB worldwide. In the past 20 years, other common bacteria including Staphylococcus aureus , Serratia marcescens and Enterococcus , have developed resistance to a wide range of antibiotics . Antibiotic-resistant organisms have become an important cause of healthcare-associated ( nosocomial ) infections. There are two groups of infectious disease that may be affected by climate change. The first group are vector-borne diseases which are transmitted via insects such as mosquitos or ticks. Some of these diseases, such as malaria , yellow fever , and dengue fever , can have potentially severe health consequences. Climate can affect the distribution of these diseases due to the changing geographic range of their vectors, with the potential to cause serious outbreaks in areas where the disease has not previously been known. The other group comprises water-borne diseases such as cholera, dysentery, and typhoid which may increase in prevalence due to changes in rainfall patterns. The October 2020 'era of pandemics' report by the United Nations ' Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services , written by 22 experts in a variety of fields, said the anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals—in particular birds and mammals —to humans. The "exponential rise" in consumption and trade of commodities such as meat , palm oil , and metals, largely facilitated by developed nations, and a growing human population , are the primary drivers of this destruction. According to Peter Daszak , the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic or any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment." Proposed policy options from the report include taxing meat production and consumption, cracking down on the illegal wildlife trade, removing high-risk species from the legal wildlife trade, eliminating subsidies to businesses that are harmful to the natural world, and establishing a global surveillance network. In June 2021, a team of scientists assembled by the Harvard Medical School Center for Health and the Global Environment warned that the primary cause of pandemics so far, the anthropogenic destruction of the natural world through such activities including deforestation and hunting , is being ignored by world leaders. Permafrost covers a fifth of the northern hemisphere and is made up of soil that has been kept at temperatures below freezing for long periods. Viable samples of viruses have been recovered from thawing permafrost, after having been frozen for many years, sometimes for millennia. There is a remote possibility that a thawed pathogen could infect humans or animals. In 2016, the commission on a Global Health Risk Framework for the Future estimated that pandemic disease events would cost the global economy over $6 trillion in the 21st century—over $60 billion per year. The same report recommended spending $4.5 billion annually on global prevention and response capabilities to reduce the threat posed by pandemic events, a figure that the World Bank Group raised to $13 billion in a 2019 report. It has been suggested that such costs be paid from a tax on aviation rather than from, e.g., income taxes, given the crucial role of air traffic in transforming local epidemics into pandemics (being the only factor considered in state-of-the-art models of long-range disease transmission ). The COVID-19 pandemic is expected to have a profound negative effect on the global economy , potentially for years to come, with substantial drops in GDP accompanied by increases in unemployment noted around the world. The slowdown of economic activity early in the COVID-19 pandemic had a profound effect on emissions of pollutants and greenhouse gases. Analysis of ice cores taken from the Swiss Alps have revealed a reduction in atmospheric lead pollution over a four-year period corresponding to the years 1349 to 1353 (when the Black Death was ravaging Europe), indicating a reduction in mining and economic activity generally.

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Sialic acid

Sialic acids are a class of alpha-keto acid sugars with a nine- carbon backbone . The term "sialic acid" ( from Greek σίαλον (síalon) ' saliva ' ) was first introduced by Swedish biochemist Gunnar Blix in 1952. The most common member of this group is N -acetylneuraminic acid (Neu5Ac or NANA) found in animals and some prokaryotes . Sialic acids are found widely distributed in animal tissues and related forms are found to a lesser extent in other organisms like in some micro-algae , bacteria and archaea . Sialic acids are commonly part of glycoproteins , glycolipids or gangliosides , where they decorate the end of sugar chains at the surface of cells or soluble proteins. However, sialic acids have been also observed in Drosophila embryos and other insects. Generally, plants seem not to contain or display sialic acids. In humans the brain has the highest sialic acid content, where these acids play an important role in neural transmission and ganglioside structure in synaptogenesis . More than 50 kinds of sialic acid are known, all of which can be obtained from a molecule of neuraminic acid by substituting its amino group or one of its hydroxyl groups. In general, the amino group bears either an acetyl or a glycolyl group, but other modifications have been described. These modifications along with linkages have shown to be tissue specific and developmentally regulated expressions , so some of them are only found on certain types of glycoconjugates in specific cells. The hydroxyl substituents may vary considerably; acetyl , lactyl , methyl , sulfate , and phosphate groups have been found. The sialic acid family includes many derivatives of the nine-carbon sugar neuraminic acid , but these acids rarely appear free in nature. Normally they can be found as components of oligosaccharide chains of mucins, glycoproteins and glycolipids occupying terminal, nonreducing positions of complex carbohydrates on both external and internal membrane areas where they are very exposed and develop important functions. The numbering of the carbon atoms starts at the carboxylate carbon and continues along the chain. The configuration that places the carboxylate in the axial position is the alpha-anomer. The alpha-anomer is the form that is found when sialic acid is bound to glycans. However, in solution, it is mainly (over 90%) in the beta-anomeric form. A bacterial enzyme with sialic acid mutarotase activity, NanM, that is able to rapidly equilibrate solutions of sialic acid to the resting equilibrium position of around 90% beta/10% alpha has been discovered. In contrast to other animals, humans are genetically unable to produce the sialic acid variant N-glycolylneuraminic acid (Neu5Gc). Small amounts of Neu5Gc detected in human tissue however may be incorporated from exogenous (nutrient) sources. Sialic acid is synthesized by glucosamine 6 phosphate and acetyl-CoA through a transferase , resulting in N -acetylglucosamine-6-P. This becomes N -acetylmannosamine-6-P through epimerization , which reacts with phosphoenolpyruvate producing N -acetylneuraminic-9-P (sialic acid). For it to become active to enter in the oligosaccharide biosynthesis process of the cell, a monophosphate nucleoside is added, which comes from a cytidine triphosphate , turning sialic acid into cytidine monophosphate-sialic acid (CMP-sialic acid). This compound is synthesized in the nucleus of the animal cell. In bacterial systems, sialic acids can be also biosynthesized by an aldolase . This enzyme uses for example a mannose derivative as a substrate, inserting three carbons from pyruvate into the resulting sialic acid structure. These enzymes can be used for chemoenzymatic synthesis of sialic acid derivatives. Sialic acid containing glycoproteins ( sialoglycoproteins ) bind selectin in humans and other organisms. Metastatic cancer cells often express a high density of sialic acid-rich glycoproteins. This overexpression of sialic acid on surfaces creates a negative charge on cell membranes. This creates repulsion between cells (cell opposition) and helps these late-stage cancer cells enter the blood stream. Recent experiments have demonstrated the presence of sialic acid in the cancer-secreted extracellular matrix . Sialic acid-rich oligosaccharides on the glycoconjugates (glycolipids, glycoproteins, proteoglycans) found on surface membranes help keep water at the surface of cells [ citation needed ] . The sialic acid-rich regions contribute to creating a negative charge on the cells' surfaces. Since water is a polar molecule with partial positive charges on both hydrogen atoms, it is attracted to cell surfaces and membranes. This also contributes to cellular fluid uptake. Sialic acid residues are present in the mucin glycoproteins of mucus. Sialic acid can "hide" mannose antigens on the surface of host cells or bacteria from mannose-binding lectin. [ citation needed ] This prevents activation of complement . Sialic acid in the form of polysialic acid is an unusual posttranslational modification that occurs on the neural cell adhesion molecules (NCAMs). In the synapse , the strong negative charge of the polysialic acid prevents NCAM cross-linking of cells. Administration of estrogen to castrated mice leads to a dose-dependent reduction of the sialic acid content of the vagina. Conversely, the sialic acid content of mouse vagina is a measure of the potency of the estrogen. Reference substances are estradiol for subcutaneous application and ethinylestradiol for oral administration. Sialic acids are found at all cell surfaces of vertebrates and some invertebrates, and also at certain bacteria that interact with vertebrates. Many viruses such as the Ad26 serotype of adenoviruses ( Adenoviridae ), rotaviruses ( Reoviridae ) and influenza viruses ( Orthomyxoviridae ) can use host-sialylated structures for binding to their target host cell. Sialic acids provide a good target for these viruses since they are highly conserved and are abundant in large numbers in virtually all cells. Unsurprisingly, sialic acids also play an important role in several human viral infections. The influenza viruses have hemagglutinin activity (HA) glycoproteins on their surfaces that bind to sialic acids found on the surface of human erythrocytes and on the cell membranes of the upper respiratory tract. This is the basis of hemagglutination when viruses are mixed with blood cells, and entry of the virus into cells of the upper respiratory tract. Widely used anti-influenza drugs ( oseltamivir and zanamivir ) are sialic acid analogs that interfere with release of newly generated viruses from infected cells by inhibiting the viral enzyme neuraminidase . Some bacteria also use host-sialylated structures for binding and recognition. For example, evidence indicates that free sialic acids can behave as a signal to some specific bacteria, like Pneumococcus . Free sialic acid possibly can help the bacterium to recognize that it has reached a vertebrate environment suitable for its colonization. Modifications of Sias, such as the N -glycolyl group at the 5 position or O -acetyl groups on the side chain, may reduce the action of bacterial sialidases. The synthesis and degradation of sialic acid are distributed in different compartments of the cell. The synthesis starts in the cytosol, where N -acetylmannosamine 6 phosphate and phosphoenolpyruvate give rise to sialic acid. Later on, Neu5Ac 9 phosphate is activated in the nucleus by a cytidine monophosphate (CMP) residue through CMP-Neu5Ac synthase. Although the linkage between sialic acid and other compounds tends to be a α binding, this specific one is the only one that is a β linkage. CMP-Neu5Ac is then transported to the endoplasmic reticulum or the Golgi apparatus, where it can be transferred to an oligosaccharide chain, becoming a new glycoconjugate. This bond can be modified by O- acetylation or O- methylation . When the glycoconjugate is mature it is transported to the cell surface. The sialidase is one of the most important enzymes of the sialic acid catabolism. It can cause the removal of sialic acid residues from the cell surface or serum sialoglycoconjugates. Usually, in higher animals, the glycoconjugates that are prone to be degraded are captured by endocytosis. After the fusion of the late endosome with the lysosome, lysosomal sialidases remove sialic acid residues. The activity of these sialidases is based on the removal of O -acetyl groups. Free sialic acid molecules are transported to the cytosol through the membrane of the lysosome. There, they can be recycled and activated again to form another nascent glycoconjugate molecule in the Golgi apparatus. Sialic acids can also be degraded to acylmannosamine and pyruvate with the cytosolic enzyme acylneuraminate lyase. Some severe diseases can depend on the presence or absence of some enzymes related to the sialic acid metabolism. Sialidosis and Sialic acid deficiency with mutations in the NANS gene (see below) would be examples of this type of disorder. Rat pups supplemented with sialic acid showed improved learning and memory as adults. A relationship between dietary sialic acid supplementation and cognitive function was seen in piglets that had been fed high doses of sialic acid. Sialic acids are related to several different diseases observed in humans. Biallelic recessive mutations in the sialic acid synthesis gene, N-acetyl-neuraminic acid synthase ( NANS ) in humans may result in a severe disease featuring intellectual disability and short stature, highlighting the importance of sialic acid in brain development. A therapeutic trial with a short-term supplementation of sialic acid given orally has failed to show a significant beneficial effect on biochemical parameters Salla disease is an extremely rare illness which is considered the mildest form of the free sialic acid accumulation disorders though its childhood form is considered an aggressive variant and people who suffer from it have mental retardation. It is an autosomic recessive disorder caused by a mutation of the chromosome 6 . It mainly affects the nervous system and it is caused by a lysosomal storage irregularity which comes from a deficit of a specific sialic acid carrier located on the lysosomal membrane Currently, there is no cure for this disease and the treatment is supportive, focusing on the control of symptoms. Subfractions of LDL cholesterol that are implicated in causing atherosclerosis have reduced levels of sialic acid. These include small high density LDL particles and electronegative LDL. Reduced levels of sialic acid in small high density LDL particles increases the affinity of those particles for the proteoglycans in arterial walls. All influenza A virus strains need sialic acid to connect with cells. There are different forms of sialic acids which have different affinity with influenza A virus variety. This diversity is an important fact that determines which species can be infected. When a certain influenza A virus is recognized by a sialic acid receptor the cell tends to endocytose the virus so the cell becomes infected.Biallelic recessive mutations in the sialic acid synthesis gene, N-acetyl-neuraminic acid synthase ( NANS ) in humans may result in a severe disease featuring intellectual disability and short stature, highlighting the importance of sialic acid in brain development. A therapeutic trial with a short-term supplementation of sialic acid given orally has failed to show a significant beneficial effect on biochemical parameters Salla disease is an extremely rare illness which is considered the mildest form of the free sialic acid accumulation disorders though its childhood form is considered an aggressive variant and people who suffer from it have mental retardation. It is an autosomic recessive disorder caused by a mutation of the chromosome 6 . It mainly affects the nervous system and it is caused by a lysosomal storage irregularity which comes from a deficit of a specific sialic acid carrier located on the lysosomal membrane Currently, there is no cure for this disease and the treatment is supportive, focusing on the control of symptoms. Subfractions of LDL cholesterol that are implicated in causing atherosclerosis have reduced levels of sialic acid. These include small high density LDL particles and electronegative LDL. Reduced levels of sialic acid in small high density LDL particles increases the affinity of those particles for the proteoglycans in arterial walls. All influenza A virus strains need sialic acid to connect with cells. There are different forms of sialic acids which have different affinity with influenza A virus variety. This diversity is an important fact that determines which species can be infected. When a certain influenza A virus is recognized by a sialic acid receptor the cell tends to endocytose the virus so the cell becomes infected.Sialic acids are highly abundant in vertebrate tissues where they are involved in many different biological processes. Originally discovered within the Deuterostome lineage of animals, sialic acids can be actually considered as a subset of a more ancient family of 9-carbon backbone monosaccharides called nonulosonic acids (NulOs), which more recently have been also found in Eubacteria and Archaea. Many pathogenic bacteria incorporate sialic acid into cell surface features like their lipopolysaccharide or capsule polysaccharides, which helps them to evade the innate immune response of the host. A recent genome level study examined a large set of sequenced microbial genomes, which indicated that biosynthetic pathways to produce nonulosonic acids (NulOs) are far more widely distributed across the phylogenetic tree of life, than previously realized. This finding is moreover supported by recent lectin staining studies and a molecular level survey on prokaryotic nonulosonic acids, showing that also many non-pathogenic and purely environmental strains produce bacterial sialic acids (NulOs). Some ( anammox ) bacteria produce NulOs that in addition to the very acidic alpha-keto acid group also display (neutralizing) basic groups (free amines). Comparable cell surface sialic acids have been produced by chemical remodelling to manipulate the cell surface charge by producing a free amine at C5, which neutralizes the negatively charged carboxyl group at C1.

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influenza virus

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Spanish flu research

A/Brevig Mission/1/1918(H1N1) A/New_York/1/18(H1N1) A/AFIP/1/1918(H1N1) A/Iowa/1/1918(H1N1) A/London/1/1918(H1N1) A/London/1/1919(H1N1) ... Look for "/1918" on the full list of H1N1 strains Spanish flu research concerns studies regarding the causes and characteristics of the Spanish flu , a variety of influenza that in 1918 was responsible for the worst influenza pandemic in modern history. Many theories about the origins and progress of the Spanish flu persisted in the literature, but it was not until 2005, when various samples of lung tissue were recovered from American World War I soldiers and from an Inupiat woman buried in permafrost in a mass grave in Brevig Mission, Alaska , that significant genetic research was made possible.There are two prevailing theories usually postulated. [ citation needed ] One theory by Alfred W. Crosby is that the virus strain originated at Fort Riley , Kansas , by two genetic mechanisms – genetic drift and antigenic shift – in viruses in poultry and swine which the fort bred for local consumption. Though initial data from a recent reconstruction of the virus suggested that it jumped directly from birds to humans , without traveling through swine, [lower-alpha 1] this has since been cast into doubt. One researcher published in 2004 argued that the disease was found in Haskell County, Kansas , as early as January 1918. A similar and even more deadly virus had been seen earlier at British camps in France and at Aldershot. Earlier investigative work published in 2000 by a team led by British virologist, John Oxford of St Bartholomew's Hospital and the Royal London Hospital , suggested that a principal British troop staging camp in Étaples , France, was at the center of the 1918 flu pandemic or at least a significant precursor virus to it. There had been a mysterious respiratory infection at the military base during the winter of 1915–1916. In 1995, Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP), wondered if it might be possible to recover the virus of 1918 flu pandemic from the dried and fixed tissue of victims. He and his colleagues, tested 10 slides of tissue sample and 2 came out positive. Taubenberger, Ann H. Reid and Thomas G. Fanning were able to amplify short segments of the viral nucleic acid using polymerase chain reaction (PCR) . The results were published in the journal Science in March 1997. On August 20, 1997, Johan Hultin recovered samples of the 1918 influenza from the frozen corpse of a Native Alaskan woman buried for nearly eight decades in permafrost near Brevig Mission, Alaska . He brought the samples to a team in Rockville, Maryland led by Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP). Brevig Mission lost approximately 85% of its population to the 1918 flu in November 1918. One of the four recovered samples contained viable genetic material of the virus. This sample provided scientists a first-hand opportunity to study the virus, which was inactivated with guanidinium thiocyanate before transport. This sample and others found in AFIP archives allowed researchers to completely analyze the critical gene structures of the 1918 virus. The archived autopsy samples had been taken from WWI Army privates Roscoe Vaughan and James Downs. The 6 February 2004 edition of Science magazine reported that two research teams, one led by Sir John Skehel, director of the National Institute for Medical Research in London , another by professor Ian Wilson of The Scripps Research Institute in San Diego , had managed to synthesize the hemagglutinin protein responsible for the flu outbreak of 1918. They did this by piecing together DNA from a lung sample from an Inuit woman buried in the Alaskan tundra and a number of preserved samples from American soldiers of the First World War. The teams had analyzed the structure of the gene and discovered how subtle alterations to the shape of a protein molecule had allowed it to move from birds to humans with such devastating effects. On 5 October 2005, Tumpey and other researchers at the Centers for Disease Control and Prevention (CDC) in Atlanta , Georgia, and the Mount Sinai School of Medicine in New York , announced that the (~13 kbp) genetic sequence of the 1918 flu strain, a subtype of avian strain H1N1 , had been reconstructed using historic tissue samples and a small part of the RNA from a modern strain. Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses . The H5N1 virus has mutated into a variety of types with differing pathogenic profiles; some pathogenic to one species but not others, some pathogenic to multiple species. The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types. In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute , Harbin , China, and Robert Webster of the St. Jude Children's Research Hospital , Memphis, Tennessee , reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity." Results reported by Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks. In December 2008, research by Yoshihiro Kawaoka of University of Wisconsin showed the presence of the three specific genes (termed PA, PB1, and PB2) and a nucleoprotein derived from the H1N1 1918 flu samples was enough to trigger similar symptoms in animal testing. Recent research of Taubenberger et al. has suggested that the 1918 virus, like H5N1, could have arisen directly from an avian influenza virus. However, researchers at University of Virginia and Australian National University have suggested that there may be an alternative interpretation of the data used in the Taubenberger et al. paper. Taubenberger et al. responded to these letters and defended their original interpretation. Other research by Tumpey and colleagues who reconstructed the H1N1 virus of 1918 came to the conclusion that it was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus. On 18 January 2007, Kobasa et al. reported that infected monkeys ( Macaca fascicularis ) exhibited classic symptoms of the 1918 pandemic and died from a cytokine storm . The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Viruses with 7 of the 10 amino acids in the human influenza locations have already been identified in currently circulating H5N1 . This has led some researchers to suggest that other mutations may surface and make the H5N1 virus capable of human-to-human transmission. Another important factor is the change of the HA protein to a binding preference for alpha-2,6 sialic acid (the major form found in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha-2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, only a handful of mutations may need to take place in order for H5N1 avian flu to become a pandemic virus like the one of 1918. However it is important to note that likelihood of mutation does not indicate the likelihood for the evolution of such a strain, since some of the necessary mutations may be constrained by stabilizing selection .In the event of another pandemic, US military researchers have proposed reusing a treatment from the deadly pandemic of 1918 in order to blunt the effects of the flu: Some military doctors injected severely afflicted patients with blood or blood plasma from people who had recovered from the flu. Data collected during that time indicates that the blood-injection treatment reduced mortality rates by as much as 50 percent. Navy researchers have launched a test to see if the 1918 treatment will work against deadly Asian bird flu. Results thus far have been inconclusive. Human H5N1 plasma may be an effective, timely, and widely available treatment for the next flu pandemic. [ citation needed ] A new international study using modern data collection methods, would be a difficult, slow process. Citing the months-long wait for a vaccine for the next pandemic, many flu experts are of the opinion that the 1918 method is something to consider. In the worldwide 1918 flu pandemic , "physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae – a name derived from the fact that it was originally considered the etiological agent – and several types of pneumococci). Only one therapeutic measure showed any hint of success: Transfusing blood from recovered patients to new victims."

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influenza virus

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Goose Guangdong virus

The Goose Guangdong virus refers to the strain A/Goose/Guangdong/1/96 (Gs/Gd)-like H5N1 HPAI viruses . It is a strain of the Influenzavirus A subtype H5N1 virus that was first detected in a goose in Guangdong in 1996. It is an HPAI (High Pathogenic Avian Influenza) virus, meaning that it can kill a very high percentage of chickens in a flock in mere days. It is believed to be the immediate precursor of the current dominant strain of HPAI A(H5N1) that evolved from 1999 to 2002 creating the Z genotype (also called "Asian lineage HPAI A(H5N1)") that is spreading globally and is epizootic (an epidemic in nonhumans) and panzootic (affecting animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling of hundreds of millions of others to stem its spread. The conversion to the Z genotype probably occurred by reassortment with a teal (duck) virus H6N1 during a mixed influenza infection:

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influenza virus

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Select agent

Under United States law , Biological select agents or toxins ( BSAT s)—or simply select agents for short—are bio-agents which (since 1997 ) have been declared by the U.S. Department of Health and Human Services (HHS) or by the U.S. Department of Agriculture (USDA) to have the "potential to pose a severe threat to public health and safety". The agents are divided into (1) HHS select agents and toxins affecting humans; (2) USDA select agents and toxins affecting agriculture; and (3) overlap select agents and toxins affecting both. The U.S. Centers for Disease Control and Prevention (CDC) regulates the laboratories which may possess, use, or transfer select agents within the United States in its Select Agent Program ( SAP )—also called the Federal Select Agent Program ( FSAP )—since 2001. The SAP was established to satisfy requirements of the USA PATRIOT Act of 2001 and the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 , which were enacted in the wake of the September 11, 2001 attacks and the subsequent 2001 anthrax attacks . Using BSATs in biomedical research prompts concerns about dual use . The federal government created the National Science Advisory Board for Biosecurity which promotes biosecurity in life science research. It is composed of government, education and industry experts who provide policy recommendations on ways to minimize the possibility that knowledge and technologies emanating from biological research will be misused to threaten public health or national security.The CDC has regulated the laboratories which may possess, use, or transfer select agents within the United States under the SAP since 2001. The SAP was established to satisfy requirements of the USA PATRIOT Act of 2001 and the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 , which were enacted in the wake of the September 11, 2001 attacks and the subsequent 2001 anthrax attacks . Using select agents in biomedical research prompts concerns about dual use . The federal government created the National Science Advisory Board for Biosecurity to promote biosecurity in life science research. It is composed of government, education and industry experts who provide policy recommendations on ways to minimize the possibility that knowledge and technologies emanating from biological research will be misused to threaten public health or national security. [ citation needed ]In July 2015, Gregory E. Demske, chief counsel to the inspector general in the HHS Office of Inspector General ( OIG ), testified that 30 civil violations of the SAP rules had been identified in the past 13 years, and that violators had paid about $2.4 million in fines. He explained that when the CDC's Division of Select Agents and Toxins detects possible SAP misconduct by an HHS worker, it coordinates with the OIG to gather facts. If it concludes that a civil violation might have occurred, it turns the case over to the OIG for possible enforcement. But if it suspects a crime, it pursues the matter with the FBI. Since passage of the Bioterrorism Act of 2002, the OIG had received 68 referrals from the CDC for possible Select Agent enforcement and found violations in 30 of those cases. Notices of violation were sent to 5 federal entities, 3 universities, and 2 other private organizations, all unnamed in his testimony. Demske remarked that no federal agencies had been fined for SAP violations.Eastern equine encephalitis virus (excluding South American genotypes) Tick-borne encephalitis -complex viruses (3 subtypes, excluding European ones) Central European tick-borne encephalitis virus Far-Eastern tick-borne encephalitis virus Russian spring and summer encephalitis virus Central European tick-borne encephalitis virus Far-Eastern tick-borne encephalitis virus Russian spring and summer encephalitis virus As of April 2021 [ update ] these biological agents and toxins are considered to "have the potential to pose a severe threat to both human and animal health, to plant health, or to animal and plant products". Eastern equine encephalitis virus (excluding South American genotypes) Tick-borne encephalitis -complex viruses (3 subtypes, excluding European ones) Central European tick-borne encephalitis virus Far-Eastern tick-borne encephalitis virus Russian spring and summer encephalitis virus Central European tick-borne encephalitis virus Far-Eastern tick-borne encephalitis virus Russian spring and summer encephalitis virus As of April 2021 [ update ] these biological agents and toxins are considered to "have the potential to pose a severe threat to both human and animal health, to plant health, or to animal and plant products". Eastern equine encephalitis virus (excluding South American genotypes) Tick-borne encephalitis -complex viruses (3 subtypes, excluding European ones) Central European tick-borne encephalitis virus Far-Eastern tick-borne encephalitis virus Russian spring and summer encephalitis virus Central European tick-borne encephalitis virus Far-Eastern tick-borne encephalitis virus Russian spring and summer encephalitis virusAs of April 2021 [ update ] these biological agents and toxins are considered to "have the potential to pose a severe threat to both human and animal health, to plant health, or to animal and plant products". Select agent regulations were revised in October 2012 to remove 19 BSATs from the list (7 Human and Overlap Agents and 12 Animal Agents).

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influenza virus

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Introduction to viruses

A virus is a tiny infectious agent that reproduces inside the cells of living hosts . When infected, the host cell is forced to rapidly produce thousands of identical copies of the original virus. Unlike most living things , viruses do not have cells that divide; new viruses assemble in the infected host cell. But unlike simpler infectious agents like prions , they contain genes , which allow them to mutate and evolve. Over 4,800 species of viruses have been described in detail out of the millions in the environment. Their origin is unclear: some may have evolved from plasmids —pieces of DNA that can move between cells—while others may have evolved from bacteria . Viruses are made of either two or three parts. All include genes . These genes contain the encoded biological information of the virus and are built from either DNA or RNA . All viruses are also covered with a protein coat to protect the genes. Some viruses may also have an envelope of fat-like substance that covers the protein coat, and makes them vulnerable to soap. A virus with this "viral envelope" uses it—along with specific receptors —to enter a new host cell. Viruses vary in shape from the simple helical and icosahedral to more complex structures. Viruses range in size from 20 to 300 nanometres ; it would take 33,000 to 500,000 of them, side by side, to stretch to 1 centimetre (0.4 in) . Viruses spread in many ways. Although many are very specific about which host species or tissue they attack, each species of virus relies on a particular method to copy itself. Plant viruses are often spread from plant to plant by insects and other organisms , known as vectors . Some viruses of humans and other animals are spread by exposure to infected bodily fluids. Viruses such as influenza are spread through the air by droplets of moisture when people cough or sneeze. Viruses such as norovirus are transmitted by the faecal–oral route , which involves the contamination of hands, food and water. Rotavirus is often spread by direct contact with infected children. The human immunodeficiency virus, HIV , is transmitted by bodily fluids transferred during sex. Others, such as the dengue virus , are spread by blood-sucking insects . Viruses, especially those made of RNA, can mutate rapidly to give rise to new types. Hosts may have little protection against such new forms. Influenza virus, for example, changes often, so a new vaccine is needed each year. Major changes can cause pandemics , as in the 2009 swine influenza that spread to most countries. Often, these mutations take place when the virus has first infected other animal hosts. Some examples of such "zoonotic" diseases include coronavirus in bats, and influenza in pigs and birds, before those viruses were transferred to humans . Viral infections can cause disease in humans, animals and plants. In healthy humans and animals, infections are usually eliminated by the immune system , which can provide lifetime immunity to the host for that virus. Antibiotics , which work against bacteria, have no impact, but antiviral drugs can treat life-threatening infections. Those vaccines that produce lifelong immunity can prevent some infections.In 1884, French microbiologist Charles Chamberland invented the Chamberland filter (or Chamberland–Pasteur filter), that contains pores smaller than bacteria . He could then pass a solution containing bacteria through the filter, and completely remove them. In the early 1890s, Russian biologist Dmitri Ivanovsky used this method to study what became known as the tobacco mosaic virus . His experiments showed that extracts from the crushed leaves of infected tobacco plants remain infectious after filtration. At the same time, several other scientists showed that, although these agents (later called viruses) were different from bacteria and about one hundred times smaller, they could still cause disease. In 1899, Dutch microbiologist Martinus Beijerinck observed that the agent only multiplied when in dividing cells . He called it a "contagious living fluid" ( Latin : contagium vivum fluidum )—or a "soluble living germ" because he could not find any germ-like particles. In the early 20th century, English bacteriologist Frederick Twort discovered viruses that infect bacteria, and French-Canadian microbiologist Félix d'Herelle described viruses that, when added to bacteria growing on agar , would lead to the formation of whole areas of dead bacteria. Counting these dead areas allowed him to calculate the number of viruses in the suspension. The invention of the electron microscope in 1931 brought the first images of viruses. In 1935, American biochemist and virologist Wendell Meredith Stanley examined the tobacco mosaic virus (TMV) and found it to be mainly made from protein . A short time later, this virus was shown to be made from protein and RNA . Rosalind Franklin developed X-ray crystallographic pictures and determined the full structure of TMV in 1955. Franklin confirmed that viral proteins formed a spiral hollow tube, wrapped by RNA, and also showed that viral RNA was a single strand, not a double helix like DNA. A problem for early scientists was that they did not know how to grow viruses without using live animals. The breakthrough came in 1931, when American pathologists Ernest William Goodpasture and Alice Miles Woodruff grew influenza , and several other viruses, in fertilised chickens' eggs. Some viruses could not be grown in chickens' eggs. This problem was solved in 1949, when John Franklin Enders , Thomas Huckle Weller , and Frederick Chapman Robbins grew polio virus in cultures of living animal cells. Over 4,800 species of viruses have been described in detail . Viruses co-exist with life wherever it occurs. They have probably existed since living cells first evolved. Their origin remains unclear because they do not fossilize , so molecular techniques have been the best way to hypothesise about how they arose. These techniques rely on the availability of ancient viral DNA or RNA, but most viruses that have been preserved and stored in laboratories are less than 90 years old. Molecular methods have only been successful in tracing the ancestry of viruses that evolved in the 20th century. New groups of viruses might have repeatedly emerged at all stages of the evolution of life. There are three major theories about the origins of viruses: There are problems with all of these theories. The regressive hypothesis does not explain why even the smallest of cellular parasites do not resemble viruses in any way. The escape or the cellular origin hypothesis does not explain the presence of unique structures in viruses that do not appear in cells. The coevolution, or "virus-first" hypothesis, conflicts with the definition of viruses, because viruses depend on host cells. Also, viruses are recognised as ancient, and to have origins that pre-date the divergence of life into the three domains . This discovery has led modern virologists to reconsider and re-evaluate these three classical hypotheses. A virus particle, also called a virion , consists of genes made from DNA or RNA which are surrounded by a protective coat of protein called a capsid . The capsid is made of many smaller, identical protein molecules called capsomers . The arrangement of the capsomers can either be icosahedral (20-sided), helical , or more complex. There is an inner shell around the DNA or RNA called the nucleocapsid , made out of proteins. Some viruses are surrounded by a bubble of lipid (fat) called an envelope , which makes them vulnerable to soap and alcohol. Viruses are among the smallest infectious agents, and are too small to be seen by light microscopy ; most of them can only be seen by electron microscopy . Their sizes range from 20 to 300 nanometres ; it would take 30,000 to 500,000 of them, side by side, to stretch to one centimetre (0.4 in). In comparison, bacteria are typically around 1000 nanometres (1 micrometer) in diameter, and host cells of higher organisms are typically a few tens of micrometers . Some viruses such as megaviruses and pandoraviruses are relatively large viruses. At around 1000 nanometres, these viruses, which infect amoebae , were discovered in 2003 and 2013. They are around ten times wider (and thus a thousand times larger in volume) than influenza viruses , and the discovery of these "giant" viruses astonished scientists. The genes of viruses are made from DNA (deoxyribonucleic acid) and, in many viruses, RNA (ribonucleic acid). The biological information contained in an organism is encoded in its DNA or RNA. Most organisms use DNA, but many viruses have RNA as their genetic material. The DNA or RNA of viruses consists of either a single strand or a double helix. Viruses can reproduce rapidly because they have relatively few genes. For example, influenza virus has only eight genes and rotavirus has eleven. In comparison, humans have 20,000–25,000. Some viral genes contain the code to make the structural proteins that form the virus particle. Other genes make non-structural proteins found only in the cells the virus infects. All cells, and many viruses, produce proteins that are enzymes that drive chemical reactions. Some of these enzymes, called DNA polymerase and RNA polymerase , make new copies of DNA and RNA. A virus's polymerase enzymes are often much more efficient at making DNA and RNA than the equivalent enzymes of the host cells, but viral RNA polymerase enzymes are error-prone, causing RNA viruses to mutate and form new strains. In some species of RNA virus, the genes are not on a continuous molecule of RNA, but are separated. The influenza virus, for example, has eight separate genes made of RNA. When two different strains of influenza virus infect the same cell, these genes can mix and produce new strains of the virus in a process called reassortment . Proteins are essential to life. Cells produce new protein molecules from amino acid building blocks based on information coded in DNA. Each type of protein is a specialist that usually only performs one function, so if a cell needs to do something new, it must make a new protein. Viruses force the cell to make new proteins that the cell does not need, but are needed for the virus to reproduce. Protein synthesis consists of two major steps: transcription and translation . Transcription is the process where information in DNA, called the genetic code , is used to produce RNA copies called messenger RNA (mRNA). These migrate through the cell and carry the code to ribosomes where it is used to make proteins. This is called translation because the protein's amino acid structure is determined by the mRNA's code. Information is hence translated from the language of nucleic acids to the language of amino acids. Some nucleic acids of RNA viruses function directly as mRNA without further modification. For this reason, these viruses are called positive-sense RNA viruses. In other RNA viruses, the RNA is a complementary copy of mRNA and these viruses rely on the cell's or their own enzyme to make mRNA. These are called negative-sense RNA viruses. In viruses made from DNA, the method of mRNA production is similar to that of the cell. The species of viruses called retroviruses behave completely differently: they have RNA, but inside the host cell a DNA copy of their RNA is made with the help of the enzyme reverse transcriptase . This DNA is then incorporated into the host's own DNA, and copied into mRNA by the cell's normal pathways. Viruses are among the smallest infectious agents, and are too small to be seen by light microscopy ; most of them can only be seen by electron microscopy . Their sizes range from 20 to 300 nanometres ; it would take 30,000 to 500,000 of them, side by side, to stretch to one centimetre (0.4 in). In comparison, bacteria are typically around 1000 nanometres (1 micrometer) in diameter, and host cells of higher organisms are typically a few tens of micrometers . Some viruses such as megaviruses and pandoraviruses are relatively large viruses. At around 1000 nanometres, these viruses, which infect amoebae , were discovered in 2003 and 2013. They are around ten times wider (and thus a thousand times larger in volume) than influenza viruses , and the discovery of these "giant" viruses astonished scientists. The genes of viruses are made from DNA (deoxyribonucleic acid) and, in many viruses, RNA (ribonucleic acid). The biological information contained in an organism is encoded in its DNA or RNA. Most organisms use DNA, but many viruses have RNA as their genetic material. The DNA or RNA of viruses consists of either a single strand or a double helix. Viruses can reproduce rapidly because they have relatively few genes. For example, influenza virus has only eight genes and rotavirus has eleven. In comparison, humans have 20,000–25,000. Some viral genes contain the code to make the structural proteins that form the virus particle. Other genes make non-structural proteins found only in the cells the virus infects. All cells, and many viruses, produce proteins that are enzymes that drive chemical reactions. Some of these enzymes, called DNA polymerase and RNA polymerase , make new copies of DNA and RNA. A virus's polymerase enzymes are often much more efficient at making DNA and RNA than the equivalent enzymes of the host cells, but viral RNA polymerase enzymes are error-prone, causing RNA viruses to mutate and form new strains. In some species of RNA virus, the genes are not on a continuous molecule of RNA, but are separated. The influenza virus, for example, has eight separate genes made of RNA. When two different strains of influenza virus infect the same cell, these genes can mix and produce new strains of the virus in a process called reassortment . Proteins are essential to life. Cells produce new protein molecules from amino acid building blocks based on information coded in DNA. Each type of protein is a specialist that usually only performs one function, so if a cell needs to do something new, it must make a new protein. Viruses force the cell to make new proteins that the cell does not need, but are needed for the virus to reproduce. Protein synthesis consists of two major steps: transcription and translation . Transcription is the process where information in DNA, called the genetic code , is used to produce RNA copies called messenger RNA (mRNA). These migrate through the cell and carry the code to ribosomes where it is used to make proteins. This is called translation because the protein's amino acid structure is determined by the mRNA's code. Information is hence translated from the language of nucleic acids to the language of amino acids. Some nucleic acids of RNA viruses function directly as mRNA without further modification. For this reason, these viruses are called positive-sense RNA viruses. In other RNA viruses, the RNA is a complementary copy of mRNA and these viruses rely on the cell's or their own enzyme to make mRNA. These are called negative-sense RNA viruses. In viruses made from DNA, the method of mRNA production is similar to that of the cell. The species of viruses called retroviruses behave completely differently: they have RNA, but inside the host cell a DNA copy of their RNA is made with the help of the enzyme reverse transcriptase . This DNA is then incorporated into the host's own DNA, and copied into mRNA by the cell's normal pathways. When a virus infects a cell, the virus forces it to make thousands more viruses. It does this by making the cell copy the virus's DNA or RNA, making viral proteins, which all assemble to form new virus particles. There are six basic, overlapping stages in the life cycle of viruses in living cells: Viruses have an extensive range of structural and biochemical effects on the host cell. These are called cytopathic effects . Most virus infections eventually result in the death of the host cell. The causes of death include cell lysis (bursting), alterations to the cell's surface membrane and apoptosis (cell "suicide"). Often cell death is caused by cessation of its normal activity due to proteins produced by the virus, not all of which are components of the virus particle. Some viruses cause no apparent changes to the infected cell. Cells in which the virus is latent (inactive) show few signs of infection and often function normally. This causes persistent infections and the virus is often dormant for many months or years. This is often the case with herpes viruses . Some viruses, such as Epstein–Barr virus , often cause cells to proliferate without causing malignancy ; but some other viruses, such as papillomavirus , are an established cause of cancer. When a cell's DNA is damaged by a virus such that the cell cannot repair itself, this often triggers apoptosis. One of the results of apoptosis is destruction of the damaged DNA by the cell itself. Some viruses have mechanisms to limit apoptosis so that the host cell does not die before progeny viruses have been produced; HIV , for example, does this. There are many ways in which viruses spread from host to host but each species of virus uses only one or two. Many viruses that infect plants are carried by organisms ; such organisms are called vectors . Some viruses that infect animals, including humans, are also spread by vectors, usually blood-sucking insects, but direct transmission is more common. Some virus infections, such as norovirus and rotavirus , are spread by contaminated food and water, by hands and communal objects , and by intimate contact with another infected person, while others like SARS-CoV-2 and influenza viruses are airborne. Viruses such as HIV, hepatitis B and hepatitis C are often transmitted by unprotected sex or contaminated hypodermic needles . To prevent infections and epidemics, it is important to know how each different kind of virus is spread. Common human diseases caused by viruses include the common cold , influenza , chickenpox and cold sores . Serious diseases such as Ebola and AIDS are also caused by viruses. Many viruses cause little or no disease and are said to be "benign". The more harmful viruses are described as virulent . Viruses cause different diseases depending on the types of cell that they infect. Some viruses can cause lifelong or chronic infections where the viruses continue to reproduce in the body despite the host's defence mechanisms. This is common in hepatitis B virus and hepatitis C virus infections. People chronically infected with a virus are known as carriers. They serve as important reservoirs of the virus. If the proportion of carriers in a given population reaches a given threshold, a disease is said to be endemic . Before the advent of vaccination, infections with viruses were common and outbreaks occurred regularly. In countries with a temperate climate, viral diseases are usually seasonal. Poliomyelitis , caused by poliovirus often occurred in the summer months. By contrast colds, influenza and rotavirus infections are usually a problem during the winter months. Other viruses, such as measles virus , caused outbreaks regularly every third year. In developing countries, viruses that cause respiratory and enteric infections are common throughout the year. Viruses carried by insects are a common cause of diseases in these settings. Zika and dengue viruses for example are transmitted by the female Aedes mosquitoes, which bite humans particularly during the mosquitoes' breeding season. Although viral pandemics are rare events, HIV—which evolved from viruses found in monkeys and chimpanzees—has been pandemic since at least the 1980s. During the 20th century there were four pandemics caused by influenza virus and those that occurred in 1918, 1957 and 1968 were severe. Before its eradication, smallpox was a cause of pandemics for more than 3,000 years. Throughout history, human migration has aided the spread of pandemic infections; first by sea and in modern times also by air. With the exception of smallpox, most pandemics are caused by newly evolved viruses. These "emergent" viruses are usually mutants of less harmful viruses that have circulated previously either in humans or in other animals. Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are caused by new types of coronaviruses . Other coronaviruses are known to cause mild infections in humans, so the virulence and rapid spread of SARS infections—that by July 2003 had caused around 8,000 cases and 800 deaths—was unexpected and most countries were not prepared. A related coronavirus emerged in Wuhan , China, in November 2019 and spread rapidly around the world. Thought to have originated in bats and subsequently named severe acute respiratory syndrome coronavirus 2 , infections with the virus cause a disease called COVID-19 , that varies in severity from mild to deadly, and led to a pandemic in 2020 . Restrictions unprecedented in peacetime were placed on international travel, and curfews imposed in several major cities worldwide. There are many types of plant virus , but often they only cause a decrease in yield , and it is not economically viable to try to control them. Plant viruses are frequently spread from plant to plant by organisms called " vectors ". These are normally insects, but some fungi , nematode worms and single-celled organisms have also been shown to be vectors. When control of plant virus infections is considered economical (perennial fruits, for example) efforts are concentrated on killing the vectors and removing alternate hosts such as weeds. Plant viruses are harmless to humans and other animals because they can only reproduce in living plant cells. Bacteriophages are viruses that infect bacteria and archaea . They are important in marine ecology : as the infected bacteria burst, carbon compounds are released back into the environment, which stimulates fresh organic growth. Bacteriophages are useful in scientific research because they are harmless to humans and can be studied easily. These viruses can be a problem in industries that produce food and drugs by fermentation and depend on healthy bacteria. Some bacterial infections are becoming difficult to control with antibiotics, so there is a growing interest in the use of bacteriophages to treat infections in humans. Animals, including humans, have many natural defences against viruses. Some are non-specific and protect against many viruses regardless of the type. This innate immunity is not improved by repeated exposure to viruses and does not retain a "memory" of the infection. The skin of animals, particularly its surface, which is made from dead cells, prevents many types of viruses from infecting the host. The acidity of the contents of the stomach destroys many viruses that have been swallowed. When a virus overcomes these barriers and enters the host, other innate defences prevent the spread of infection in the body. A special hormone called interferon is produced by the body when viruses are present, and this stops the viruses from reproducing by killing the infected cells and their close neighbours. Inside cells, there are enzymes that destroy the RNA of viruses. This is called RNA interference . Some blood cells engulf and destroy other virus-infected cells. Specific immunity to viruses develops over time and white blood cells called lymphocytes play a central role. Lymphocytes retain a "memory" of virus infections and produce many special molecules called antibodies . These antibodies attach to viruses and stop the virus from infecting cells. Antibodies are highly selective and attack only one type of virus. The body makes many different antibodies, especially during the initial infection. After the infection subsides, some antibodies remain and continue to be produced, usually giving the host lifelong immunity to the virus. Plants have elaborate and effective defence mechanisms against viruses. One of the most effective is the presence of so-called resistance (R) genes . Each R gene confers resistance to a particular virus by triggering localised areas of cell death around the infected cell, which can often be seen with the unaided eye as large spots. This stops the infection from spreading. RNA interference is also an effective defence in plants. When they are infected, plants often produce natural disinfectants that destroy viruses, such as salicylic acid , nitric oxide and reactive oxygen molecules . The major way bacteria defend themselves from bacteriophages is by producing enzymes which destroy foreign DNA. These enzymes, called restriction endonucleases , cut up the viral DNA that bacteriophages inject into bacterial cells. Vaccines simulate a natural infection and its associated immune response, but do not cause the disease. Their use has resulted in the eradication of smallpox and a dramatic decline in illness and death caused by infections such as polio , measles , mumps and rubella . Vaccines are available to prevent over fourteen viral infections of humans and more are used to prevent viral infections of animals. Vaccines may consist of either live or killed viruses. Live vaccines contain weakened forms of the virus, but these vaccines can be dangerous when given to people with weak immunity . In these people, the weakened virus can cause the original disease. Biotechnology and genetic engineering techniques are used to produce "designer" vaccines that only have the capsid proteins of the virus. Hepatitis B vaccine is an example of this type of vaccine. These vaccines are safer because they can never cause the disease. Since the mid-1980s, the development of antiviral drugs has increased rapidly, mainly driven by the AIDS pandemic. Antiviral drugs are often nucleoside analogues , which masquerade as DNA building blocks ( nucleosides ). When the replication of virus DNA begins, some of the fake building blocks are used. This prevents DNA replication because the drugs lack the essential features that allow the formation of a DNA chain. When DNA production stops the virus can no longer reproduce. Examples of nucleoside analogues are aciclovir for herpes virus infections and lamivudine for HIV and hepatitis B virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral drugs. Other antiviral drugs target different stages of the viral life cycle. HIV is dependent on an enzyme called the HIV-1 protease for the virus to become infectious. There is a class of drugs called protease inhibitors , which bind to this enzyme and stop it from functioning. Hepatitis C is caused by an RNA virus. In 80% of those infected, the disease becomes chronic , and they remain infectious for the rest of their lives unless they are treated. There are effective treatments that use direct-acting antivirals . Treatments for chronic carriers of the hepatitis B virus have been developed by a similar strategy, using lamivudine and other anti-viral drugs. In both diseases, the drugs stop the virus from reproducing and the interferon kills any remaining infected cells. HIV infections are usually treated with a combination of antiviral drugs, each targeting a different stage in the virus's life cycle. There are drugs that prevent the virus from attaching to cells, others that are nucleoside analogues and some poison the virus's enzymes that it needs to reproduce. The success of these drugs is proof of the importance of knowing how viruses reproduce. Common human diseases caused by viruses include the common cold , influenza , chickenpox and cold sores . Serious diseases such as Ebola and AIDS are also caused by viruses. Many viruses cause little or no disease and are said to be "benign". The more harmful viruses are described as virulent . Viruses cause different diseases depending on the types of cell that they infect. Some viruses can cause lifelong or chronic infections where the viruses continue to reproduce in the body despite the host's defence mechanisms. This is common in hepatitis B virus and hepatitis C virus infections. People chronically infected with a virus are known as carriers. They serve as important reservoirs of the virus. If the proportion of carriers in a given population reaches a given threshold, a disease is said to be endemic . Before the advent of vaccination, infections with viruses were common and outbreaks occurred regularly. In countries with a temperate climate, viral diseases are usually seasonal. Poliomyelitis , caused by poliovirus often occurred in the summer months. By contrast colds, influenza and rotavirus infections are usually a problem during the winter months. Other viruses, such as measles virus , caused outbreaks regularly every third year. In developing countries, viruses that cause respiratory and enteric infections are common throughout the year. Viruses carried by insects are a common cause of diseases in these settings. Zika and dengue viruses for example are transmitted by the female Aedes mosquitoes, which bite humans particularly during the mosquitoes' breeding season. Although viral pandemics are rare events, HIV—which evolved from viruses found in monkeys and chimpanzees—has been pandemic since at least the 1980s. During the 20th century there were four pandemics caused by influenza virus and those that occurred in 1918, 1957 and 1968 were severe. Before its eradication, smallpox was a cause of pandemics for more than 3,000 years. Throughout history, human migration has aided the spread of pandemic infections; first by sea and in modern times also by air. With the exception of smallpox, most pandemics are caused by newly evolved viruses. These "emergent" viruses are usually mutants of less harmful viruses that have circulated previously either in humans or in other animals. Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are caused by new types of coronaviruses . Other coronaviruses are known to cause mild infections in humans, so the virulence and rapid spread of SARS infections—that by July 2003 had caused around 8,000 cases and 800 deaths—was unexpected and most countries were not prepared. A related coronavirus emerged in Wuhan , China, in November 2019 and spread rapidly around the world. Thought to have originated in bats and subsequently named severe acute respiratory syndrome coronavirus 2 , infections with the virus cause a disease called COVID-19 , that varies in severity from mild to deadly, and led to a pandemic in 2020 . Restrictions unprecedented in peacetime were placed on international travel, and curfews imposed in several major cities worldwide. If the proportion of carriers in a given population reaches a given threshold, a disease is said to be endemic . Before the advent of vaccination, infections with viruses were common and outbreaks occurred regularly. In countries with a temperate climate, viral diseases are usually seasonal. Poliomyelitis , caused by poliovirus often occurred in the summer months. By contrast colds, influenza and rotavirus infections are usually a problem during the winter months. Other viruses, such as measles virus , caused outbreaks regularly every third year. In developing countries, viruses that cause respiratory and enteric infections are common throughout the year. Viruses carried by insects are a common cause of diseases in these settings. Zika and dengue viruses for example are transmitted by the female Aedes mosquitoes, which bite humans particularly during the mosquitoes' breeding season. Although viral pandemics are rare events, HIV—which evolved from viruses found in monkeys and chimpanzees—has been pandemic since at least the 1980s. During the 20th century there were four pandemics caused by influenza virus and those that occurred in 1918, 1957 and 1968 were severe. Before its eradication, smallpox was a cause of pandemics for more than 3,000 years. Throughout history, human migration has aided the spread of pandemic infections; first by sea and in modern times also by air. With the exception of smallpox, most pandemics are caused by newly evolved viruses. These "emergent" viruses are usually mutants of less harmful viruses that have circulated previously either in humans or in other animals. Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) are caused by new types of coronaviruses . Other coronaviruses are known to cause mild infections in humans, so the virulence and rapid spread of SARS infections—that by July 2003 had caused around 8,000 cases and 800 deaths—was unexpected and most countries were not prepared. A related coronavirus emerged in Wuhan , China, in November 2019 and spread rapidly around the world. Thought to have originated in bats and subsequently named severe acute respiratory syndrome coronavirus 2 , infections with the virus cause a disease called COVID-19 , that varies in severity from mild to deadly, and led to a pandemic in 2020 . Restrictions unprecedented in peacetime were placed on international travel, and curfews imposed in several major cities worldwide. There are many types of plant virus , but often they only cause a decrease in yield , and it is not economically viable to try to control them. Plant viruses are frequently spread from plant to plant by organisms called " vectors ". These are normally insects, but some fungi , nematode worms and single-celled organisms have also been shown to be vectors. When control of plant virus infections is considered economical (perennial fruits, for example) efforts are concentrated on killing the vectors and removing alternate hosts such as weeds. Plant viruses are harmless to humans and other animals because they can only reproduce in living plant cells. Bacteriophages are viruses that infect bacteria and archaea . They are important in marine ecology : as the infected bacteria burst, carbon compounds are released back into the environment, which stimulates fresh organic growth. Bacteriophages are useful in scientific research because they are harmless to humans and can be studied easily. These viruses can be a problem in industries that produce food and drugs by fermentation and depend on healthy bacteria. Some bacterial infections are becoming difficult to control with antibiotics, so there is a growing interest in the use of bacteriophages to treat infections in humans. Animals, including humans, have many natural defences against viruses. Some are non-specific and protect against many viruses regardless of the type. This innate immunity is not improved by repeated exposure to viruses and does not retain a "memory" of the infection. The skin of animals, particularly its surface, which is made from dead cells, prevents many types of viruses from infecting the host. The acidity of the contents of the stomach destroys many viruses that have been swallowed. When a virus overcomes these barriers and enters the host, other innate defences prevent the spread of infection in the body. A special hormone called interferon is produced by the body when viruses are present, and this stops the viruses from reproducing by killing the infected cells and their close neighbours. Inside cells, there are enzymes that destroy the RNA of viruses. This is called RNA interference . Some blood cells engulf and destroy other virus-infected cells. Specific immunity to viruses develops over time and white blood cells called lymphocytes play a central role. Lymphocytes retain a "memory" of virus infections and produce many special molecules called antibodies . These antibodies attach to viruses and stop the virus from infecting cells. Antibodies are highly selective and attack only one type of virus. The body makes many different antibodies, especially during the initial infection. After the infection subsides, some antibodies remain and continue to be produced, usually giving the host lifelong immunity to the virus. Plants have elaborate and effective defence mechanisms against viruses. One of the most effective is the presence of so-called resistance (R) genes . Each R gene confers resistance to a particular virus by triggering localised areas of cell death around the infected cell, which can often be seen with the unaided eye as large spots. This stops the infection from spreading. RNA interference is also an effective defence in plants. When they are infected, plants often produce natural disinfectants that destroy viruses, such as salicylic acid , nitric oxide and reactive oxygen molecules . The major way bacteria defend themselves from bacteriophages is by producing enzymes which destroy foreign DNA. These enzymes, called restriction endonucleases , cut up the viral DNA that bacteriophages inject into bacterial cells. Animals, including humans, have many natural defences against viruses. Some are non-specific and protect against many viruses regardless of the type. This innate immunity is not improved by repeated exposure to viruses and does not retain a "memory" of the infection. The skin of animals, particularly its surface, which is made from dead cells, prevents many types of viruses from infecting the host. The acidity of the contents of the stomach destroys many viruses that have been swallowed. When a virus overcomes these barriers and enters the host, other innate defences prevent the spread of infection in the body. A special hormone called interferon is produced by the body when viruses are present, and this stops the viruses from reproducing by killing the infected cells and their close neighbours. Inside cells, there are enzymes that destroy the RNA of viruses. This is called RNA interference . Some blood cells engulf and destroy other virus-infected cells. Specific immunity to viruses develops over time and white blood cells called lymphocytes play a central role. Lymphocytes retain a "memory" of virus infections and produce many special molecules called antibodies . These antibodies attach to viruses and stop the virus from infecting cells. Antibodies are highly selective and attack only one type of virus. The body makes many different antibodies, especially during the initial infection. After the infection subsides, some antibodies remain and continue to be produced, usually giving the host lifelong immunity to the virus. Plants have elaborate and effective defence mechanisms against viruses. One of the most effective is the presence of so-called resistance (R) genes . Each R gene confers resistance to a particular virus by triggering localised areas of cell death around the infected cell, which can often be seen with the unaided eye as large spots. This stops the infection from spreading. RNA interference is also an effective defence in plants. When they are infected, plants often produce natural disinfectants that destroy viruses, such as salicylic acid , nitric oxide and reactive oxygen molecules . The major way bacteria defend themselves from bacteriophages is by producing enzymes which destroy foreign DNA. These enzymes, called restriction endonucleases , cut up the viral DNA that bacteriophages inject into bacterial cells. Vaccines simulate a natural infection and its associated immune response, but do not cause the disease. Their use has resulted in the eradication of smallpox and a dramatic decline in illness and death caused by infections such as polio , measles , mumps and rubella . Vaccines are available to prevent over fourteen viral infections of humans and more are used to prevent viral infections of animals. Vaccines may consist of either live or killed viruses. Live vaccines contain weakened forms of the virus, but these vaccines can be dangerous when given to people with weak immunity . In these people, the weakened virus can cause the original disease. Biotechnology and genetic engineering techniques are used to produce "designer" vaccines that only have the capsid proteins of the virus. Hepatitis B vaccine is an example of this type of vaccine. These vaccines are safer because they can never cause the disease. Since the mid-1980s, the development of antiviral drugs has increased rapidly, mainly driven by the AIDS pandemic. Antiviral drugs are often nucleoside analogues , which masquerade as DNA building blocks ( nucleosides ). When the replication of virus DNA begins, some of the fake building blocks are used. This prevents DNA replication because the drugs lack the essential features that allow the formation of a DNA chain. When DNA production stops the virus can no longer reproduce. Examples of nucleoside analogues are aciclovir for herpes virus infections and lamivudine for HIV and hepatitis B virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral drugs. Other antiviral drugs target different stages of the viral life cycle. HIV is dependent on an enzyme called the HIV-1 protease for the virus to become infectious. There is a class of drugs called protease inhibitors , which bind to this enzyme and stop it from functioning. Hepatitis C is caused by an RNA virus. In 80% of those infected, the disease becomes chronic , and they remain infectious for the rest of their lives unless they are treated. There are effective treatments that use direct-acting antivirals . Treatments for chronic carriers of the hepatitis B virus have been developed by a similar strategy, using lamivudine and other anti-viral drugs. In both diseases, the drugs stop the virus from reproducing and the interferon kills any remaining infected cells. HIV infections are usually treated with a combination of antiviral drugs, each targeting a different stage in the virus's life cycle. There are drugs that prevent the virus from attaching to cells, others that are nucleoside analogues and some poison the virus's enzymes that it needs to reproduce. The success of these drugs is proof of the importance of knowing how viruses reproduce. Vaccines simulate a natural infection and its associated immune response, but do not cause the disease. Their use has resulted in the eradication of smallpox and a dramatic decline in illness and death caused by infections such as polio , measles , mumps and rubella . Vaccines are available to prevent over fourteen viral infections of humans and more are used to prevent viral infections of animals. Vaccines may consist of either live or killed viruses. Live vaccines contain weakened forms of the virus, but these vaccines can be dangerous when given to people with weak immunity . In these people, the weakened virus can cause the original disease. Biotechnology and genetic engineering techniques are used to produce "designer" vaccines that only have the capsid proteins of the virus. Hepatitis B vaccine is an example of this type of vaccine. These vaccines are safer because they can never cause the disease. Since the mid-1980s, the development of antiviral drugs has increased rapidly, mainly driven by the AIDS pandemic. Antiviral drugs are often nucleoside analogues , which masquerade as DNA building blocks ( nucleosides ). When the replication of virus DNA begins, some of the fake building blocks are used. This prevents DNA replication because the drugs lack the essential features that allow the formation of a DNA chain. When DNA production stops the virus can no longer reproduce. Examples of nucleoside analogues are aciclovir for herpes virus infections and lamivudine for HIV and hepatitis B virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral drugs. Other antiviral drugs target different stages of the viral life cycle. HIV is dependent on an enzyme called the HIV-1 protease for the virus to become infectious. There is a class of drugs called protease inhibitors , which bind to this enzyme and stop it from functioning. Hepatitis C is caused by an RNA virus. In 80% of those infected, the disease becomes chronic , and they remain infectious for the rest of their lives unless they are treated. There are effective treatments that use direct-acting antivirals . Treatments for chronic carriers of the hepatitis B virus have been developed by a similar strategy, using lamivudine and other anti-viral drugs. In both diseases, the drugs stop the virus from reproducing and the interferon kills any remaining infected cells. HIV infections are usually treated with a combination of antiviral drugs, each targeting a different stage in the virus's life cycle. There are drugs that prevent the virus from attaching to cells, others that are nucleoside analogues and some poison the virus's enzymes that it needs to reproduce. The success of these drugs is proof of the importance of knowing how viruses reproduce. Viruses are the most abundant biological entity in aquatic environments; one teaspoon of seawater contains about ten million viruses, and they are essential to the regulation of saltwater and freshwater ecosystems. Most are bacteriophages, which are harmless to plants and animals. They infect and destroy the bacteria in aquatic microbial communities and this is the most important mechanism of recycling carbon in the marine environment. The organic molecules released from the bacterial cells by the viruses stimulate fresh bacterial and algal growth. Microorganisms constitute more than 90% of the biomass in the sea. It is estimated that viruses kill approximately 20% of this biomass each day and that there are fifteen times as many viruses in the oceans as there are bacteria and archaea. They are mainly responsible for the rapid destruction of harmful algal blooms , which often kill other marine life. The number of viruses in the oceans decreases further offshore and deeper into the water, where there are fewer host organisms. Their effects are far-reaching; by increasing the amount of respiration in the oceans, viruses are indirectly responsible for reducing the amount of carbon dioxide in the atmosphere by approximately 3 gigatonnes of carbon per year. Marine mammals are also susceptible to viral infections. In 1988 and 2002, thousands of harbour seals were killed in Europe by phocine distemper virus . Many other viruses, including caliciviruses, herpesviruses, adenoviruses and parvoviruses, circulate in marine mammal populations. Viruses can also serve as an alternative food source for microorganisms which engage in virovory , supplying nucleic acids, nitrogen, and phosphorus through their consumption.

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influenza virus

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Orthornavirae

Positive-strand RNA viruses Negative-strand RNA viruses Double-stranded RNA viruses Orthornavirae is a kingdom of viruses that have genomes made of ribonucleic acid (RNA), including genes which encode an RNA-dependent RNA polymerase (RdRp). The RdRp is used to transcribe the viral RNA genome into messenger RNA (mRNA) and to replicate the genome. Viruses in this kingdom share a number of characteristics which promote rapid evolution , including high rates of genetic mutation , recombination , and reassortment . Viruses in Orthornavirae belong to the realm Riboviria . They are descended from a common ancestor that may have been a non-viral molecule that encoded a reverse transcriptase instead of an RdRp for replication. The kingdom is subdivided into five phyla that separate member viruses based on their genome type, host range, and genetic similarity. Viruses with three genome types are included: positive-strand RNA viruses , negative-strand RNA viruses , and double-stranded RNA viruses . Many of the most widely known viral diseases are caused by members of this kingdom, including coronaviruses , the Ebola virus , influenza viruses , the measles virus , and the rabies virus , as well as the first virus ever discovered, tobacco mosaic virus . In modern history, RdRp-encoding RNA viruses have caused numerous disease outbreaks, and they infect many economically important crops. Most eukaryotic viruses, including most human, animal, and plant viruses, are RdRp-encoding RNA viruses. In contrast, there are relatively few prokaryotic viruses in the kingdom.The first part of Orthornavirae comes from Greek ὀρθός [orthós], meaning straight, the middle part, rna , refers to RNA, and - virae is the suffix used for virus kingdoms. RNA viruses in Orthornavirae typically do not encode many proteins, but most positive-sense, single-stranded (+ssRNA) viruses and some double-stranded RNA (dsRNA) viruses encode a major capsid protein that has a single jelly roll fold , so named because the folded structure of the protein contains a structure that resembles a jelly roll . Many also possess an envelope , a type of lipid membrane that typically surrounds the capsid. In particular, the viral envelope is near-universal among negative-sense, single-stranded (-ssRNA) viruses. Viruses in Orthornavirae have three different types of genomes: dsRNA, +ssRNA, and -ssRNA. Single-stranded RNA viruses have either a positive or negative sense strand , and dsRNA viruses have both. This structure of the genome is important in terms of transcription to synthesize viral mRNA as well as replication of the genome, both of which are carried out by the viral enzyme RNA-dependent RNA polymerase (RdRp), also called RNA replicase. Positive-strand RNA viruses have genomes that can function as mRNA, so transcription is not necessary. However, +ssRNA will produce dsRNA forms as part of the process of replicating their genomes. From the dsRNA, additional positive strands are synthesized, which may be used as mRNA or for genomes for progeny. Because +ssRNA viruses create intermediate dsRNA forms, they have to avoid the host's immune system in order to replicate. +ssRNA viruses accomplish this by replicating in membrane-associated vesicles that are used as replication factories. For many +ssRNA viruses, subgenomic portions of the genome will be transcribed to translate specific proteins, whereas others will transcribe a polyprotein that is cleaved to produce separate proteins. Negative-strand RNA viruses have genomes that function as templates from which mRNA can be synthesized directly by RdRp. Replication is the same process but executed on the positive sense antigenome, during which RdRp ignores all transcription signals so that a complete -ssRNA genome can be synthesized. -ssRNA viruses vary between those that initiate transcription by the RdRp creating a cap on the 5'-end (usually pronounced "five prime end") of the genome or by snatching a cap from host mRNA and attaching it to the viral RNA. For many -ssRNA viruses, at the end of transcription, RdRp stutters on a uracil in the genome, synthesizing hundreds of adenines in a row as part of creating a polyadenylated tail for the mRNA. Some -ssRNA viruses are essentially ambisense, and have proteins encoded by both the positive and negative strand, so mRNA is synthesized directly from the genome and from a complementary strand. For dsRNA viruses, RdRp transcribes mRNA by using the negative strand as a template. Positive strands may also be used as templates to synthesize negative strands for the construction of genomic dsRNA. dsRNA is not a molecule produced by cells, so cellular life has evolved mechanisms to detect and inactivate viral dsRNA. To counter this, dsRNA viruses typically retain their genomes inside of viral capsid in order to evade the host's immune system. RNA viruses in Orthornavirae experience a high rate of genetic mutations because RdRp is prone to making errors in replication since it typically lacks proofreading mechanisms to repair errors. [note 1] Mutations in RNA viruses are often influenced by host factors such as dsRNA-dependent adenosine deaminases , which edit viral genomes by changing adenosines to inosines . Mutations in genes that are essential for replication lead to a reduced number of progeny, so viral genomes typically contain sequences that are highly conserved over time with relatively few mutations. Many RdRp-encoding RNA viruses also experience a high rate of genetic recombination , though rates of recombination vary significantly, with lower rates in -ssRNA viruses and higher rates in dsRNA and +ssRNA viruses. There are two types of recombination: copy choice recombination and reassortment. Copy choice recombination occurs when the RdRp switches templates during synthesis without releasing the prior, newly created RNA strand, which generates a genome of mixed ancestry. Reassortment , which is restricted to viruses with segmented genomes, has segments from different genomes packaged into a single virion, or virus particle, which also produces hybrid progeny. For reassortment, some segmented viruses package their genomes into multiple virions, which produces genomes that are random mixtures of parents, whereas for those that are packaged into a single virion, typically individual segments are swapped. Both forms of recombination can only occur if more than one virus is present in a cell, and the more alleles are present, the more likely recombination is to occur. A key difference between copy choice recombination and reassortment is that copy choice recombination can occur anywhere in a genome, whereas reassortment swaps fully-replicated segments. Therefore, copy choice recombination can produce non-functional viral proteins whereas reassortment cannot. The mutation rate of a virus is associated with the rate of genetic recombinations. Higher mutation rates increase both the number of advantageous and disadvantageous mutations, whereas higher rates of recombination allows for beneficial mutations to be separated from deleterious ones. [ vague ] Therefore, higher rates of mutations and recombinations, up to a certain point, improve viruses' ability to adapt. Notable examples of this include reassortments that enable cross-species transmission of influenza viruses, which have led to numerous pandemics, as well as the emergence of drug-resistance influenza strains via mutations that were reassorted. RNA viruses in Orthornavirae typically do not encode many proteins, but most positive-sense, single-stranded (+ssRNA) viruses and some double-stranded RNA (dsRNA) viruses encode a major capsid protein that has a single jelly roll fold , so named because the folded structure of the protein contains a structure that resembles a jelly roll . Many also possess an envelope , a type of lipid membrane that typically surrounds the capsid. In particular, the viral envelope is near-universal among negative-sense, single-stranded (-ssRNA) viruses. Viruses in Orthornavirae have three different types of genomes: dsRNA, +ssRNA, and -ssRNA. Single-stranded RNA viruses have either a positive or negative sense strand , and dsRNA viruses have both. This structure of the genome is important in terms of transcription to synthesize viral mRNA as well as replication of the genome, both of which are carried out by the viral enzyme RNA-dependent RNA polymerase (RdRp), also called RNA replicase. Positive-strand RNA viruses have genomes that can function as mRNA, so transcription is not necessary. However, +ssRNA will produce dsRNA forms as part of the process of replicating their genomes. From the dsRNA, additional positive strands are synthesized, which may be used as mRNA or for genomes for progeny. Because +ssRNA viruses create intermediate dsRNA forms, they have to avoid the host's immune system in order to replicate. +ssRNA viruses accomplish this by replicating in membrane-associated vesicles that are used as replication factories. For many +ssRNA viruses, subgenomic portions of the genome will be transcribed to translate specific proteins, whereas others will transcribe a polyprotein that is cleaved to produce separate proteins. Negative-strand RNA viruses have genomes that function as templates from which mRNA can be synthesized directly by RdRp. Replication is the same process but executed on the positive sense antigenome, during which RdRp ignores all transcription signals so that a complete -ssRNA genome can be synthesized. -ssRNA viruses vary between those that initiate transcription by the RdRp creating a cap on the 5'-end (usually pronounced "five prime end") of the genome or by snatching a cap from host mRNA and attaching it to the viral RNA. For many -ssRNA viruses, at the end of transcription, RdRp stutters on a uracil in the genome, synthesizing hundreds of adenines in a row as part of creating a polyadenylated tail for the mRNA. Some -ssRNA viruses are essentially ambisense, and have proteins encoded by both the positive and negative strand, so mRNA is synthesized directly from the genome and from a complementary strand. For dsRNA viruses, RdRp transcribes mRNA by using the negative strand as a template. Positive strands may also be used as templates to synthesize negative strands for the construction of genomic dsRNA. dsRNA is not a molecule produced by cells, so cellular life has evolved mechanisms to detect and inactivate viral dsRNA. To counter this, dsRNA viruses typically retain their genomes inside of viral capsid in order to evade the host's immune system. Positive-strand RNA viruses have genomes that can function as mRNA, so transcription is not necessary. However, +ssRNA will produce dsRNA forms as part of the process of replicating their genomes. From the dsRNA, additional positive strands are synthesized, which may be used as mRNA or for genomes for progeny. Because +ssRNA viruses create intermediate dsRNA forms, they have to avoid the host's immune system in order to replicate. +ssRNA viruses accomplish this by replicating in membrane-associated vesicles that are used as replication factories. For many +ssRNA viruses, subgenomic portions of the genome will be transcribed to translate specific proteins, whereas others will transcribe a polyprotein that is cleaved to produce separate proteins. Negative-strand RNA viruses have genomes that function as templates from which mRNA can be synthesized directly by RdRp. Replication is the same process but executed on the positive sense antigenome, during which RdRp ignores all transcription signals so that a complete -ssRNA genome can be synthesized. -ssRNA viruses vary between those that initiate transcription by the RdRp creating a cap on the 5'-end (usually pronounced "five prime end") of the genome or by snatching a cap from host mRNA and attaching it to the viral RNA. For many -ssRNA viruses, at the end of transcription, RdRp stutters on a uracil in the genome, synthesizing hundreds of adenines in a row as part of creating a polyadenylated tail for the mRNA. Some -ssRNA viruses are essentially ambisense, and have proteins encoded by both the positive and negative strand, so mRNA is synthesized directly from the genome and from a complementary strand. For dsRNA viruses, RdRp transcribes mRNA by using the negative strand as a template. Positive strands may also be used as templates to synthesize negative strands for the construction of genomic dsRNA. dsRNA is not a molecule produced by cells, so cellular life has evolved mechanisms to detect and inactivate viral dsRNA. To counter this, dsRNA viruses typically retain their genomes inside of viral capsid in order to evade the host's immune system. RNA viruses in Orthornavirae experience a high rate of genetic mutations because RdRp is prone to making errors in replication since it typically lacks proofreading mechanisms to repair errors. [note 1] Mutations in RNA viruses are often influenced by host factors such as dsRNA-dependent adenosine deaminases , which edit viral genomes by changing adenosines to inosines . Mutations in genes that are essential for replication lead to a reduced number of progeny, so viral genomes typically contain sequences that are highly conserved over time with relatively few mutations. Many RdRp-encoding RNA viruses also experience a high rate of genetic recombination , though rates of recombination vary significantly, with lower rates in -ssRNA viruses and higher rates in dsRNA and +ssRNA viruses. There are two types of recombination: copy choice recombination and reassortment. Copy choice recombination occurs when the RdRp switches templates during synthesis without releasing the prior, newly created RNA strand, which generates a genome of mixed ancestry. Reassortment , which is restricted to viruses with segmented genomes, has segments from different genomes packaged into a single virion, or virus particle, which also produces hybrid progeny. For reassortment, some segmented viruses package their genomes into multiple virions, which produces genomes that are random mixtures of parents, whereas for those that are packaged into a single virion, typically individual segments are swapped. Both forms of recombination can only occur if more than one virus is present in a cell, and the more alleles are present, the more likely recombination is to occur. A key difference between copy choice recombination and reassortment is that copy choice recombination can occur anywhere in a genome, whereas reassortment swaps fully-replicated segments. Therefore, copy choice recombination can produce non-functional viral proteins whereas reassortment cannot. The mutation rate of a virus is associated with the rate of genetic recombinations. Higher mutation rates increase both the number of advantageous and disadvantageous mutations, whereas higher rates of recombination allows for beneficial mutations to be separated from deleterious ones. [ vague ] Therefore, higher rates of mutations and recombinations, up to a certain point, improve viruses' ability to adapt. Notable examples of this include reassortments that enable cross-species transmission of influenza viruses, which have led to numerous pandemics, as well as the emergence of drug-resistance influenza strains via mutations that were reassorted. The exact origin of Orthornavirae is not well established, but the viral RdRp shows a relation to the reverse transcriptase (RT) enzymes of group II introns that encode RTs and retrotransposons , the latter of which are self-replicating DNA sequences that integrate themselves into other parts of the same DNA molecule. A larger study (2022) where new lieneages (phyla) were described, has suggested that RNA viruses descend from the RNA world , suggesting that retroelements (retrotransposons and group II introns) originated from an ancestor related to the phylum Lenarviricota and that members of a newly discovered Taraviricota lineage (phylum) would be the ancestors of all RNA viruses. According to this study the genomes of both dsRNA, +ssRNA and -ssRNA evolved independently and were altered several times in evolution. RNA viruses that encode RdRp are assigned to the kingdom Orthornavirae , which contains five official phyla, six unofficial phyla and several taxa that are unassigned to a phylum due to lack of information. The five phyla are separated based on the genome types, host ranges, and genetic similarity of member viruses. The unassigned taxa are listed hereafter (- viridae denotes family and - virus denotes genus). The kingdom contains three groups in the Baltimore classification system, which groups viruses together based on their manner of mRNA synthesis, and which is often used alongside standard virus taxonomy, which is based on evolutionary history. Those three groups are Group III: dsRNA viruses, Group IV: +ssRNA viruses, and Group V: -ssRNA viruses. RNA viruses are associated with a wide range of disease, including many of the most widely known viral diseases. Notable disease-causing viruses in Orthornavirae include: Animal viruses in Orthornavirae include orbiviruses , which cause various diseases in ruminants and horses, including Bluetongue virus , African horse sickness virus , Equine encephalosis virus , and epizootic hemorrhagic disease virus . The vesicular stomatitis virus causes disease in cattle, horses, and pigs. Bats harbor many viruses including ebolaviruses and henipaviruses , which also can cause disease in humans. Similarly, arthropod viruses in the Flavivirus and Phlebovirus genera are numerous and often transmitted to humans. Coronaviruses and influenza viruses cause disease in various vertebrates, including bats, birds, and pigs. Plant viruses in the kingdom are numerous and infect many economically important crops. Tomato spotted wilt virus is estimated to cause more than 1 billion USD in damages annually, affecting more than 800 plant species including chrysanthemum, lettuce, peanut, pepper, and tomato. Cucumber mosaic virus infects more than 1,200 plant species and likewise causes significant crop losses. Potato virus Y causes significant reductions in yield and quality for pepper, potato, tobacco, and tomato, and Plum pox virus is the most important virus among stone fruit crops. Brome mosaic virus , while not causing significant economic losses, is found throughout much of the world and primarily infects grasses, including cereals. Diseases caused by RNA viruses in Orthornavirae have been known throughout much of history, but their cause was only discovered in modern times. As a whole, RNA viruses were discovered during a time period of major advancements in molecular biology, including the discovery of mRNA as the immediate carrier of genetic information for protein synthesis. Tobacco mosaic virus was discovered in 1898 and was the first virus to be discovered. Viruses in the kingdom that are transmitted by arthropods have been a key target in the development of vector control , which often aims to prevent viral infections. In modern history, numerous disease outbreaks have been caused by RdRp-encoding RNA viruses, including outbreaks caused by coronaviruses, ebola, and influenza. Orthornavirae was established in 2019 as a kingdom within the realm Riboviria , intended to accommodate all RdRp-encoding RNA viruses. Prior to 2019, Riboviria was established in 2018 and included only RdRp-encoding RNA viruses. In 2019, Riboviria was expanded to also include reverse transcribing viruses, placed under the kingdom Pararnavirae , so Orthornavirae was established to separate RdRp-encoding RNA viruses from reversing transcribing viruses.

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influenza virus

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Global spread of H5N1 in 2005

The global spread of (highly pathogenic) H5N1 in birds is considered a significant pandemic threat. While prior H5N1 strains have been known, they were significantly different from the current H5N1 strain on a genetic level, making the global spread of this new strain unprecedented. The current H5N1 strain is a fast-mutating , highly pathogenic avian influenza virus (HPAI) found in multiple bird species. It is both epizootic (an epidemic in non-humans) and panzootic (a disease affecting animals of many species especially over a wide area). Unless otherwise indicated, "H5N1" in this article refers to the recent highly pathogenic strain of H5N1. In January 2005 an outbreak of avian influenza affected thirty three out of sixty four cities and provinces in Vietnam , leading to the forced killing of nearly 1.2 million poultry. Up to 140 million birds are believed to have died or been killed because of the outbreak. In April 2005 an unprecedented die-off began of over 6,000 migratory birds at Qinghai Lake in central China over three months. This strain of H5N1 is the same strain as is spread west by migratory birds over at least the next ten months. In August 2005 H5N1 spread to Kazakhstan , Mongolia and Russia . On September 30, 2005, David Nabarro , the newly appointed Senior United Nations System Coordinator for Avian and Human Influenza, warned the world that an outbreak of avian influenza could kill 5 to 150 million people. David Nabarro later stated that as the virus had spread to migratory birds, an outbreak could start in Africa or the Middle East . Later in 2005 H5N1 spread to Turkey , Romania , Croatia and Kuwait . Notes:August 3, 2005 August 11, 2005 August 22, 2005September 30, 2005October 13, 2005 October 15, 2005 October 19, 2005 October 26, 2005 October 31, 2005November 12, 2005December 30, 2005 "China confirms its third human death from bird flu. That brings the death toll [...] to 74, comprising 14 victims in Thailand, four in Cambodia, 11 in Indonesia, 42 in Vietnam and three in China."

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influenza virus

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1557 influenza pandemic

In 1557, a pandemic strain of influenza emerged in Asia , then spread to Africa , Europe , and eventually the Americas . This flu was highly infectious and presented with intense, occasionally lethal symptoms. Medical historians like Thomas Short , Lazare Rivière and Charles Creighton gathered descriptions of catarrhal fevers recognized as influenza by modern physicians attacking populations with the greatest intensity between 1557 and 1559. The 1557 flu saw governments, for possibly the first time, inviting physicians to instill bureaucratic organization into epidemic responses. It is also the first pandemic where influenza is pathologically linked to miscarriages , given its first English names, and is reliably recorded as having spread globally. Influenza caused higher burial rates, near-universal infection, and economic turmoil as it returned in repeated waves.According to a European chronicler surnamed Fonseca who wrote Disputat. de Garotillo, the 1557 influenza pandemic first broke out in Asia . The flu spread west along established trade and pilgrimage routes before reaching the Ottoman Empire and the Middle East . An epidemic of a flu-like illness is recorded for September 1557 in Portuguese Goa . In the summer of 1557 parts of Europe had just suffered outbreaks of plague , typhus , measles , and smallpox when influenza arrived from the Ottoman Empire and North Africa . The flu spread west through Europe aboard merchant ships in the Mediterranean Sea , again taking advantage of trade and pilgrimage routes. Death rates were highest in children, those with preexisting conditions, the elderly, and those who were bled. Outbreaks were particularly severe in communities suffering from food scarcity. The epidemics of fevers and respiratory illness eventually became referred to as the new sickness in England, new acquaintance in Scotland, and coqueluche or simply catarrh by medical historians in the rest of Europe. Because it afflicted entire populations at once in mass outbreaks, some contemporary scholars thought the flu was caused by stars, contaminated vapors brought about by damp weather, or the dryness of the air. Ultimately the 1557 flu lasted in varying waves of intensity for around four years in epidemics that increased European death rates, disrupted the highest levels of society, and frequently spread to other continents. The flu pandemic first reached Europe in 1557 from the Ottoman Empire along trade and shipping routes connected to Constantinople , brought to Asia Minor by infected travelers from the Middle East. At the time, the Ottoman Empire's territory included most of the Balkans and Bulgaria. This gave influenza unrestricted access to Athens , Sofia , and Sarajevo as it spread throughout the empire. Influenza set sail from the capital, Constantinople, into the recently conquered North African territories of Tripoli (1551) and the Habesh (1557), from where it likely ricocheted to Malta from North Africa via merchant ships, as during the pandemic of 1510 . On land, influenza spread north from the Ottoman Empire over Wallachia to the Kingdom of Poland and Grand Duchy of Lithuania before moving west into continental Europe. [ citation needed ] Influenza arrived in the Kingdom of Sicily in June at Palermo , whence it spread across the island. Church services, Sicilian social life, and the economy were disrupted as the flu sickened a large portion of the population. The Sicilian Senate asked a well-known Palermitan physician named Giovanni Filippo Ingrassia to help combat the epidemic in an advisory capacity, which he accepted. Ingrassia approached epidemic responses as a collaboration between healthcare and government officials, and was the first known "health care professional" to propose that a system for monitoring epidemics of contagious catarrhal fevers would aid in early detection and epidemic control. Flu spread quickly from Sicily into the Kingdom of Naples on the lower part of the Italian Peninsula , moving upward along the coastline. In Urbino , Venetian court poet Bernardo Tasso , his son Torquato , and the occupants of a monastery fell sick "from hand to hand" with influenza for four to five days. Though the epidemic left the entire city of Urbino ill, most individuals recovered without complications. By the time Bernardo had traveled to northern Italy on August 3 the disease had already spread into the rest of Europe. In Lombardy there was an outbreak of "suffocating catarrh" that could quickly become fatal. The symptoms were so severe that some members of the population suspected a mass poisoning had occurred. Padua began to see cases in August, with sickness lasting into September. German medical historian Justus Hecker writes that the young population of Padua had been reeling from a dual outbreak of measles and smallpox since the spring when a new illness, featuring extreme cough and headache, began to afflict the citizens in late summer. The illness was referred to as coqueluche. Switzerland was also reached by the disease in August. "Catarrh" swept through the Swiss plateaus from August to September and almost disrupted the graduate studies of Swiss physician Felix Plater , who was sickened by severe fits of coughing while a candidate for his doctorate. French physician and medical historian Lazare Rivière documented an anonymous physician's descriptions of a flu outbreak occurring in the Languedoc region of France in July 1557. The disease, often called coqueluche by the French, caused a severe outbreak in Nîmes that featured a fast onset of symptoms like headaches, fevers, loss of appetite, fatigue, and intense coughing. Most of those who died from the disease did so on the fourth day, but some succumbed up to 11 days after first symptoms. Across Languedoc influenza had a high mortality rate, with up to 200 people per day dying in Toulouse at the height of the region's epidemic. Italian physician Francisco Vallerioli, known as François Valleriola, was a witness to the epidemic in France and described the 1557 flu's symptoms as featuring a fever, severe headache, intense coughing, shortness of breath, chills, hoarseness, and expulsion of phlegm after 7 to 14 days. French lawyer Étienne Pasquier wrote that the disease began with a severe pain in the head and a 12- to 15-hour fever while sufferers' noses "ran like a fountain." Paris saw its judiciary disrupted when the Paris Law Court suspended its meetings to slow the spread of flu. Medical historian Charles-Jacques Saillant described this influenza as especially fatal to those who were treated with bleeding and very dangerous to children. The 1557 influenza severely impacted the British Isles. British medical historian Charles Creighton cited a contemporary writer, Wriothesley, who noted in 1557 "this summer reigned in England divers strange and new sicknesses, taking men and women in their heads; as strange agues and fevers, whereof many died." 18th Century physician Thomas Short wrote that those who succumbed to the flu "were let blood of or had unsound viscera." Flu blighted the army of Mary I of England by leaving her government unable to train sufficient reinforcements for Henry Manners, 2nd Earl of Rutland to protect Calais from an impending French assault, and by January 1558 the Duke of Guise had claimed the under-protected city in the name of France. Influenza significantly contributed to England's unusually high death rates for 1557–58: Data compiled on over 100 parishes in England found that the mortality rates increased by up to 60% in some areas during the flu epidemic, even though diseases like true plague were not heavily present in England at the time. Dr. Short found that the number of burials for market towns was much higher than christenings from 1557 to 1562. For example, the annual number of burials in Tonbridge increased from 33 on average in 1556 to 61 in 1557, 105 in 1558, and 94 in 1559. Before the flu epidemic, England had suffered from a poor harvest and widespread famine that medical historian Thomas Short believed made the epidemic more deadly. Influenza returned in 1558. Contemporary historian John Stow wrote that during "winter the quarterne agues continued in like manner" to 1557's epidemic. On 6 September 1558 the Governor of the Isle of Wight , Lord St. John , wrote in a despatch to Mary I of England about a highly-contagious illness afflicting more than half the people of Southampton , the Isle of Wight, and Portsmouth (places where Lord St. John had stationed troops). A second despatch from 11 P.M. of 6 October indicated "from the mayor of Dover that there is no plague there, but the people that daily die are those that come out of the ships, and such poor people as come out of Calais, of the new sickness." One of the commissioners for the surrender of Calais found Sir William Pickering, former knight-marshal to King Henry VIII , "very sore of this new burning ague. He has had four sore fits, and is brought very low, and in danger of his life if they continue as they have done." Influenza began to move north through England, felling numerous farmers and leaving large quantities of grain unharvested before it reached London around mid-late October. Queen Mary and Archbishop of Canterbury Reginald Pole , who had both been in poor health before flu broke out in London, likely died of influenza within 12 hours of each other on 17 November 1558. Two of Mary's physicians died as well. Ultimately around 8000 other Londoners likely died of influenza during the epidemic, including many elders and parish priests. New waves of "agues" and fevers were recorded in England into 1559. These repeated outbreaks proved unusually deadly for populations already suffering from extensive rains and poor harvests. From 1557 to 1559 the nation's population contracted by 2%. The sheer numbers of people dying from epidemics and famine in England caused economic inflation to flatten out. In the late 1550s the English language had not yet developed a proper name for the flu, despite previous epidemics. Thus 1557's epidemic was either described as a "plague" (like many epidemics with notable mortality), "ague" (most generally) or "new disease" in England. "The sweat" was one name used to describe the usually deadly, flu-like fevers and "agues" plaguing the English countryside from 1557 to 1558, despite no reliable records of sweating sickness after 1551. Doctor John Jones, a prominent 16th Century London physician, refers in his book Dyall of Agues to a "great sweat" during the reign of Mary I of England. After the 1557 pandemic English nicknames for the flu began to appear in letters, like "the new disease" in England and "the newe acquaintance" in Scotland. When the entire royal court of Mary, Queen of Scots was struck down with influenza in Edinburgh in November 1562, Lord Randolph described the outbreak as "a new disease, that is common in this town, called here 'the newe acquaintance,' which passed also through her whole court, neigh sparing lord, lady, nor damoysell, not so much as either French or English. It is a pain in their heads that have it, and a soreness in their stomachs, with a great cough, that remaineth with some longer with other short time, as it findeth apt bodies for the nature of the disease...There was not an appearance of danger, nor manie that died of the disease, except some old folks." Mary Stuart herself spent six days sick in her bedchambers. Habsburg Netherlands was also heavily impacted by the flu in October. Dutch historian Petrus Forestus described an outbreak in Alkmaar where 2000 fell sick with flu and 200 perished in a span of three weeks. Forestus himself became sick with the flu and related that it "...began with a slight fever like a common catarrh, and showed its great malignancy only by degrees. Sudden fits of suffocation then came on, and the pain of the chest was so distressing that patients imagined they must die in the paroxysm . The complaint was increased still by a tight, convulsive cough. Death did not take place till the 9th or 14th day." He further observed that the flu was very dangerous to pregnant women, killing at least eight such citizens in Alkmaar who contracted it. Influenza's symptoms came on suddenly and attacked thousands of the city's residents at the same time. Hunger likely contributed to a higher death toll, as the authorities had been struggling to provide food to the needy amid a severe bread shortage during the summer. Attempting to explain the epidemic of fevers and respiratory illness affecting the Low Countries , Flemish physician Rembert Dodoens suggested that the mass outbreaks of illness were caused by a dry, hot summer following a very cold winter. Spain was widely and severely impacted by influenza, which chroniclers recognized as a highly contagious catarrhal fever. Influenza likely arrived in Spain around July, with the first cases being reported near Madrid in August. British medical historian Thomas Short wrote that "At Mantua Carpentaria, three miles outside of Madrid, the first cases were reported...There it began with a roughness of the jaws, small cough, then a strong fever with a pain in the head, back, and legs. Some felt as though they were corded over the breast, with a weight at the stomach, all which continued to the third day at the furthest. Then the fever went off, with a sweat of bleeding at the nose. In some few, it turned to a pleurisy of fatal peripneumony." Bloodletting greatly increased the risk of mortality, and it was observed in Mantua Carpentaria that "2000 were let blood of and all died." The flu then entered Spain's capital city, where it rapidly spread to all parts of the Spanish mainland. [ citation needed ] Cases expanded exponentially as merchants, pilgrims, and other travelers leaving Madrid transported the virus to cities and towns across the country. According to King Phillip II's doctor Luis de Mercado, "All the population was attacked the same day, and the same time of day. It was catarrh, marked by fever of the double tertian type, with such pernicious symptoms that many died." The season's poor harvests and hunger in the Spanish population, as well as negligent medical care, likely contributed to the severity of the influenza pandemic in Spain . Flu symptoms could be so intense that the region's physicians often distinguished it from other contagious, seasonal pneumonias that spread from East Europe. Sixteenth century Spaniards frequently referred to any mass outbreak of deadly disease generically as a pestilencia , and "plagues" are recognized as occurring in Valencia and Granada during the years 1557–59, despite pathological records of true plague (like descriptions of buboes) occurring in the area at the time being scant. Influenza hit the Kingdom of Portugal at the same time as it spread throughout Spain, with an impact that spread across the Atlantic Ocean. The kingdom had just suffered food shortages due to 1556-57's poor harvest, which would have exacerbated the effects of the flu on hungry patients. A violent storm had just hit Portugal and severely damaged the Palace of Enxobregas, and in following with attributing outbreaks of influenza to the weather Portuguese historians like Ignácio Barbosa-Machado attributed the epidemic in the kingdom to the storm with little opposition. Barbosa-Machado referred to 1557 as the "anno de catarro." The flu pandemic first reached Europe in 1557 from the Ottoman Empire along trade and shipping routes connected to Constantinople , brought to Asia Minor by infected travelers from the Middle East. At the time, the Ottoman Empire's territory included most of the Balkans and Bulgaria. This gave influenza unrestricted access to Athens , Sofia , and Sarajevo as it spread throughout the empire. Influenza set sail from the capital, Constantinople, into the recently conquered North African territories of Tripoli (1551) and the Habesh (1557), from where it likely ricocheted to Malta from North Africa via merchant ships, as during the pandemic of 1510 . On land, influenza spread north from the Ottoman Empire over Wallachia to the Kingdom of Poland and Grand Duchy of Lithuania before moving west into continental Europe. [ citation needed ]Influenza arrived in the Kingdom of Sicily in June at Palermo , whence it spread across the island. Church services, Sicilian social life, and the economy were disrupted as the flu sickened a large portion of the population. The Sicilian Senate asked a well-known Palermitan physician named Giovanni Filippo Ingrassia to help combat the epidemic in an advisory capacity, which he accepted. Ingrassia approached epidemic responses as a collaboration between healthcare and government officials, and was the first known "health care professional" to propose that a system for monitoring epidemics of contagious catarrhal fevers would aid in early detection and epidemic control. Flu spread quickly from Sicily into the Kingdom of Naples on the lower part of the Italian Peninsula , moving upward along the coastline. In Urbino , Venetian court poet Bernardo Tasso , his son Torquato , and the occupants of a monastery fell sick "from hand to hand" with influenza for four to five days. Though the epidemic left the entire city of Urbino ill, most individuals recovered without complications. By the time Bernardo had traveled to northern Italy on August 3 the disease had already spread into the rest of Europe. In Lombardy there was an outbreak of "suffocating catarrh" that could quickly become fatal. The symptoms were so severe that some members of the population suspected a mass poisoning had occurred. Padua began to see cases in August, with sickness lasting into September. German medical historian Justus Hecker writes that the young population of Padua had been reeling from a dual outbreak of measles and smallpox since the spring when a new illness, featuring extreme cough and headache, began to afflict the citizens in late summer. The illness was referred to as coqueluche. Switzerland was also reached by the disease in August. "Catarrh" swept through the Swiss plateaus from August to September and almost disrupted the graduate studies of Swiss physician Felix Plater , who was sickened by severe fits of coughing while a candidate for his doctorate.French physician and medical historian Lazare Rivière documented an anonymous physician's descriptions of a flu outbreak occurring in the Languedoc region of France in July 1557. The disease, often called coqueluche by the French, caused a severe outbreak in Nîmes that featured a fast onset of symptoms like headaches, fevers, loss of appetite, fatigue, and intense coughing. Most of those who died from the disease did so on the fourth day, but some succumbed up to 11 days after first symptoms. Across Languedoc influenza had a high mortality rate, with up to 200 people per day dying in Toulouse at the height of the region's epidemic. Italian physician Francisco Vallerioli, known as François Valleriola, was a witness to the epidemic in France and described the 1557 flu's symptoms as featuring a fever, severe headache, intense coughing, shortness of breath, chills, hoarseness, and expulsion of phlegm after 7 to 14 days. French lawyer Étienne Pasquier wrote that the disease began with a severe pain in the head and a 12- to 15-hour fever while sufferers' noses "ran like a fountain." Paris saw its judiciary disrupted when the Paris Law Court suspended its meetings to slow the spread of flu. Medical historian Charles-Jacques Saillant described this influenza as especially fatal to those who were treated with bleeding and very dangerous to children. The 1557 influenza severely impacted the British Isles. British medical historian Charles Creighton cited a contemporary writer, Wriothesley, who noted in 1557 "this summer reigned in England divers strange and new sicknesses, taking men and women in their heads; as strange agues and fevers, whereof many died." 18th Century physician Thomas Short wrote that those who succumbed to the flu "were let blood of or had unsound viscera." Flu blighted the army of Mary I of England by leaving her government unable to train sufficient reinforcements for Henry Manners, 2nd Earl of Rutland to protect Calais from an impending French assault, and by January 1558 the Duke of Guise had claimed the under-protected city in the name of France. Influenza significantly contributed to England's unusually high death rates for 1557–58: Data compiled on over 100 parishes in England found that the mortality rates increased by up to 60% in some areas during the flu epidemic, even though diseases like true plague were not heavily present in England at the time. Dr. Short found that the number of burials for market towns was much higher than christenings from 1557 to 1562. For example, the annual number of burials in Tonbridge increased from 33 on average in 1556 to 61 in 1557, 105 in 1558, and 94 in 1559. Before the flu epidemic, England had suffered from a poor harvest and widespread famine that medical historian Thomas Short believed made the epidemic more deadly. Influenza returned in 1558. Contemporary historian John Stow wrote that during "winter the quarterne agues continued in like manner" to 1557's epidemic. On 6 September 1558 the Governor of the Isle of Wight , Lord St. John , wrote in a despatch to Mary I of England about a highly-contagious illness afflicting more than half the people of Southampton , the Isle of Wight, and Portsmouth (places where Lord St. John had stationed troops). A second despatch from 11 P.M. of 6 October indicated "from the mayor of Dover that there is no plague there, but the people that daily die are those that come out of the ships, and such poor people as come out of Calais, of the new sickness." One of the commissioners for the surrender of Calais found Sir William Pickering, former knight-marshal to King Henry VIII , "very sore of this new burning ague. He has had four sore fits, and is brought very low, and in danger of his life if they continue as they have done." Influenza began to move north through England, felling numerous farmers and leaving large quantities of grain unharvested before it reached London around mid-late October. Queen Mary and Archbishop of Canterbury Reginald Pole , who had both been in poor health before flu broke out in London, likely died of influenza within 12 hours of each other on 17 November 1558. Two of Mary's physicians died as well. Ultimately around 8000 other Londoners likely died of influenza during the epidemic, including many elders and parish priests. New waves of "agues" and fevers were recorded in England into 1559. These repeated outbreaks proved unusually deadly for populations already suffering from extensive rains and poor harvests. From 1557 to 1559 the nation's population contracted by 2%. The sheer numbers of people dying from epidemics and famine in England caused economic inflation to flatten out. In the late 1550s the English language had not yet developed a proper name for the flu, despite previous epidemics. Thus 1557's epidemic was either described as a "plague" (like many epidemics with notable mortality), "ague" (most generally) or "new disease" in England. "The sweat" was one name used to describe the usually deadly, flu-like fevers and "agues" plaguing the English countryside from 1557 to 1558, despite no reliable records of sweating sickness after 1551. Doctor John Jones, a prominent 16th Century London physician, refers in his book Dyall of Agues to a "great sweat" during the reign of Mary I of England. After the 1557 pandemic English nicknames for the flu began to appear in letters, like "the new disease" in England and "the newe acquaintance" in Scotland. When the entire royal court of Mary, Queen of Scots was struck down with influenza in Edinburgh in November 1562, Lord Randolph described the outbreak as "a new disease, that is common in this town, called here 'the newe acquaintance,' which passed also through her whole court, neigh sparing lord, lady, nor damoysell, not so much as either French or English. It is a pain in their heads that have it, and a soreness in their stomachs, with a great cough, that remaineth with some longer with other short time, as it findeth apt bodies for the nature of the disease...There was not an appearance of danger, nor manie that died of the disease, except some old folks." Mary Stuart herself spent six days sick in her bedchambers. Habsburg Netherlands was also heavily impacted by the flu in October. Dutch historian Petrus Forestus described an outbreak in Alkmaar where 2000 fell sick with flu and 200 perished in a span of three weeks. Forestus himself became sick with the flu and related that it "...began with a slight fever like a common catarrh, and showed its great malignancy only by degrees. Sudden fits of suffocation then came on, and the pain of the chest was so distressing that patients imagined they must die in the paroxysm . The complaint was increased still by a tight, convulsive cough. Death did not take place till the 9th or 14th day." He further observed that the flu was very dangerous to pregnant women, killing at least eight such citizens in Alkmaar who contracted it. Influenza's symptoms came on suddenly and attacked thousands of the city's residents at the same time. Hunger likely contributed to a higher death toll, as the authorities had been struggling to provide food to the needy amid a severe bread shortage during the summer. Attempting to explain the epidemic of fevers and respiratory illness affecting the Low Countries , Flemish physician Rembert Dodoens suggested that the mass outbreaks of illness were caused by a dry, hot summer following a very cold winter. Spain was widely and severely impacted by influenza, which chroniclers recognized as a highly contagious catarrhal fever. Influenza likely arrived in Spain around July, with the first cases being reported near Madrid in August. British medical historian Thomas Short wrote that "At Mantua Carpentaria, three miles outside of Madrid, the first cases were reported...There it began with a roughness of the jaws, small cough, then a strong fever with a pain in the head, back, and legs. Some felt as though they were corded over the breast, with a weight at the stomach, all which continued to the third day at the furthest. Then the fever went off, with a sweat of bleeding at the nose. In some few, it turned to a pleurisy of fatal peripneumony." Bloodletting greatly increased the risk of mortality, and it was observed in Mantua Carpentaria that "2000 were let blood of and all died." The flu then entered Spain's capital city, where it rapidly spread to all parts of the Spanish mainland. [ citation needed ] Cases expanded exponentially as merchants, pilgrims, and other travelers leaving Madrid transported the virus to cities and towns across the country. According to King Phillip II's doctor Luis de Mercado, "All the population was attacked the same day, and the same time of day. It was catarrh, marked by fever of the double tertian type, with such pernicious symptoms that many died." The season's poor harvests and hunger in the Spanish population, as well as negligent medical care, likely contributed to the severity of the influenza pandemic in Spain . Flu symptoms could be so intense that the region's physicians often distinguished it from other contagious, seasonal pneumonias that spread from East Europe. Sixteenth century Spaniards frequently referred to any mass outbreak of deadly disease generically as a pestilencia , and "plagues" are recognized as occurring in Valencia and Granada during the years 1557–59, despite pathological records of true plague (like descriptions of buboes) occurring in the area at the time being scant. Influenza hit the Kingdom of Portugal at the same time as it spread throughout Spain, with an impact that spread across the Atlantic Ocean. The kingdom had just suffered food shortages due to 1556-57's poor harvest, which would have exacerbated the effects of the flu on hungry patients. A violent storm had just hit Portugal and severely damaged the Palace of Enxobregas, and in following with attributing outbreaks of influenza to the weather Portuguese historians like Ignácio Barbosa-Machado attributed the epidemic in the kingdom to the storm with little opposition. Barbosa-Machado referred to 1557 as the "anno de catarro." There are records of the New World eventually being reached by the flu in 1557, brought to the Spanish and Portuguese Empires by sailors from Europe. Influenza arrived in Central America in 1557, likely aboard Spanish ships sailing to New Spain . During that year there were epidemics of flu recorded in the south Atlantic states, Gulf area, and Southwest. The Native American Cherokee appear to have been affected during this wave, and it may have spread along newly established trade routes between Spanish colonies in the New World . The flu also reached South America. Anthropologist Henry F. Dobyns described a 1557 epidemic of influenza in Ecuador in which European and Native populations were both left sick with severe coughing. In Colonial Brazil , Portuguese missionaries did not take breaks from religious activities when they became sick. Missionaries like the Society of Jesus in Brazil founder Manuel da Nóbrega continued to preach, host mass, and baptize converts in the New World even when symptomatic with contagious illnesses like influenza. As a result, flu would have quickly spread through Portuguese colonies due to mandatory church attendance. In 1559 the flu struck colonial Brazil with a wave of illness recorded along the coastal state of Bahia : That February, the region of Espírito Santo was struck by an outbreak of lung infections, dysentery, and "fevers that they say immediately attacked the hearts, and which quickly struck them down." Populations of natives attempted to flee the infection afflicting their communities, spreading influenza northward. European missionaries suspected such severe epidemics among the native populations to be a form of divine punishment, and referred to the outbreaks of pleurisy and dysentery among the natives in Bahia to be "the sword of God's wrath." Missionaries like Francisco Pires took some pity on the sick children of natives, whom they often regarded as innocent, and frequently baptized them during epidemics in the belief they'd "saved" their souls. Baptism rates in native communities were deeply connected with outbreaks of disease, and missionary policies of conducting religious activities while sick likely helped spread the flu.Influenza attacked Africa through the Ottoman Empire , which by 1557 was expanding its territories in the northern and eastern parts of the continent. Egypt , which had been conquered by the Ottoman Empire around 40 years prior, became an access point for influenza to travel south through the Red Sea along shipping routes. The pandemic's most memorable effects on the Ottoman army in Africa are recorded as part of the 1559 wave. [ citation needed ] The Kingdom of Portugal had supported the Abyssinian (Ethiopian) Empire in their war against the Ottoman expansion of the Habesh Eyalet and sent aid to their emperor, including a team with Andrés de Oviedo in 1557 who recorded the events. In 1559 the Ottoman Empire struggled with a severe wave of influenza: After the deaths of Emperor Gelawdewos and most of the Portuguese attaché in battle, the flu killed thousands of the Ottoman army's troops occupying the port city of Massawa . Massawa was claimed by the Ottomans from Medri Bahri during their conquest of Habesh in 1557, but the pandemic's 1559 wave challenged their army's hold onto territory around the city after flu cut down a large number of the Ottoman forces. Because of the epidemic Ottoman soldiers were soon recalled back to the ports, even though the emperor had been slain, and shortly afterwards Gelawdewos's brother Menas ascended to the Abyssinian throne and converted from Islam to Christianity . The Kingdom of Portugal had supported the Abyssinian (Ethiopian) Empire in their war against the Ottoman expansion of the Habesh Eyalet and sent aid to their emperor, including a team with Andrés de Oviedo in 1557 who recorded the events. In 1559 the Ottoman Empire struggled with a severe wave of influenza: After the deaths of Emperor Gelawdewos and most of the Portuguese attaché in battle, the flu killed thousands of the Ottoman army's troops occupying the port city of Massawa . Massawa was claimed by the Ottomans from Medri Bahri during their conquest of Habesh in 1557, but the pandemic's 1559 wave challenged their army's hold onto territory around the city after flu cut down a large number of the Ottoman forces. Because of the epidemic Ottoman soldiers were soon recalled back to the ports, even though the emperor had been slain, and shortly afterwards Gelawdewos's brother Menas ascended to the Abyssinian throne and converted from Islam to Christianity . Most physicians of the time subscribed to the theory of humorism , and believed the cosmos or climate directly affected the health of entire communities. Physicians treating the flu often used treatments called coctions to remove excess humors they believed to be causing illness. Dr. Thomas Short described treatments for the 1557 influenza as having included gargling "rose water, quinces, mulberries, and sealed earth." "Gentle bleeding" was used on the first day of the infection only, as frequently used medical techniques like bloodletting and purgation were often fatal for influenza. In Urbino, "diet and good governance" were recognized as common ways sufferers managed their illness. The 1557 pandemic's nature as a worldwide, highly-contagious respiratory disease with fast onset of flu-like symptoms has led many physicians, from medical historians like Charles Creighton to modern epidemiologists, to consider the causative disease as influenza. "Well documented descriptions from medical observers" who witnessed the effects of the pandemic as it spread through populations have been reviewed by numerous medical historians in the centuries since. Contemporary physicians to the 1557 flu, like Ingrassia, Valleriola, Dodoens, and Mercado, described symptoms like severe coughing , fever , myalgia , and pneumonia that all occurred within a short period of time and led to death in days if a case was to be fatal. Infections became so widespread in countries that influences like the weather, stars, and mass poisoning were blamed by observers for the outbreaks, a reoccurring pattern in influenza epidemics that has contributed to the disease's name. Prior to greater research being conducted into influenza in the 19th century, some medical historians considered the descriptions of epidemic "angina" from 1557 to be scarlet fever , whooping cough , and diphtheria . But the most striking features of scarlet fever and diphtheria, like rashes or pseudomembranes, remain unmentioned by any of the 1557 pandemic's observers and the first recognized whooping cough epidemic is a localized outbreak in Paris from 1578. These illnesses can resemble the flu in their early stages but pandemic influenza is distinguished by its fast-moving, unrestricted epidemics of severe respiratory disease affecting all ages with widespread infections and mortalities. [ citation needed ]

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influenza virus

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Baloxavir marboxil

({(12a R )-12-[(11 S )-7,8-Difluoro-6,11-dihydrodibenzo[ b , e ]thiepin-11-yl]-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1 H -[1,4]oxazino[3,4- c ]pyrido[2,1- f ] [1,2,4]triazin-7-yl}oxy)methyl methyl carbonate O=C(OCOC(C(C=C1)=O)=C(N1N([C@@H]2C3=CC=CC=C3SCC4=C(F)C(F)=CC=C24)[C@@]5([H])N6CCOC5)C6=O)OC InChI=1S/C27H23F2N3O7S/c1-36-27(35)39-14-38-25-19(33)8-9-31-24(25)26(34)30-10-11-37-12-21(30)32(31)23-15-6-7-18(28)22(29)17(15)13-40-20-5-3-2-4-16(20)23/h2-9,21,23H,10-14H2,1H3/t21-,23+/m1/s1 Key:RZVPBGBYGMDSBG-GGAORHGYSA-N Baloxavir marboxil , sold under the brand name Xofluza , is an antiviral medication for treatment of influenza A and influenza B . It was approved for medical use both in Japan and in the United States in 2018, and is taken as a single dose by mouth . It may reduce the duration of flu symptoms by about a day, but is prone to selection of resistant mutants that render it ineffectual. [ unreliable medical source? ] Baloxavir marboxil was developed as a prodrug strategy, with its metabolism releasing the active agent, baloxavir acid (BXA). Baloxavir acid then functions as enzyme inhibitor , targeting the influenza virus' cap -dependent endonuclease activity, used in " cap snatching " by the virus' polymerase complex, a process essential to its life-cycle. The most common side effects of baloxavir marboxil include diarrhea , bronchitis , nausea , sinusitis , and headache . The US Food and Drug Administration (FDA) considers baloxavir marboxil to be a first-in-class medication . Baloxavir marboxil is an influenza medication, an antiviral , for individuals who are twelve years of age or older, that have presented symptoms of this infection for no more than 48 hours. The efficacy of baloxavir marboxil administered after 48 hours has not been tested. In October 2019, the FDA approved an updated indication for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications. In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu. In August 2022, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people five years of age and older after contact with an individual who has the flu. In the EU, baloxavir marboxil is indicated for the treatment of uncomplicated influenza and for post-exposure prophylaxis of influenza in individuals aged twelve years of age and older. Baloxavir marboxil is available in tablet form and as granules for mixing in water. In 2.2% of baloxavir recipients in the Phase II trial and in about 10% of baloxavir recipients in the Phase III trial, the infecting influenza strain had acquired resistance to the drug, due to variants of the polymerase protein displaying substitutions of isoleucine-38, specifically, the I38T, I38M, or I38F mutations. There is continuing research into and clinical concern over the resistance appearing in recipients, in response to treatment with this drug. Baloxavir marboxil is available in tablet form and as granules for mixing in water. In 2.2% of baloxavir recipients in the Phase II trial and in about 10% of baloxavir recipients in the Phase III trial, the infecting influenza strain had acquired resistance to the drug, due to variants of the polymerase protein displaying substitutions of isoleucine-38, specifically, the I38T, I38M, or I38F mutations. There is continuing research into and clinical concern over the resistance appearing in recipients, in response to treatment with this drug. Baloxavir marboxil should not be co-administered with dairy products, calcium-fortified beverages, or laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminum or zinc. Common side effects following the single dose administration of baloxavir marboxil include diarrhea, bronchitis, common cold, headache, and nausea. Adverse events were reported in 21% of people who received baloxavir, 25% of those receiving placebo, and 25% of oseltamivir. Baloxavir marboxil is an influenza therapeutic agent, specifically, an enzyme inhibitor targeting the influenza virus' cap -dependent endonuclease activity, one of the activities of the virus polymerase complex. In particular, it inhibits a process known as cap snatching , [ medical citation needed ] by which the virus derives short, capped primers from host cell RNA transcripts, which it then uses for polymerase-catalyzed synthesis of its needed viral mRNAs . A polymerase subunit binds to the host pre-mRNAs at their 5' caps, then the polymerase's endonuclease activity catalyzes its cleavage "after 10–13 nucleotides". [ medical citation needed ] As such, its mechanism is distinct from neuraminidase inhibitors such as oseltamivir and zanamivir . Baloxavir marboxil is a substituted pyridone derivative of a polycyclic family, whose chemical synthesis has been reported in a number of ways by the company discovering it, Shionogi and Co. of Japan (as well as others); the Shionogi reports have appeared several times in the Japanese patent literature between 2016 and 2019, providing insight into possible industrial synthetic routes that may be in use. Baloxavir marboxil (BXM) is a prodrug whose active agent, baloxavir acid (BXA) is released rapidly in vivo , as the hydrolysis of baloxavir marboxil is catalyzed by arylacetamide deacetylases in cells of the blood, liver, and lumen of the small intestine. The compound numbers for baloxavir marboxil and baloxavir acid used in publications by Shionogi and others during discovery and development (prior to assignment of a United States Adopted Name (USAN)) were, respectively, S-033188 and S-033447. As reported in a review of the patent literature, the carbonic acid ester (carbonate) moiety of the prodrug—shown in the lower left-hand corner of the image above—was prepared during discovery and development research from a late stage 2-hydroxy- 4-pyridone precursor by treatment with chloromethyl methyl carbonate. As of September 2018, in the only report of a Phase III randomized, controlled trial, baloxavir reduced the duration of influenza symptoms of otherwise healthy participants by about one day compared with a placebo treatment group, and comparable with what was seen for an oseltamivir treatment group. On the first day after baloxavir was started in its treatment group of participants, viral loads decreased more than in participants in either the oseltamivir or placebo groups; however, after five days, the effect on viral load of the single dose of baloxavir was indistinguishable from the effect observed following the complete, 5-day regimen of oseltamivir in its treatment group. [ verification needed ] Baloxavir marboxil was developed for the market by Shionogi Co., a Japanese pharmaceutical company, and Switzerland -based Roche AG . The names under which baloxavir marboxil and baloxavir acid appear in Shionogi research reporting are S-033188 and S-033447, respectively. [ citation needed ]Japan's Ministry of Health, Labour and Welfare (JMHLW) and the US Food and Drug Administration (FDA) approved baloxavir marboxil based on evidence of its benefits and side effects from two clinical trials in adult and pediatric participants with uncomplicated influenza (Trial 1, 1518T0821 and Trial 2, NCT02954354 ), involving 1119 participants. [ better source needed ] [ verification needed ] Both trials included clinical sites and participants in Japan, with Trial 2 adding clinical locations in the United States. Baloxavir marboxil was approved for sale in Japan in February 2018. [ better source needed ] In October 2018, the FDA approved it for the treatment of acute uncomplicated influenza in people twelve years of age and older who have been symptomatic for no more than 48 hours. The FDA application of baloxavir marboxil was granted priority review in the United States, and approval of Xofluza was granted to Shionogi & Co., Ltd. in October 2018. Specifically, the FDA approved the use of baloxavir marboxil for people at high risk of developing influenza-related complications. In October 2019, the FDA approved an updated indication for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications. In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu. Baloxavir marboxil was approved for medical use in Australia in February 2020. The safety and efficacy of baloxavir marboxil, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 subjects where participants were assigned to receive either baloxavir marboxil, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms. In both trials, subjects treated with baloxavir marboxil had a shorter time to alleviation of symptoms compared with subjects who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received baloxavir marboxil and those who received the other flu treatment. The safety and efficacy of baloxavir marboxil for post-flu exposure prevention is supported by one randomized, double-blind, controlled trial in which 607 subjects, twelve years of age and older who were exposed to a person with influenza in their household, received either a single dose of baloxavir marboxil or a single dose of a placebo. Of these 607 subjects, 303 received baloxavir marboxil and 304 received the placebo. The trial's primary endpoint was the proportion of subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10. Of those who received baloxavir marboxil, 1% of subjects met these criteria, compared to 13% of subjects who received a placebo for the clinical trial. Baloxavir marboxil was approved for medical use in the European Union in January 2021. Japan's Ministry of Health, Labour and Welfare (JMHLW) and the US Food and Drug Administration (FDA) approved baloxavir marboxil based on evidence of its benefits and side effects from two clinical trials in adult and pediatric participants with uncomplicated influenza (Trial 1, 1518T0821 and Trial 2, NCT02954354 ), involving 1119 participants. [ better source needed ] [ verification needed ] Both trials included clinical sites and participants in Japan, with Trial 2 adding clinical locations in the United States. Baloxavir marboxil was approved for sale in Japan in February 2018. [ better source needed ] In October 2018, the FDA approved it for the treatment of acute uncomplicated influenza in people twelve years of age and older who have been symptomatic for no more than 48 hours. The FDA application of baloxavir marboxil was granted priority review in the United States, and approval of Xofluza was granted to Shionogi & Co., Ltd. in October 2018. Specifically, the FDA approved the use of baloxavir marboxil for people at high risk of developing influenza-related complications. In October 2019, the FDA approved an updated indication for the treatment of acute, uncomplicated influenza in people twelve years of age and older at risk of influenza complications. In November 2020, the FDA approved an updated indication to include post-exposure prevention of influenza (flu) for people twelve years of age and older after contact with an individual who has the flu. Baloxavir marboxil was approved for medical use in Australia in February 2020. The safety and efficacy of baloxavir marboxil, an antiviral drug taken as a single oral dose, was demonstrated in two randomized controlled clinical trials of 1,832 subjects where participants were assigned to receive either baloxavir marboxil, a placebo, or another antiviral flu treatment within 48 hours of experiencing flu symptoms. In both trials, subjects treated with baloxavir marboxil had a shorter time to alleviation of symptoms compared with subjects who took the placebo. In the second trial, there was no difference in the time to alleviation of symptoms between subjects who received baloxavir marboxil and those who received the other flu treatment. The safety and efficacy of baloxavir marboxil for post-flu exposure prevention is supported by one randomized, double-blind, controlled trial in which 607 subjects, twelve years of age and older who were exposed to a person with influenza in their household, received either a single dose of baloxavir marboxil or a single dose of a placebo. Of these 607 subjects, 303 received baloxavir marboxil and 304 received the placebo. The trial's primary endpoint was the proportion of subjects who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to day 10. Of those who received baloxavir marboxil, 1% of subjects met these criteria, compared to 13% of subjects who received a placebo for the clinical trial. Baloxavir marboxil was approved for medical use in the European Union in January 2021.

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influenza virus

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Hemagglutinin

In molecular biology , hemagglutinins (alternatively spelled haemagglutinin , from the Greek haima , 'blood' + Latin gluten , 'glue') are receptor-binding membrane fusion glycoproteins produced by viruses in the Paramyxoviridae and Orthomyxoviridae families. Hemagglutinins are responsible for binding to receptors on red blood cells to initiate viral attachment and infection . The agglutination of red cells occurs when antibodies on one cell bind to those on others, causing amorphous aggregates of clumped cells. Hemagglutinins recognize cell-surface glycoconjugates containing sialic acid on the surface of host red blood cells with a low affinity, and use them to enter the endosome of host cells. In the endosome, hemagglutinins are activated at a pH of 5 - 6.5 to undergo conformational changes that enable viral attachment through a fusion peptide . Virologist George K. Hirst discovered agglutination and hemagglutinins in 1941. Alfred Gottschalk proved in 1957 that hemagglutinins bind a virus to a host cell by attaching to sialic acids on carbohydrate side chains of cell-membrane glycoproteins and glycolipids . Hemagglutinins are small proteins that project from the virus membrane surface as 135 Angstrom (à ) long spikes with a diameter of 30-50 à . Each spike is made up of three identical monomer subunits, making the protein a homotrimer . These monomers are formed of two glycopeptides , HA1 and HA2, and linked by two disulphide polypeptides including membrane-distal HA1 and the smaller membrane-proximal HA2. X-Ray crystallography and spectroscopy were used to identify that the majority of the protein structures is made of α-helical proteins. In addition to the homotrimeric core structure, hemagglutinins have four subdomains: the membrane-distal receptor binding R subdomain, the vestigial domain E, that functions as a receptor-destroying esterase , the fusion domain F, and the membrane anchor subdomain M. The membrane anchor subdomain forms elastic protein chains linking the hemagglutinin to the ectodomain.

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Bubonic plague

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Bubonic plague

Bubonic plague is one of three types of plague caused by the bacterium Yersinia pestis . One to seven days after exposure to the bacteria, flu-like symptoms develop. These symptoms include fever , headaches , and vomiting , as well as swollen and painful lymph nodes occurring in the area closest to where the bacteria entered the skin. Acral necrosis , the dark discoloration of skin, is another symptom. Occasionally, swollen lymph nodes, known as " buboes ", may break open. The three types of plague are the result of the route of infection: bubonic plague, septicemic plague , and pneumonic plague . Bubonic plague is mainly spread by infected fleas from small animals . It may also result from exposure to the body fluids from a dead plague-infected animal. Mammals such as rabbits , hares , and some cat species are susceptible to bubonic plague, and typically die upon contraction. In the bubonic form of plague, the bacteria enter through the skin through a flea bite and travel via the lymphatic vessels to a lymph node , causing it to swell. Diagnosis is made by finding the bacteria in the blood, sputum , or fluid from lymph nodes. Prevention is through public health measures such as not handling dead animals in areas where plague is common. While vaccines against the plague have been developed, the World Health Organization recommends that only high-risk groups, such as certain laboratory personnel and health care workers, get inoculated. Several antibiotics are effective for treatment, including streptomycin , gentamicin , and doxycycline . Without treatment, plague results in the death of 30% to 90% of those infected. Death, if it occurs, is typically within 10 days. With treatment, the risk of death is around 10%. Globally between 2010 and 2015 there were 3,248 documented cases, which resulted in 584 deaths. The countries with the greatest number of cases are the Democratic Republic of the Congo , Madagascar , and Peru . The plague is considered the likely cause of the Black Death that swept through Asia, Europe, and Africa in the 14th century and killed an estimated 50 million people, including about 25% to 60% of the European population. Because the plague killed so many of the working population, wages rose due to the demand for labor. Some historians see this as a turning point in European economic development . The disease is also considered to have been responsible for the Plague of Justinian , originating in the Eastern Roman Empire in the 6th century CE, as well as the third epidemic , affecting China , Mongolia , and India , originating in the Yunnan Province in 1855. The term bubonic is derived from the Greek word Î²Î¿Ï Î²ÏŽÎ½ , meaning "groin." The bubonic plague is an infection of the lymphatic system , usually resulting from the bite of an infected flea, Xenopsylla cheopis (the Oriental rat flea ). Several flea species carried the bubonic plague, such as Pulex irritans (the human flea ), Xenopsylla cheopis , and Ceratophyllus fasciatus . Xenopsylla cheopis was the most effective flea species for transmission. The flea is parasitic on house and field rats and seeks out other prey when its rodent host dies. Rats were an amplifying factor to bubonic plague due to their common association with humans as well as the nature of their blood. The rat's blood allows the rat to withstand a major concentration of the plague. The bacteria form aggregates in the gut of infected fleas, and this results in the flea regurgitating ingested blood, which is now infected, into the bite site of a rodent or human host. Once established, the bacteria rapidly spread to the lymph nodes of the host and multiply. The fleas that transmit the disease only directly infect humans when the rat population in the area is wiped out from a mass infection. Furthermore, in areas with a large population of rats, the animals can harbor low levels of the plague infection without causing human outbreaks. With no new rat inputs being added to the population from other areas, the infection only spread to humans in very rare cases of overcrowding. After being transmitted via the bite of an infected flea, the Y. pestis bacteria become localized in an inflamed lymph node , where they begin to colonize and reproduce. Infected lymph nodes develop hemorrhages, which result in the death of tissue. Y. pestis bacilli can resist phagocytosis and even reproduce inside phagocytes and kill them. As the disease progresses, the lymph nodes can hemorrhage and become swollen and necrotic . Bubonic plague can progress to lethal septicemic plague in some cases. The plague is also known to spread to the lungs and become the disease known as the pneumonic plague . Symptoms appear 2–7 days after getting bitten and they include: The best-known symptom of bubonic plague is one or more infected, enlarged, and painful lymph nodes, known as buboes . Buboes associated with the bubonic plague are commonly found in the armpits, upper femoral area, groin, and neck region. These buboes will grow and become more painful over time, often to the point of bursting. Symptoms include heavy breathing, continuous vomiting of blood ( hematemesis ), aching limbs, coughing, and extreme pain caused by the decay or decomposition of the skin while the person is still alive. Additional symptoms include extreme fatigue, gastrointestinal problems, spleen inflammation, lenticulae (black dots scattered throughout the body), delirium, coma , organ failure, and death. Organ failure is a result of the bacteria infecting organs through the bloodstream. Other forms of the disease include septicemic plague and pneumonic plague , in which the bacterium reproduces in the person's blood and lungs respectively. Laboratory testing is required in order to diagnose and confirm plague. Ideally, confirmation is through the identification of Y. pestis culture from a patient sample. Confirmation of infection can be done by examining serum taken during the early and late stages of infection . To quickly screen for the Y. pestis antigen in patients, rapid dipstick tests have been developed for field use. Samples taken for testing include: Bubonic plague outbreaks are controlled by pest control and modern sanitation techniques. This disease uses fleas commonly found on rats as a vector to jump from animals to humans. The mortality rate is highest in the summer and early fall. The successful control of rat populations in dense urban areas is essential to outbreak prevention. One example is the use of a machine called the Sulfurozador , used to deliver sulphur dioxide to eradicate the pest that spread the bubonic plague in Buenos Aires, Argentina during the early 18th century. Targeted chemoprophylaxis , sanitation , and vector control also played a role in controlling the 2003 Oran outbreak of the bubonic plague. Another means of prevention in large European cities was a city-wide quarantine to not only limit interaction with people who were infected, but also to limit the interaction with the infected rats. Several classes of antibiotic are effective in treating bubonic plague. These include aminoglycosides such as streptomycin and gentamicin , tetracyclines (especially doxycycline ), and the fluoroquinolone ciprofloxacin . Mortality associated with treated cases of bubonic plague is about 1–15%, compared to a mortality of 40–60% in untreated cases. People potentially infected with the plague need immediate treatment and should be given antibiotics within 24 hours of the first symptoms to prevent death. Other treatments include oxygen, intravenous fluids, and respiratory support. People who have had contact with anyone infected by pneumonic plague are given prophylactic antibiotics. Using the broad-based antibiotic streptomycin has proven to be dramatically successful against the bubonic plague within 12 hours of infection. Globally between 2010 and 2015, there were 3,248 documented cases, which resulted in 584 deaths. The countries with the greatest number of cases are the Democratic Republic of the Congo , Madagascar , and Peru . For over a decade since 2001, Zambia, India, Malawi, Algeria, China, Peru, and the Democratic Republic of the Congo had the most plague cases, with over 1,100 cases in the Democratic Republic of the Congo alone. From 1,000 to 2,000 cases are conservatively reported per year to the WHO . From 2012 to 2017, reflecting political unrest and poor hygienic conditions, Madagascar began to host regular epidemics. Between 1900 and 2015, the United States had 1,036 human plague cases, with an average of 9 cases per year. In 2015, 16 people in the western United States developed plague, including 2 cases in Yosemite National Park . These US cases usually occur in rural northern New Mexico, northern Arizona, southern Colorado, California, southern Oregon, and far western Nevada. In November 2017, the Madagascar Ministry of Health reported an outbreak to the WHO (World Health Organization) with more cases and deaths than any recent outbreak in the country. Unusually, most of the cases were pneumonic rather than bubonic. In June 2018, a child was confirmed to be the first person in Idaho to be infected by bubonic plague in nearly 30 years. A couple died in May 2019, in Mongolia, while hunting marmots . Another two people in the province of Inner Mongolia, China, were treated in November 2019 for the disease. In July 2020, in Bayannur , Inner Mongolia of China, a human case of bubonic plague was reported. Officials responded by activating a city-wide plague-prevention system for the remainder of the year. Also in July 2020, in Mongolia, a teenager died from bubonic plague after consuming infected marmot meat. Yersinia pestis has been discovered in archaeological finds from the Late Bronze Age (~3800 BP ). The bacteria is identified by ancient DNA in human teeth from Asia and Europe dating from 2,800 to 5,000 years ago. Some authors have suggested that the plague was responsible for the Neolithic decline . The first recorded epidemic affected the Sasanian Empire and their arch-rivals, the Eastern Roman Empire (Byzantine Empire) and was named the Plague of Justinian (541–549 AD) after emperor Justinian I , who was infected but survived through extensive treatment. The pandemic resulted in the deaths of an estimated 25 million (6th century outbreak) to 50 million people (two centuries of recurrence). The historian Procopius wrote, in Volume II of History of the Wars , of his personal encounter with the plague and the effect it had on the rising empire. In the spring of 542, the plague arrived in Constantinople, working its way from port city to port city and spreading around the Mediterranean Sea , later migrating inland eastward into Asia Minor and west into Greece and Italy. The Plague of Justinian is said to have been "completed" in the middle of the 8th century. Because the infectious disease spread inland by the transferring of merchandise through Justinian's efforts in acquiring luxurious goods of the time and exporting supplies, his capital became the leading exporter of the bubonic plague. Procopius, in his work Secret History , declared that Justinian was a demon of an emperor who either created the plague himself or was being punished for his sinfulness. Medieval society's increasing population was put to deadly halt when, in the Late Middle Ages , Europe experienced the deadliest disease outbreak in history. They called it the Great Dying or The Great Pestilence, later coined The Black Death. Lasting in potency for roughly 6 years, 1346–1352, the Black Death claimed one-third of the European human population. Having mortality rates as high as 70%-80%. Some historians believe that society subsequently became more violent as the mass mortality rate cheapened life and thus increased warfare, crime, popular revolt, waves of flagellants , and persecution. The Black Death originated in Central Asia and spread from Italy and then throughout other European countries. Arab historians Ibn Al-Wardni and Almaqrizi believed the Black Death originated in Mongolia. Chinese records also show a huge outbreak in Mongolia in the early 1330s. In 2022, researchers presented evidence that the plague originated near Lake Issyk-Kul in Kyrgyzstan . The Mongols had cut the trade route (the Silk Road ) between China and Europe, which halted the spread of the Black Death from eastern Russia to Western Europe. The European epidemic may have begun with the siege of Caffa , an attack that Mongols launched on the Italian merchants' last trading station in the region, Caffa , in the Crimea . In late 1346, plague broke out among the besiegers and from them penetrated the town. The Mongol forces catapulted plague-infested corpses into Caffa as a form of attack, one of the first known instances of biological warfare . When spring arrived, the Italian merchants fled on their ships, unknowingly carrying the Black Death. Carried by the fleas on rats, the plague initially spread to humans near the Black Sea and then outwards to the rest of Europe as a result of people fleeing from one area to another. Rats migrated with humans, traveling among grain bags, clothing, ships, wagons, and grain husks. Continued research indicates that black rats , those that primarily transmitted the disease, prefer grain as a primary meal. Due to this, the major bulk grain fleets that transported major city's food shipments from Africa and Alexandria to heavily populated areas, and were then unloaded by hand, played a role in increasing the transmission effectiveness of the plague. The plague resurfaced for a third time in the mid-19th century; this is also known as "the modern pandemic". Like the two previous outbreaks, this one also originated in Eastern Asia , most likely in Yunnan , a province of China, where there are several natural plague foci . The initial outbreaks occurred in the second half of the 18th century. The disease remained localized in Southwest China for several years before spreading. In the city of Canton , beginning in January 1894, the disease had killed 80,000 people by June. Daily water traffic with the nearby city of Hong Kong rapidly spread the plague there, killing over 2,400 within two months during the 1894 Hong Kong plague . The third pandemic spread the disease to port cities throughout the world in the second half of the 19th century and the early 20th century via shipping routes. The plague infected people in Chinatown in San Francisco from 1900 to 1904, and in the nearby locales of Oakland and the East Bay again from 1907 to 1909. During the former outbreak, in 1902, authorities made permanent the Chinese Exclusion Act , a law originally signed into existence by President Chester A. Arthur in 1882. The Act was supposed to last for 10 years, but was renewed in 1892 with the Geary Act , then followed by the 1902 decision. The last major outbreak in the United States occurred in Los Angeles in 1924, though the disease is still present in wild rodents and can be passed to humans that come in contact with them. According to the World Health Organization , the pandemic was considered active until 1959, when worldwide casualties dropped to 200 per year. In 1994, a plague outbreak in five Indian states caused an estimated 700 infections (including 52 deaths) and triggered a large migration of Indians within India as they tried to avoid the disease. [ citation needed ] It was during the 1894 Hong Kong plague outbreak that Alexandre Yersin isolated the bacterium responsible ( Yersinia pestis ), a few days after Japanese bacteriologist Kitasato Shibasaburō had isolated it. However, the latter's description was imprecise and also expressed doubts of its relation to the disease, and thus the bacterium is today only named after Yersin. The first recorded epidemic affected the Sasanian Empire and their arch-rivals, the Eastern Roman Empire (Byzantine Empire) and was named the Plague of Justinian (541–549 AD) after emperor Justinian I , who was infected but survived through extensive treatment. The pandemic resulted in the deaths of an estimated 25 million (6th century outbreak) to 50 million people (two centuries of recurrence). The historian Procopius wrote, in Volume II of History of the Wars , of his personal encounter with the plague and the effect it had on the rising empire. In the spring of 542, the plague arrived in Constantinople, working its way from port city to port city and spreading around the Mediterranean Sea , later migrating inland eastward into Asia Minor and west into Greece and Italy. The Plague of Justinian is said to have been "completed" in the middle of the 8th century. Because the infectious disease spread inland by the transferring of merchandise through Justinian's efforts in acquiring luxurious goods of the time and exporting supplies, his capital became the leading exporter of the bubonic plague. Procopius, in his work Secret History , declared that Justinian was a demon of an emperor who either created the plague himself or was being punished for his sinfulness. Medieval society's increasing population was put to deadly halt when, in the Late Middle Ages , Europe experienced the deadliest disease outbreak in history. They called it the Great Dying or The Great Pestilence, later coined The Black Death. Lasting in potency for roughly 6 years, 1346–1352, the Black Death claimed one-third of the European human population. Having mortality rates as high as 70%-80%. Some historians believe that society subsequently became more violent as the mass mortality rate cheapened life and thus increased warfare, crime, popular revolt, waves of flagellants , and persecution. The Black Death originated in Central Asia and spread from Italy and then throughout other European countries. Arab historians Ibn Al-Wardni and Almaqrizi believed the Black Death originated in Mongolia. Chinese records also show a huge outbreak in Mongolia in the early 1330s. In 2022, researchers presented evidence that the plague originated near Lake Issyk-Kul in Kyrgyzstan . The Mongols had cut the trade route (the Silk Road ) between China and Europe, which halted the spread of the Black Death from eastern Russia to Western Europe. The European epidemic may have begun with the siege of Caffa , an attack that Mongols launched on the Italian merchants' last trading station in the region, Caffa , in the Crimea . In late 1346, plague broke out among the besiegers and from them penetrated the town. The Mongol forces catapulted plague-infested corpses into Caffa as a form of attack, one of the first known instances of biological warfare . When spring arrived, the Italian merchants fled on their ships, unknowingly carrying the Black Death. Carried by the fleas on rats, the plague initially spread to humans near the Black Sea and then outwards to the rest of Europe as a result of people fleeing from one area to another. Rats migrated with humans, traveling among grain bags, clothing, ships, wagons, and grain husks. Continued research indicates that black rats , those that primarily transmitted the disease, prefer grain as a primary meal. Due to this, the major bulk grain fleets that transported major city's food shipments from Africa and Alexandria to heavily populated areas, and were then unloaded by hand, played a role in increasing the transmission effectiveness of the plague. The plague resurfaced for a third time in the mid-19th century; this is also known as "the modern pandemic". Like the two previous outbreaks, this one also originated in Eastern Asia , most likely in Yunnan , a province of China, where there are several natural plague foci . The initial outbreaks occurred in the second half of the 18th century. The disease remained localized in Southwest China for several years before spreading. In the city of Canton , beginning in January 1894, the disease had killed 80,000 people by June. Daily water traffic with the nearby city of Hong Kong rapidly spread the plague there, killing over 2,400 within two months during the 1894 Hong Kong plague . The third pandemic spread the disease to port cities throughout the world in the second half of the 19th century and the early 20th century via shipping routes. The plague infected people in Chinatown in San Francisco from 1900 to 1904, and in the nearby locales of Oakland and the East Bay again from 1907 to 1909. During the former outbreak, in 1902, authorities made permanent the Chinese Exclusion Act , a law originally signed into existence by President Chester A. Arthur in 1882. The Act was supposed to last for 10 years, but was renewed in 1892 with the Geary Act , then followed by the 1902 decision. The last major outbreak in the United States occurred in Los Angeles in 1924, though the disease is still present in wild rodents and can be passed to humans that come in contact with them. According to the World Health Organization , the pandemic was considered active until 1959, when worldwide casualties dropped to 200 per year. In 1994, a plague outbreak in five Indian states caused an estimated 700 infections (including 52 deaths) and triggered a large migration of Indians within India as they tried to avoid the disease. [ citation needed ] It was during the 1894 Hong Kong plague outbreak that Alexandre Yersin isolated the bacterium responsible ( Yersinia pestis ), a few days after Japanese bacteriologist Kitasato Shibasaburō had isolated it. However, the latter's description was imprecise and also expressed doubts of its relation to the disease, and thus the bacterium is today only named after Yersin. The scale of death and social upheaval associated with plague outbreaks has made the topic prominent in many historical and fictional accounts since the disease was first recognized. The Black Death in particular is described and referenced in numerous contemporary sources , some of which, including works by Chaucer , Boccaccio , and Petrarch , are considered part of the Western canon . The Decameron , by Boccaccio, is notable for its use of a frame story involving individuals who have fled Florence for a secluded villa to escape the Black Death. First-person, sometimes sensationalized or fictionalized, accounts of living through plague years have also been popular across centuries and cultures. For example, Samuel Pepys 's diary makes several references to his first-hand experiences of the Great Plague of London in 1665–66. Later works, such as Albert Camus 's novel The Plague or Ingmar Bergman 's film The Seventh Seal have used bubonic plague in settings, such as quarantined cities in either medieval or modern times, as a backdrop to explore a variety of concepts. Common themes include the breakdown of society, institutions, and individuals during the plague, the cultural and psychological existential confrontation with mortality, and the allegorical use of the plague about contemporary moral or spiritual questions. [ citation needed ] Some of the earliest instances of biological warfare were said to have been products of the plague, as armies of the 14th century were recorded catapulting diseased corpses over the walls of towns and villages to spread the pestilence. This was done by Jani Beg when he attacked the city of Kaffa in 1343. Later, plague was used during the Second Sino-Japanese War as a bacteriological weapon by the Imperial Japanese Army . These weapons were provided by Shirō Ishii 's units and used in experiments on humans before being used in the field. For example, in 1940, the Imperial Japanese Army Air Service bombed Ningbo with fleas carrying the bubonic plague. During the Khabarovsk War Crime Trials , the accused, such as Major General Kiyoshi Kawashima, testified that, in 1941, 40 members of Unit 731 air-dropped plague -contaminated fleas on Changde . These operations caused epidemic plague outbreaks. Substantial research has been done regarding the origin of the plague and how it traveled through the continent. Mitochondrial DNA of modern rats in Western Europe indicated that these rats came from two different areas, one being Africa and the other unclear. The research regarding this pandemic has greatly increased with technology. Through archaeo-molecular investigation, researchers have discovered the DNA of plague bacillus in the dental core of those that fell ill to the plague. Analysis of teeth of the deceased allows researchers to further understand both the demographics and mortuary patterns of the disease. For example, in 2013 in England, archeologists uncovered a burial mound to reveal 17 bodies, mainly children, who had died of the Bubonic plague. They analyzed these burial remains using radiocarbon dating to determine they were from the 1530s, and dental core analysis revealed the presence of Yersinia pestis. Other evidence for rats that are currently still being researched consists of gnaw marks on bones, predator pellets and rat remains that were preserved in situ . This research allows individuals to trace early rat remains to track the path traveled and in turn connect the impact of the Bubonic Plague to specific breeds of rats. Burial sites, known as plague pits, offer archaeologists an opportunity to study the remains of people who died from the plague. Another research study indicates that these separate pandemics were all interconnected. A current computer model indicates that the disease did not go away in between these pandemics. It rather lurked within the rat population for years without causing human epidemics. Some of the earliest instances of biological warfare were said to have been products of the plague, as armies of the 14th century were recorded catapulting diseased corpses over the walls of towns and villages to spread the pestilence. This was done by Jani Beg when he attacked the city of Kaffa in 1343. Later, plague was used during the Second Sino-Japanese War as a bacteriological weapon by the Imperial Japanese Army . These weapons were provided by Shirō Ishii 's units and used in experiments on humans before being used in the field. For example, in 1940, the Imperial Japanese Army Air Service bombed Ningbo with fleas carrying the bubonic plague. During the Khabarovsk War Crime Trials , the accused, such as Major General Kiyoshi Kawashima, testified that, in 1941, 40 members of Unit 731 air-dropped plague -contaminated fleas on Changde . These operations caused epidemic plague outbreaks. Substantial research has been done regarding the origin of the plague and how it traveled through the continent. Mitochondrial DNA of modern rats in Western Europe indicated that these rats came from two different areas, one being Africa and the other unclear. The research regarding this pandemic has greatly increased with technology. Through archaeo-molecular investigation, researchers have discovered the DNA of plague bacillus in the dental core of those that fell ill to the plague. Analysis of teeth of the deceased allows researchers to further understand both the demographics and mortuary patterns of the disease. For example, in 2013 in England, archeologists uncovered a burial mound to reveal 17 bodies, mainly children, who had died of the Bubonic plague. They analyzed these burial remains using radiocarbon dating to determine they were from the 1530s, and dental core analysis revealed the presence of Yersinia pestis. Other evidence for rats that are currently still being researched consists of gnaw marks on bones, predator pellets and rat remains that were preserved in situ . This research allows individuals to trace early rat remains to track the path traveled and in turn connect the impact of the Bubonic Plague to specific breeds of rats. Burial sites, known as plague pits, offer archaeologists an opportunity to study the remains of people who died from the plague. Another research study indicates that these separate pandemics were all interconnected. A current computer model indicates that the disease did not go away in between these pandemics. It rather lurked within the rat population for years without causing human epidemics.

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Bubonic plague

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Third plague pandemic

The third plague pandemic was a major bubonic plague pandemic that began in Yunnan , China, in 1855. This episode of bubonic plague spread to all inhabited continents, and ultimately led to more than 12 million deaths in India and China (and perhaps over 15 million worldwide ), and at least 10 million Indians were killed in British Raj India alone, making it one of the deadliest pandemics in history. According to the World Health Organization , the pandemic was considered active until 1960 when worldwide casualties dropped to 200 per year. Plague deaths have continued at a lower level for every year since. The name refers to the third of at least three known major plague pandemics. The first began with the Plague of Justinian , which ravaged the Byzantine Empire and surrounding areas in 541 and 542; the pandemic persisted in successive waves until the middle of the 8th century. The second began with the Black Death , which killed at least one third of Europe 's population in a series of expanding waves of infection from 1346 to 1353; this pandemic recurred regularly until the 19th century. Casualty patterns indicate that waves of this late-19th-century/early-20th-century pandemic may have come from two different sources. The first was primarily bubonic and was carried around the world through ocean-going trade, through transporting infected persons, rats , and cargoes harboring fleas . The second, more virulent strain, was primarily pneumonic in character with a strong person-to-person contagion. This strain was largely confined to Asia. [ citation needed ]The bubonic plague was endemic in populations of infected ground rodents in Central Asia and was a known cause of death among the migrant and established human populations in that region for centuries. An influx of new people because of political conflicts and global trade led to the spread of the disease throughout the world from Asia to the rest of Europe, to reach Africa and the Americas . [ citation needed ] A natural reservoir or nidus for plague is in western Yunnan and is still an ongoing health risk. The third pandemic of plague originated in the area after a rapid influx of Han Chinese to exploit the demand for minerals, primarily copper , in the second half of the 19th century. By 1850, the population had exploded to over 7 million people. Increasing transportation throughout the region brought people in contact with plague-infected fleas , the primary vector between the yellow-breasted rat ( Rattus flavipectus ) and humans. People brought the fleas and rats back into growing urban areas, where small outbreaks sometimes reached epidemic proportions. The plague spread further and began to appear in the Pearl River delta, including Canton and Hong Kong . Although William McNeil and others believe the plague to have been brought from the interior to the coastal regions by troops returning from battles against the Muslim rebels, Benedict suggested evidence to favor the growing and lucrative opium trade, which began after about 1840. In the city of Canton, beginning in March 1894, the disease killed 80,000 people in a few weeks. Daily water-traffic with the nearby city of Hong Kong rapidly spread the plague. Within two months, after 100,000 deaths, the death rates dropped below epidemic rates, but the disease continued to be endemic in Hong Kong until 1929. The network of global shipping ensured the widespread distribution of the disease over the next few decades. Recorded outbreaks included the following: Each of the areas, as well as Great Britain , France , and other areas of Europe, continued to experience plague outbreaks and casualties until the 1960s, although extremely few of these occurred after 1950. The last significant outbreak of plague associated with the pandemic occurred in Peru and Argentina in 1945. [ citation needed ] The 1894 Hong Kong plague was a major outbreak of the third global pandemic from the late 19th century to the early 20th century. The first case, discovered in May 1894, was a hospital clerk who had just returned from Canton . The hardest hit was the mountainous area in Sheung Wan , the most densely-populated area in Hong Kong, characterised by Chinese-style buildings. From May to October 1894, the plague killed more than 6,000 people, leading to the exodus of one third of the population. In the 30 years starting in 1926 [ dubious – discuss ] , the plague occurred in Hong Kong almost every year and killed more than 20,000 people. Through maritime traffic, the epidemic spread to the rest of the country after 1894 and eventually spread to British Raj India where about ten million Indians were killed . There were several reasons for the rapid outbreak and spread of the plague. Firstly, in the early days, Sheung Wan was a Chinese settlement. Houses — in the mountains — had no drainage channels, toilets, or running water. The houses were small and the floors were not paved. Secondly, during the Ching Ming Festival in 1894, many Chinese living in Hong Kong returned to the countryside to tend to family graves, which coincided with the outbreak of the epidemic in Canton and the introduction of bacteria into Hong Kong. Thirdly, in the first four months of 1894, rainfall decreased and soil dried up, accelerating the spread of the plague. The main preventive measures were setting up plague hospitals and deploying medical staff to treat and isolate plague patients; conducting house-to-house search operations, discovering and transferring plague patients, and cleaning and disinfecting infected houses and areas; and setting up designated cemeteries and assigning a person responsible for transporting and burying the plague dead. The 1894 Hong Kong plague was a major outbreak of the third global pandemic from the late 19th century to the early 20th century. The first case, discovered in May 1894, was a hospital clerk who had just returned from Canton . The hardest hit was the mountainous area in Sheung Wan , the most densely-populated area in Hong Kong, characterised by Chinese-style buildings. From May to October 1894, the plague killed more than 6,000 people, leading to the exodus of one third of the population. In the 30 years starting in 1926 [ dubious – discuss ] , the plague occurred in Hong Kong almost every year and killed more than 20,000 people. Through maritime traffic, the epidemic spread to the rest of the country after 1894 and eventually spread to British Raj India where about ten million Indians were killed . There were several reasons for the rapid outbreak and spread of the plague. Firstly, in the early days, Sheung Wan was a Chinese settlement. Houses — in the mountains — had no drainage channels, toilets, or running water. The houses were small and the floors were not paved. Secondly, during the Ching Ming Festival in 1894, many Chinese living in Hong Kong returned to the countryside to tend to family graves, which coincided with the outbreak of the epidemic in Canton and the introduction of bacteria into Hong Kong. Thirdly, in the first four months of 1894, rainfall decreased and soil dried up, accelerating the spread of the plague. The main preventive measures were setting up plague hospitals and deploying medical staff to treat and isolate plague patients; conducting house-to-house search operations, discovering and transferring plague patients, and cleaning and disinfecting infected houses and areas; and setting up designated cemeteries and assigning a person responsible for transporting and burying the plague dead. Researchers working in Asia during the "Third Pandemic" identified plague vectors and the plague bacillus. In 1894, in Hong Kong, Swiss-born French bacteriologist Alexandre Yersin isolated the responsible bacterium ( Yersinia pestis , named for Yersin) and determined the common mode of transmission. His discoveries led in time to modern treatment methods, including insecticides , the use of antibiotics and eventually plague vaccines . In 1898, French researcher Paul-Louis Simond demonstrated the role of fleas as a vector. The disease is caused by a bacterium usually transmitted by the bite of fleas from an infected host, often a black rat . The bacteria are transferred from the blood of infected rats to flea ( Xenopsylla cheopis ). The bacillus multiplies in the stomach of the flea, blocking it. When the flea next bites a mammal, the consumed blood is regurgitated along with the bacillus into the bloodstream of the bitten animal. Any serious outbreak of plague in humans is preceded by an outbreak in the rodent population. During the outbreak, infected fleas that have lost their normal rodent hosts seek other sources of blood. The British colonial government in India pressed medical researcher Waldemar Haffkine to develop a plague vaccine. After three months of persistent work with a limited staff, a form for human trials was ready. On January 10, 1897, Haffkine tested it on himself. After the initial test was reported to the authorities, volunteers at the Byculla jail were used in a control test. All inoculated prisoners survived the epidemics, while seven inmates of the control group died. By the turn of the century, the number of inoculees in India alone reached four million. Haffkine was appointed the Director of the Plague Laboratory (now called the Haffkine Institute ) in Bombay. In the early 1900s, despite the increasing knowledge of germ theory and the rapid growth of scientific communities around the prevention of major disease, there was little the international communities could do other than create standard protocols for how to deal with an outbreak of the plague. In 1897 and 1903, two conventions were held known as International Sanitary Conferences; the first in Venice and the second in Paris, to help deal with threat of the new outbreaks of the bubonic plague. From these conventions was formed an international disease convention supervised by the Office International d'Hygiene Publique (OIHP) in Paris which would be one of the major predecessors of the League of Nations health organization. From these conventions came the standard Protocols used in dealing with the bubonic plague throughout the early 1900s. These protocols were often old fashioned and were generally summarized as the 3 "I's": Isolation, Incineration, and Inoculation. Isolation is a standard protocol of many modern disease outbreaks, but the usage of incineration was a protocol of disease control used most uniquely for dealing with the bubonic plague. Burning was used often to deal with the Plague as it was believed to the be most effective way to eliminate strains of the disease from places inhabited by the infected. But it was also a problematic technique as it led to the creation of many out-of-control fires that devastated communities, the most notable being the great fire in Honolulu which devastated the Chinatown community there. Inoculation was the usage of newly invented plague vaccines, with some in India being recorded to have an efficacy of over 50%. In many instances, the third plague pandemic either revealed or exacerbated major social conflicts and racial inequalities. Many of the ports infected during the plague were at the time in British colonies. Because of this, the British authorities often ended up enforcing western hygiene and medical practices and radical quarantine measures in countries and provinces such as India, South Africa and Hong Kong. In India harsh quarantines were initially implemented by the British governments, leading to Indian resentment of quarantine measures. In South Africa, when the plague broke out in Cape Colony , the colonial government forced a large group of Black South Africans to move out of a supposed slum into areas on the outskirts of the city, which historians have argued as a racially-motivated move by White South Africans to segregate Blacks into other parts of the city. In Hong Kong the British enforced many locally unfamiliar medical practices, such as floating plague victims out on boats onto the water and cooling plague victims with ice, which scared many Chinese residents of Hong Kong and led to their migrating back to mainland China, which was then even more badly affected by the plague. Another instance of social harm caused by the response to the plague is the "great fire of Honolulu " in 1900, in which much of Chinatown in Honolulu was burned by the Honolulu Board of Health in order to control the plague, rendering over 7,000 Chinese and Japanese residents homeless. In America when the plague reached San Francisco, the medical board of the city implemented a strict quarantine of the entire Chinatown district after discovering only one case of the plague; this has led historians to question whether this measure was motivated by racial bias among medical professionals.

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Bubonic plague

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Black Death

The Black Death was a bubonic plague pandemic occurring in Europe from 1346 to 1353. One of the most fatal pandemics in human history, as many as 50 million people perished, perhaps 50% of Europe's 14th century population. Bubonic plague is caused by the bacterium Yersinia pestis and spread by fleas . One of the most significant events in European history, the Black Death had far-reaching population, economic, and cultural impacts. It was the beginning of the second plague pandemic . The plague created religious, social and economic upheavals, with profound effects on the course of European history. The origin of the Black Death is disputed. Genetic analysis points to the evolution of Yersinia pestis in the Tian Shan mountains on the border between Kyrgyzstan and China 2,600 years ago. The immediate territorial origins of the Black Death and its outbreak remain unclear, with some evidence pointing towards Central Asia , China , the Middle East , and Europe . The pandemic was reportedly first introduced to Europe during the siege of the Genoese trading port of Kaffa in Crimea by the Golden Horde army of Jani Beg in 1347. From Crimea, it was most likely carried by fleas living on the black rats that travelled on Genoese ships, spreading through the Mediterranean Basin and reaching North Africa , Western Asia , and the rest of Europe via Constantinople , Sicily , and the Italian Peninsula . There is evidence that once it came ashore, the Black Death mainly spread from person-to-person as pneumonic plague , thus explaining the quick inland spread of the epidemic, which was faster than would be expected if the primary vector was rat fleas causing bubonic plague. In 2022, it was discovered that there was a sudden surge of deaths in what is today Kyrgyzstan from the Black Death in the late 1330s; when combined with genetic evidence, this implies that the initial spread may not have been due to Mongol conquests in the 14th century, as previously speculated. The Black Death was the second great natural disaster to strike Europe during the Late Middle Ages (the first one being the Great Famine of 1315–1317 ) and is estimated to have killed 30% to 60% of the European population, as well as approximately 33% of the population of the Middle East. There were further outbreaks throughout the Late Middle Ages and, also due to other contributing factors (the Crisis of the Late Middle Ages ), the European population did not regain its 14th century level until the 16th century. [lower-alpha 1] Outbreaks of the plague recurred around the world until the early 19th century.European writers contemporary with the plague described the disease in Latin as pestis or pestilentia , ' pestilence ' ; epidemia , ' epidemic ' ; mortalitas , ' mortality ' . In English prior to the 18th century, the event was called the "pestilence" or "great pestilence", "the plague" or the "great death". Subsequent to the pandemic "the furste moreyn " (first murrain ) or "first pestilence" was applied, to distinguish the mid-14th century phenomenon from other infectious diseases and epidemics of plague. The 1347 pandemic plague was not referred to specifically as "black" in the time of occurrence in any European language, though the expression "black death" had occasionally been applied to fatal disease beforehand. "Black death" was not used to describe the plague pandemic in English until the 1750s; the term is first attested in 1755, where it translated Danish : den sorte død , lit. ' the black death ' . This expression as a proper name for the pandemic had been popularized by Swedish and Danish chroniclers in the 15th and early 16th centuries, and in the 16th and 17th centuries was transferred to other languages as a calque : Icelandic : svarti dauði , German : der schwarze Tod , and French : la mort noire . Previously, most European languages had named the pandemic a variant or calque of the Latin : magna mortalitas , lit. ' Great Death ' . The phrase 'black death' – describing Death as black – is very old. Homer used it in the Odyssey to describe the monstrous Scylla , with her mouths "full of black Death" ( Ancient Greek : πλεῖοι μέλανος Θανάτοιο , romanized : pleîoi mélanos Thanátoio ). Seneca the Younger may have been the first to describe an epidemic as 'black death', ( Latin : mors atra ) but only in reference to the acute lethality and dark prognosis of disease. The 12th–13th century French physician Gilles de Corbeil had already used atra mors to refer to a "pestilential fever" ( febris pestilentialis ) in his work On the Signs and Symptoms of Diseases ( De signis et symptomatibus aegritudium ). The phrase mors nigra , ' black death ' , was used in 1350 by Simon de Covino (or Couvin), a Belgian astronomer, in his poem "On the Judgement of the Sun at a Feast of Saturn" ( De judicio Solis in convivio Saturni ), which attributes the plague to an astrological conjunction of Jupiter and Saturn. His use of the phrase is not connected unambiguously with the plague pandemic of 1347 and appears to refer to the fatal outcome of disease. The historian Cardinal Francis Aidan Gasquet wrote about the Great Pestilence in 1893 and suggested that it had been "some form of the ordinary Eastern or bubonic plague". [lower-alpha 2] In 1908, Gasquet said use of the name atra mors for the 14th-century epidemic first appeared in a 1631 book on Danish history by J. I. Pontanus : "Commonly and from its effects, they called it the black death" ( Vulgo & ab effectu atram mortem vocitabant ). Research from 2017 suggests plague first infected humans in Europe and Asia in the Late Neolithic - Early Bronze Age . Research in 2018 found evidence of Yersinia pestis in an ancient Swedish tomb, which may have been associated with the " Neolithic decline " around 3000 BCE, in which European populations fell significantly. This Y. pestis may have been different from more modern types, with bubonic plague transmissible by fleas first known from Bronze Age remains near Samara . The symptoms of bubonic plague are first attested in a fragment of Rufus of Ephesus preserved by Oribasius ; these ancient medical authorities suggest bubonic plague had appeared in the Roman Empire before the reign of Trajan , six centuries before arriving at Pelusium in the reign of Justinian I . In 2013, researchers confirmed earlier speculation that the cause of the Plague of Justinian (541–549 CE, with recurrences until 750) was Y . pestis . This is known as the first plague pandemic . In 610, the Chinese physician Chao Yuanfang described a "malignant bubo" "coming in abruptly with high fever together with the appearance of a bundle of nodes beneath the tissue." The Chinese physician Sun Simo who died in 652 also mentioned a "malignant bubo" and plague that was common in Lingnan ( Guangzhou ). Ole Jørgen Benedictow believes that this indicates it was an offshoot of the first plague pandemic which made its way eastward to Chinese territory by around 600. A report by the Medical Faculty of Paris stated that a conjunction of planets had caused "a great pestilence in the air" ( miasma theory ). Muslim religious scholars taught that the pandemic was a "martyrdom and mercy" from God, assuring the believer's place in paradise. For non-believers, it was a punishment. Some Muslim doctors cautioned against trying to prevent or treat a disease sent by God. Others adopted preventive measures and treatments for plague used by Europeans. These Muslim doctors also depended on the writings of the ancient Greeks. Due to climate change in Asia , rodents began to flee the dried-out grasslands to more populated areas, spreading the disease. The plague disease, caused by the bacterium Yersinia pestis , is enzootic (commonly present) in populations of fleas carried by ground rodents , including marmots , in various areas, including Central Asia , Kurdistan , Western Asia , North India , Uganda and the western United States. Y. pestis was discovered by Alexandre Yersin , a pupil of Louis Pasteur , during an epidemic of bubonic plague in Hong Kong in 1894; Yersin also proved this bacillus was present in rodents and suggested the rat was the main vehicle of transmission. The mechanism by which Y. pestis is usually transmitted was established in 1898 by Paul-Louis Simond and was found to involve the bites of fleas whose midguts had become obstructed by replicating Y. pestis several days after feeding on an infected host. This blockage starves the fleas, drives them to aggressive feeding behaviour, and causes them to try and clear the blockage via regurgitation , resulting in thousands of plague bacteria flushing into the feeding site and infecting the host. The bubonic plague mechanism was also dependent on two populations of rodents: one resistant to the disease, which act as hosts , keeping the disease endemic , and a second that lacks resistance. When the second population dies, the fleas move on to other hosts, including people, thus creating a human epidemic . Definitive confirmation of the role of Y. pestis arrived in 2010 with a publication in PLOS Pathogens by Haensch et al. [lower-alpha 3] They assessed the presence of DNA / RNA with polymerase chain reaction (PCR) techniques for Y. pestis from the tooth sockets in human skeletons from mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. The authors concluded that this new research, together with prior analyses from the south of France and Germany, "ends the debate about the cause of the Black Death, and unambiguously demonstrates that Y. pestis was the causative agent of the epidemic plague that devastated Europe during the Middle Ages". In 2011 these results were further confirmed with genetic evidence derived from Black Death victims in the East Smithfield burial site in England. Schuenemann et al. concluded in 2011 "that the Black Death in medieval Europe was caused by a variant of Y. pestis that may no longer exist". Later in 2011, Bos et al. reported in Nature the first draft genome of Y. pestis from plague victims from the same East Smithfield cemetery and indicated that the strain that caused the Black Death is ancestral to most modern strains of Y. pestis . Later genomic papers have further confirmed the phylogenetic placement of the Y. pestis strain responsible for the Black Death as both the ancestor of later plague epidemics—including the third plague pandemic —and the descendant of the strain responsible for the Plague of Justinian . In addition, plague genomes from prehistory have been recovered. DNA taken from 25 skeletons from 14th century London showed that plague is a strain of Y. pestis almost identical to that which hit Madagascar in 2013 . Further DNA evidence also proves the role of Y. pestis and traces the source to the Tian Shan mountains in Kyrgyzstan . Researchers are hampered by a lack of reliable statistics from this period. Most work has been done on the spread of the disease in England, where estimates of overall population at the start of the plague vary by over 100%, as no census was undertaken in England between the time of publication of the Domesday Book of 1086 and the poll tax of the year 1377. Estimates of plague victims are usually extrapolated from figures for the clergy. Mathematical modelling is used to match the spreading patterns and the means of transmission . In 2018 researchers suggested an alternative model in which "the disease was spread from human fleas and body lice to other people". The second model claims to better fit the trends of the plague's death toll, as the rat-flea-human hypothesis would have produced a delayed but very high spike in deaths, contradicting historical death data. Lars Walløe argued that these authors "take it for granted that Simond's infection model, black rat → rat flea → human, which was developed to explain the spread of plague in India, is the only way an epidemic of Yersinia pestis infection could spread". Similarly, Monica Green has argued that greater attention is needed to the range of (especially non- commensal ) animals that might be involved in the transmission of plague. Archaeologist Barney Sloane has argued that there is insufficient evidence of the extinction of numerous rats in the archaeological record of the medieval waterfront in London, and that the disease spread too quickly to support the thesis that Y. pestis was spread from fleas on rats; he argues that transmission must have been person to person. This theory is supported by research in 2018 which suggested transmission was more likely by body lice and fleas during the second plague pandemic . Academic debate continues, but no single alternative explanation for the plague's spread has achieved widespread acceptance. Many scholars arguing for Y. pestis as the major agent of the pandemic suggest that its extent and symptoms can be explained by a combination of bubonic plague with other diseases, including typhus , smallpox and respiratory infections . In addition to the bubonic infection, others point to additional septicemic and pneumonic forms of plague, which lengthen the duration of outbreaks throughout the seasons and help account for its high mortality rate and additional recorded symptoms. In 2014, Public Health England announced the results of an examination of 25 bodies exhumed in the Clerkenwell area of London, as well as of wills registered in London during the period, which supported the pneumonic hypothesis. Currently, while osteoarcheologists have conclusively verified the presence of Y. pestis bacteria in burial sites across northern Europe through examination of bones and dental pulp , no other epidemic pathogen has been discovered to bolster the alternative explanations. The importance of hygiene was not recognized until the 19th century and the germ theory of disease . Until then streets were usually unhygienic, with live animals and human parasites facilitating the spread of transmissible disease . By the early 14th century, so much filth had collected inside urban Europe that French and Italian cities were naming streets after human waste. In medieval Paris, several street names were inspired by merde, the French word for "shit". There were rue Merdeux, rue Merdelet, rue Merdusson, rue des Merdons and rue Merdiere—as well as a rue du Pipi. Pigs, cattle, chickens, geese, goats and horses roamed the streets of medieval London and Paris. Medieval homeowners were supposed to police their housefronts, including removing animal dung, but most urbanites were careless. William E. Cosner, a resident of the London suburb of Farringdon Without, received a complaint alleging that "men could not pass [by his house] for the stink [of] . . . horse dung and horse piss." One irate Londoner complained that the runoff from the local slaughterhouse had made his garden "stinking and putrid", while another charged that the blood from slain animals flooded nearby streets and lanes, "making a foul corruption and abominable sight to all dwelling near." In much of medieval Europe, sanitation legislation consisted of an ordinance requiring homeowners to shout, "Look out below!" three times before dumping a full chamber pot into the street. Early Christians considered bathing a temptation. With this danger in mind, St. Benedict declared, "To those who are well, and especially to the young, bathing shall seldom be permitted." St. Agnes took the injunction to heart and died without ever bathing. According to a team of medical geneticists led by Mark Achtman , Yersinia pestis "evolved in or near China" over 2,600 years ago. Later research by a team led by Galina Eroshenko placed its origins more specifically in the Tian Shan mountains on the border between Kyrgyzstan and China. However more recent research notes that the previous sampling contained East Asian bias and that sampling since then has discovered strains of Y. pestis in the Caucasus region previously thought to be restricted to China. There is also no physical or specific textual evidence of the Black Death in 14th century China. As a result, China's place in the sequence of the plague's spread is still debated to this day. According to Charles Creighton, records of epidemics in 14th century China suggest nothing more than typhus and major Chinese outbreaks of epidemic disease post-date the European epidemic by several years. The earliest Chinese descriptions of the bubonic plague do not appear until the 1640s. Nestorian gravesites dating from 1338 to 1339 near Issyk-Kul have inscriptions referring to plague, which has led some historians and epidemiologists to think they mark the outbreak of the epidemic ; this is supported by recent direct findings of Y. pestis DNA in teeth samples from graves in the area with inscriptions referring to "pestilence" as the cause of death. Epidemics killed an estimated 25 million across Asia during the fifteen years before the Black Death reached Constantinople in 1347. The evidence does not suggest, at least at present, that these mortality crises were caused by plague. Although some scholars, including McNeill and Cao, see the 1333 outbreak as a prelude to the outbreaks in Europe from the late 1340s to the early 1350s, scholars of the Yuan and Ming periods remain skeptical about such an interpretation. Nonetheless, the remarkably high mortality rates during the Datong mortality should discourage us from rejecting the possibility of localized/regional outbreaks of plague in different parts of China, albeit differing in scale from, and unrelated to, the pandemic mortality of the Black Death. What we lack is any indication of a plague pandemic that engulfed vast territories of the Yuan Empire and later moved into western Eurasia through Central Asia. According to John Norris, evidence from Issyk-Kul indicates a small sporadic outbreak characteristic of transmission from rodents to humans with no wide-scale impact. According to Achtman, the dating of the plague suggests that it was not carried along the Silk Road , and its widespread appearance in that region probably postdates the European outbreak. Additionally, the Silk Road had already been heavily disrupted before the spread of the Black Death; Western and Middle Eastern traders found it difficult to trade on the Silk Road by 1325 and impossible by 1340, making its role in the spread of plague less likely. There are no records of the symptoms of the Black Death from Mongol sources or writings from travelers east of the Black Sea prior to the Crimean outbreak in 1346. Others still favor an origin in China. The theory of Chinese origin implicates the Silk Road, the disease possibly spreading alongside Mongol armies and traders, or possibly arriving via ship—however, this theory is still contested. It is speculated that rats aboard Zheng He 's ships in the 15th century may have carried the plague to Southeast Asia , India and Africa. Research on the Delhi Sultanate and the Yuan Dynasty shows no evidence of any serious epidemic in fourteenth-century India and no specific evidence of plague in fourteenth-century China, suggesting that the Black Death may not have reached these regions. Ole Benedictow argues that since the first clear reports of the Black Death come from Kaffa , the Black Death most likely originated in the nearby plague focus on the northwestern shore of the Caspian Sea . Demographic historians estimate that China's population fell by at least 15 per cent, and perhaps as much as a third, between 1340 and 1370. This population loss coincided with the Black Death that ravaged Europe and much of the Islamic world in 1347–52. However, there is a conspicuous lack of evidence for pandemic disease on the scale of the Black Death in China at this time. War and famine – and the diseases that typically accompanied them – probably were the main causes of mortality in the final decades of Mongol rule. Monica H. Green suggests that other parts of Eurasia outside the west do not contain the same evidence of the Black Plague, because there were actually four strains of Yersinia pestis that became predominant in different parts of the world. Mongol records of illness such as food poisoning may have been referring to the Black Plague. Another theory is that the plague originated near Europe and cycled through the Mediterranean, Northern Europe and Russia before making its way to China. Other historians, such as John Norris and Ole Benedictaw, believe the plague likely originated in Europe or the Middle East, and never reached China. Norris specifically argues for an origin in Kurdistan rather than Central Asia. The seventh year after it began, it came to England and first began in the towns and ports joining on the seacoasts, in Dorsetshire , where, as in other counties, it made the country quite void of inhabitants so that there were almost none left alive. ... But at length it came to Gloucester , yea even to Oxford and to London, and finally it spread over all England and so wasted the people that scarce the tenth person of any sort was left alive. Geoffrey the Baker , Chronicon Angliae Plague was reportedly first introduced to Europe via Genoese traders from their port city of Kaffa in the Crimea in 1347. During a protracted siege of the city in 1345–1346, the Mongol Golden Horde army of Jani Beg —whose mainly Tatar troops were suffering from the disease— catapulted infected corpses over the city walls of Kaffa to infect the inhabitants, though it is also likely that infected rats travelled across the siege lines to spread the epidemic to the inhabitants. As the disease took hold, Genoese traders fled across the Black Sea to Constantinople , where the disease first arrived in Europe in summer 1347. The epidemic there killed the 13-year-old son of the Byzantine emperor , John VI Kantakouzenos , who wrote a description of the disease modelled on Thucydides 's account of the 5th century BCE Plague of Athens , noting the spread of the Black Death by ship between maritime cities. Nicephorus Gregoras , while writing to Demetrios Kydones , described the rising death toll, the futility of medicine, and the panic of the citizens. The first outbreak in Constantinople lasted a year, but the disease recurred ten times before 1400. Carried by twelve Genoese galleys, plague arrived by ship in Sicily in October 1347; the disease spread rapidly all over the island. Galleys from Kaffa reached Genoa and Venice in January 1348, but it was the outbreak in Pisa a few weeks later that was the entry point into northern Italy. Towards the end of January, one of the galleys expelled from Italy arrived in Marseilles . From Italy , the disease spread northwest across Europe, striking France , Spain , Portugal, and England by June 1348, then spreading east and north through Germany , Scotland and Scandinavia from 1348 to 1350. It was introduced into Norway in 1349 when a ship landed at Askøy , then spread to Bjørgvin (modern Bergen ). Finally, it spread to northwestern Russia in 1351. Plague was less common in parts of Europe with less-established trade relations, including the majority of the Basque Country , isolated parts of Belgium and the Netherlands , and isolated Alpine villages throughout the continent. According to some epidemiologists, periods of unfavorable weather decimated plague-infected rodent populations, forcing their fleas onto alternative hosts, inducing plague outbreaks which often peaked in the hot summers of the Mediterranean and during the cool autumn months of the southern Baltic region . [lower-alpha 4] Among many other culprits of plague contagiousness, pre-existing malnutrition weakened the immune response, contributing to an immense decline in European population. The disease struck various regions in the Middle East and North Africa during the pandemic , leading to serious depopulation and permanent change in both economic and social structures. By autumn 1347, plague had reached Alexandria in Egypt, transmitted by sea from Constantinople via a single merchant ship carrying slaves. By late summer 1348 it reached Cairo, capital of the Mamluk Sultanate , cultural center of the Islamic world , and the largest city in the Mediterranean Basin ; the Bahriyya child sultan an-Nasir Hasan fled and more than a third of the 600,000 residents died. The Nile was choked with corpses despite Cairo having a medieval hospital, the late 13th century bimaristan of the Qalawun complex . The historian al-Maqrizi described the abundant work for grave-diggers and practitioners of funeral rites ; plague recurred in Cairo more than fifty times over the following one and a half centuries. During 1347, the disease travelled eastward to Gaza by April; by July it had reached Damascus , and in October plague had broken out in Aleppo . That year, in the territory of modern Lebanon , Syria , Israel and Palestine , the cities of Ascalon , Acre , Jerusalem , Sidon and Homs were all infected. In 1348–1349, the disease reached Antioch . The city's residents fled to the north, but most of them ended up dying during the journey. Within two years, the plague had spread throughout the Islamic world, from Arabia across North Africa. [ page needed ] The pandemic spread westwards from Alexandria along the African coast, while in April 1348 Tunis was infected by ship from Sicily. Tunis was then under attack by an army from Morocco; this army dispersed in 1348 and brought the contagion with them to Morocco, whose epidemic may also have been seeded from the Islamic city of Almería in al-Andalus . Mecca became infected in 1348 by pilgrims performing the Hajj . In 1351 or 1352, the Rasulid sultan of the Yemen , al-Mujahid Ali , was released from Mamluk captivity in Egypt and carried plague with him on his return home. During 1349, records show the city of Mosul suffered a massive epidemic, and the city of Baghdad experienced a second round of the disease. Symptoms of the plague include fever of 38–41 °C (100–106 °F) , headaches, painful aching joints , nausea and vomiting, and a general feeling of malaise . Left untreated, 80% of victims die within eight days. Contemporary accounts of the pandemic are varied and often imprecise. The most commonly noted symptom was the appearance of buboes (or gavocciolos ) in the groin, neck and armpits, which oozed pus and bled when opened. Boccaccio 's description: In men and women alike it first betrayed itself by the emergence of certain tumours in the groin or armpits, some of which grew as large as a common apple, others as an egg ... From the two said parts of the body this deadly gavocciolo soon began to propagate and spread itself in all directions indifferently; after which the form of the malady began to change, black spots or livid making their appearance in many cases on the arm or the thigh or elsewhere, now few and large, now minute and numerous. As the gavocciolo had been and still was an infallible token of approaching death, such also were these spots on whomsoever they showed themselves. [lower-alpha 5] This was followed by acute fever and vomiting of blood . Most people died two to seven days after initial infection. Freckle-like spots and rashes, which may have been caused by flea-bites , were identified as another potential sign of plague. Lodewijk Heyligen , whose master Cardinal Colonna died of plague in 1348, noted a distinct form of the disease, pneumonic plague , that infected the lungs and led to respiratory problems. Symptoms include fever, cough and blood-tinged sputum . As the disease progresses, sputum becomes free-flowing and bright red. Pneumonic plague has a mortality rate of 90–95%. Septicemic plague is the least common of the three forms, with a mortality rate near 100%. Symptoms are high fevers and purple skin patches ( purpura due to disseminated intravascular coagulation ). In cases of pneumonic and particularly septicemic plague, the progress of the disease is so rapid that there would often be no time for the development of the enlarged lymph nodes that were noted as buboes. There are no exact figures for the death toll; the rate varied widely by locality. Urban centers with higher populations suffered longer periods of abnormal mortality. Some estimate that it may have killed between 75,000,000 and 200,000,000 people in Eurasia. [ better source needed ] A study published in 2022 of pollen samples across Europe from 1250 to 1450 was used to estimate changes in agricultural output before and after the Black Death. The authors found great variability in different regions, with evidence for high mortality in areas of Scandinavia, France, western Germany, Greece and central Italy, but uninterrupted agricultural growth in central and eastern Europe, Iberia and Ireland. The authors concluded that "the pandemic was immensely destructive in some areas, but in others it had a far lighter touch ... [the study methodology] invalidates histories of the Black Death that assume Y. pestis was uniformly prevalent, or nearly so, across Europe and that the pandemic had a devastating demographic impact everywhere." The Black Death killed, by various estimations, from 25 to 60% of Europe's population. Robert S. Gottfried writes that as early as 1351, "agents for Pope Clement VI calculated the number of dead in Christian Europe at 23,840,000. With a preplague population of about 75 million, Clement's figure accounts for mortality of 31%-a rate about midway between the 50% mortality estimated for East Anglia, Tuscany, and parts of Scandinavia, and the less-than-15% morbidity for Bohemia and Galicia. And it is unerringly close to Froissart's claim that "a third of the world died," a measurement probably drawn from St. John's figure of mortality from plague in the Book of Revelation , a favorite medieval source of information." Ole J. Benedictow proposes 60% mortality rate for Europe as a whole based on available data, with up to 80% based on poor nutritional conditions in the 14th century. [lower-alpha 6] According to medieval historian Philip Daileader , it is likely that over four years, 45–50% of the European population died of plague. [lower-alpha 7] The mortality rate of the Black Death in the 14th century was far greater than the worst 20th-century outbreaks of Y. pestis plague, which occurred in India and killed as much as 3% of the population of certain cities. The overwhelming number of deceased bodies produced by the Black Death caused the necessity of mass burial sites in Europe, sometimes including up to several hundred or several thousand skeletons. The mass burial sites that have been excavated have allowed archaeologists to continue interpreting and defining the biological, sociological, historical and anthropological implications of the Black Death. In 1348, the disease spread so rapidly that nearly a third of the European population perished before any physicians or government authorities had time to reflect upon its origins. In crowded cities, it was not uncommon for as much as 50% of the population to die. Half of Paris' population of 100,000 people died. In Italy, the population of Florence was reduced from between 110,000 and 120,000 inhabitants in 1338 to 50,000 in 1351. At least 60% of the population of Hamburg and Bremen perished, and a similar percentage of Londoners may have died from the disease as well, leaving a death toll of approximately 62,000 between 1346 and 1353. [lower-alpha 8] Florence's tax records suggest that 80% of the city's population died within four months in 1348. Before 1350, there were about 170,000 settlements in Germany, and this was reduced by nearly 40,000 by 1450. The disease bypassed some areas, with the most isolated areas being less vulnerable to contagion . Plague did not appear in Flanders until the turn of the 15th century, and the impact was less severe on the populations of Hainaut , Finland , northern Germany and areas of Poland. Monks, nuns and priests were especially hard-hit since they cared for people ill with the plague. In 1382 the physician to the Avignon Papacy , Raimundo Chalmel de Vinario ( Latin : Magister Raimundus , lit. ' Master Raymond ' ), observed the decreasing mortality rate of successive outbreaks of plague in 1347–1348, 1362, 1371 and 1382 in his treatise On Epidemics ( De epidemica ). In the first outbreak, two thirds of the population contracted the illness and most patients died; in the next, half the population became ill but only some died; by the third, a tenth were affected and many survived; while by the fourth occurrence, only one in twenty people were sickened and most of them survived. By the 1380s in Europe, the plague predominantly affected children. Chalmel de Vinario recognised that bloodletting was ineffective (though he continued to prescribe bleeding for members of the Roman Curia , whom he disliked), and said that all true cases of plague were caused by astrological factors and were incurable; he was never able to effect a cure. The populations of some Italian cities, notably Florence , did not regain their pre-14th century size until the 19th century. The most widely accepted estimate for the Middle East, including Iraq, Iran and Syria, during this time, is for a death toll of about a third of the population. The Black Death killed about 40% of Egypt's population. In Cairo, with a population numbering as many as 600,000, and possibly the largest city west of China, between one third and 40% of the inhabitants died within eight months. By the 18th century, the population of Cairo was halved from its numbers in 1347. Italian chronicler Agnolo di Tura recorded his experience from Siena , where plague arrived in May 1348: Father abandoned child, wife husband, one brother another; for this illness seemed to strike through the breath and sight. And so they died. And none could be found to bury the dead for money or friendship. Members of a household brought their dead to a ditch as best they could, without priest, without divine offices ... great pits were dug and piled deep with the multitude of dead. And they died by the hundreds both day and night ... And as soon as those ditches were filled more were dug ... And I, Agnolo di Tura ... buried my five children with my own hands. And there were also those who were so sparsely covered with earth that the dogs dragged them forth and devoured many bodies throughout the city. There was no one who wept for any death, for all awaited death. And so many died that all believed it was the end of the world. It has been suggested that the Black Plague, like other outbreaks through history, disproportionately affected the poorest people and those already in worse physical condition than the wealthier citizens. But along with population decline from the pandemic, wages soared in response to a subsequent labor shortage. Many laborers, artisans and craftsmen—those living from money-wages alone—suffered a reduction in real incomes owing to rampant inflation. Landowners were also pushed to substitute monetary rents for labor services in an effort to keep tenants. The trade disruptions in the Mongol Empire caused by the Black Death was one of the reasons for its collapse. A study performed by Thomas Van Hoof of the Utrecht University suggests that the innumerable deaths brought on by the pandemic cooled the climate by freeing up land and triggering reforestation . This may have led to the Little Ice Age . Renewed religious fervor and fanaticism increased in the wake of the Black Death. Some Europeans targeted "various groups such as Jews , friars , foreigners, beggars, pilgrims ", lepers and Romani , blaming them for the crisis. Lepers , and others with skin diseases such as acne or psoriasis , were killed throughout Europe. Because 14th-century healers and governments were at a loss to explain or stop the disease, Europeans turned to astrological forces, earthquakes and the poisoning of wells by Jews as possible reasons for outbreaks. Many believed the epidemic was a punishment by God for their sins, and could be relieved by winning God's forgiveness . There were many attacks against Jewish communities. In the Strasbourg massacre of February 1349, about 2,000 Jews were murdered. In August 1349, the Jewish communities in Mainz and Cologne were annihilated. By 1351, 60 major and 150 smaller Jewish communities had been destroyed. During this period many Jews relocated to Poland , where they received a welcome from King Casimir the Great . One theory that has been advanced is that the Black Death's devastation of Florence , between 1348 and 1350, resulted in a shift in the world view of people in 14th-century Italy that ultimately led to the Renaissance . Italy was particularly badly hit by the pandemic, and the resulting familiarity with death may have caused thinkers to dwell more on their lives on Earth, rather than on spirituality and the afterlife . [lower-alpha 9] It has also been argued that the Black Death prompted a new wave of piety, manifested in the sponsorship of religious works of art. This does not fully explain why the Renaissance occurred in Italy in the 14th century; the Renaissance's emergence was most likely the result of the complex interaction of the above factors, in combination with an influx of Greek scholars after the fall of the Byzantine Empire . As a result of the drastic reduction in the populace the value of the working class increased, and commoners came to enjoy more freedom. To answer the increased need for labor, workers travelled in search of the most favorable position economically. [ better source needed ] Prior to the emergence of the Black Death, the continent was considered a feudalistic society, composed of fiefs and city-states frequently managed by the Catholic Church. The pandemic completely restructured both religion and political forces; survivors began to turn to other forms of spirituality and the power dynamics of the fiefs and city-states crumbled. The survivors of the pandemic found not only that the prices of food were lower but also that lands were more abundant, and many of them inherited property from their dead relatives, and this probably contributed to the destabilization of feudalism . The word " quarantine " has its roots in this period, though the practice of isolating people to prevent the spread of disease is older. In the city-state of Ragusa (modern Dubrovnik , Croatia), a thirty-day isolation period was implemented in 1377 for new arrivals to the city from plague-affected areas. The isolation period was later extended to forty days, and given the name "quarantino" from the Italian word for "forty". A report by the Medical Faculty of Paris stated that a conjunction of planets had caused "a great pestilence in the air" ( miasma theory ). Muslim religious scholars taught that the pandemic was a "martyrdom and mercy" from God, assuring the believer's place in paradise. For non-believers, it was a punishment. Some Muslim doctors cautioned against trying to prevent or treat a disease sent by God. Others adopted preventive measures and treatments for plague used by Europeans. These Muslim doctors also depended on the writings of the ancient Greeks. Due to climate change in Asia , rodents began to flee the dried-out grasslands to more populated areas, spreading the disease. The plague disease, caused by the bacterium Yersinia pestis , is enzootic (commonly present) in populations of fleas carried by ground rodents , including marmots , in various areas, including Central Asia , Kurdistan , Western Asia , North India , Uganda and the western United States. Y. pestis was discovered by Alexandre Yersin , a pupil of Louis Pasteur , during an epidemic of bubonic plague in Hong Kong in 1894; Yersin also proved this bacillus was present in rodents and suggested the rat was the main vehicle of transmission. The mechanism by which Y. pestis is usually transmitted was established in 1898 by Paul-Louis Simond and was found to involve the bites of fleas whose midguts had become obstructed by replicating Y. pestis several days after feeding on an infected host. This blockage starves the fleas, drives them to aggressive feeding behaviour, and causes them to try and clear the blockage via regurgitation , resulting in thousands of plague bacteria flushing into the feeding site and infecting the host. The bubonic plague mechanism was also dependent on two populations of rodents: one resistant to the disease, which act as hosts , keeping the disease endemic , and a second that lacks resistance. When the second population dies, the fleas move on to other hosts, including people, thus creating a human epidemic . Definitive confirmation of the role of Y. pestis arrived in 2010 with a publication in PLOS Pathogens by Haensch et al. [lower-alpha 3] They assessed the presence of DNA / RNA with polymerase chain reaction (PCR) techniques for Y. pestis from the tooth sockets in human skeletons from mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. The authors concluded that this new research, together with prior analyses from the south of France and Germany, "ends the debate about the cause of the Black Death, and unambiguously demonstrates that Y. pestis was the causative agent of the epidemic plague that devastated Europe during the Middle Ages". In 2011 these results were further confirmed with genetic evidence derived from Black Death victims in the East Smithfield burial site in England. Schuenemann et al. concluded in 2011 "that the Black Death in medieval Europe was caused by a variant of Y. pestis that may no longer exist". Later in 2011, Bos et al. reported in Nature the first draft genome of Y. pestis from plague victims from the same East Smithfield cemetery and indicated that the strain that caused the Black Death is ancestral to most modern strains of Y. pestis . Later genomic papers have further confirmed the phylogenetic placement of the Y. pestis strain responsible for the Black Death as both the ancestor of later plague epidemics—including the third plague pandemic —and the descendant of the strain responsible for the Plague of Justinian . In addition, plague genomes from prehistory have been recovered. DNA taken from 25 skeletons from 14th century London showed that plague is a strain of Y. pestis almost identical to that which hit Madagascar in 2013 . Further DNA evidence also proves the role of Y. pestis and traces the source to the Tian Shan mountains in Kyrgyzstan . Researchers are hampered by a lack of reliable statistics from this period. Most work has been done on the spread of the disease in England, where estimates of overall population at the start of the plague vary by over 100%, as no census was undertaken in England between the time of publication of the Domesday Book of 1086 and the poll tax of the year 1377. Estimates of plague victims are usually extrapolated from figures for the clergy. Mathematical modelling is used to match the spreading patterns and the means of transmission . In 2018 researchers suggested an alternative model in which "the disease was spread from human fleas and body lice to other people". The second model claims to better fit the trends of the plague's death toll, as the rat-flea-human hypothesis would have produced a delayed but very high spike in deaths, contradicting historical death data. Lars Walløe argued that these authors "take it for granted that Simond's infection model, black rat → rat flea → human, which was developed to explain the spread of plague in India, is the only way an epidemic of Yersinia pestis infection could spread". Similarly, Monica Green has argued that greater attention is needed to the range of (especially non- commensal ) animals that might be involved in the transmission of plague. Archaeologist Barney Sloane has argued that there is insufficient evidence of the extinction of numerous rats in the archaeological record of the medieval waterfront in London, and that the disease spread too quickly to support the thesis that Y. pestis was spread from fleas on rats; he argues that transmission must have been person to person. This theory is supported by research in 2018 which suggested transmission was more likely by body lice and fleas during the second plague pandemic . Academic debate continues, but no single alternative explanation for the plague's spread has achieved widespread acceptance. Many scholars arguing for Y. pestis as the major agent of the pandemic suggest that its extent and symptoms can be explained by a combination of bubonic plague with other diseases, including typhus , smallpox and respiratory infections . In addition to the bubonic infection, others point to additional septicemic and pneumonic forms of plague, which lengthen the duration of outbreaks throughout the seasons and help account for its high mortality rate and additional recorded symptoms. In 2014, Public Health England announced the results of an examination of 25 bodies exhumed in the Clerkenwell area of London, as well as of wills registered in London during the period, which supported the pneumonic hypothesis. Currently, while osteoarcheologists have conclusively verified the presence of Y. pestis bacteria in burial sites across northern Europe through examination of bones and dental pulp , no other epidemic pathogen has been discovered to bolster the alternative explanations. A report by the Medical Faculty of Paris stated that a conjunction of planets had caused "a great pestilence in the air" ( miasma theory ). Muslim religious scholars taught that the pandemic was a "martyrdom and mercy" from God, assuring the believer's place in paradise. For non-believers, it was a punishment. Some Muslim doctors cautioned against trying to prevent or treat a disease sent by God. Others adopted preventive measures and treatments for plague used by Europeans. These Muslim doctors also depended on the writings of the ancient Greeks. Due to climate change in Asia , rodents began to flee the dried-out grasslands to more populated areas, spreading the disease. The plague disease, caused by the bacterium Yersinia pestis , is enzootic (commonly present) in populations of fleas carried by ground rodents , including marmots , in various areas, including Central Asia , Kurdistan , Western Asia , North India , Uganda and the western United States. Y. pestis was discovered by Alexandre Yersin , a pupil of Louis Pasteur , during an epidemic of bubonic plague in Hong Kong in 1894; Yersin also proved this bacillus was present in rodents and suggested the rat was the main vehicle of transmission. The mechanism by which Y. pestis is usually transmitted was established in 1898 by Paul-Louis Simond and was found to involve the bites of fleas whose midguts had become obstructed by replicating Y. pestis several days after feeding on an infected host. This blockage starves the fleas, drives them to aggressive feeding behaviour, and causes them to try and clear the blockage via regurgitation , resulting in thousands of plague bacteria flushing into the feeding site and infecting the host. The bubonic plague mechanism was also dependent on two populations of rodents: one resistant to the disease, which act as hosts , keeping the disease endemic , and a second that lacks resistance. When the second population dies, the fleas move on to other hosts, including people, thus creating a human epidemic . Definitive confirmation of the role of Y. pestis arrived in 2010 with a publication in PLOS Pathogens by Haensch et al. [lower-alpha 3] They assessed the presence of DNA / RNA with polymerase chain reaction (PCR) techniques for Y. pestis from the tooth sockets in human skeletons from mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. The authors concluded that this new research, together with prior analyses from the south of France and Germany, "ends the debate about the cause of the Black Death, and unambiguously demonstrates that Y. pestis was the causative agent of the epidemic plague that devastated Europe during the Middle Ages". In 2011 these results were further confirmed with genetic evidence derived from Black Death victims in the East Smithfield burial site in England. Schuenemann et al. concluded in 2011 "that the Black Death in medieval Europe was caused by a variant of Y. pestis that may no longer exist". Later in 2011, Bos et al. reported in Nature the first draft genome of Y. pestis from plague victims from the same East Smithfield cemetery and indicated that the strain that caused the Black Death is ancestral to most modern strains of Y. pestis . Later genomic papers have further confirmed the phylogenetic placement of the Y. pestis strain responsible for the Black Death as both the ancestor of later plague epidemics—including the third plague pandemic —and the descendant of the strain responsible for the Plague of Justinian . In addition, plague genomes from prehistory have been recovered. DNA taken from 25 skeletons from 14th century London showed that plague is a strain of Y. pestis almost identical to that which hit Madagascar in 2013 . Further DNA evidence also proves the role of Y. pestis and traces the source to the Tian Shan mountains in Kyrgyzstan . Researchers are hampered by a lack of reliable statistics from this period. Most work has been done on the spread of the disease in England, where estimates of overall population at the start of the plague vary by over 100%, as no census was undertaken in England between the time of publication of the Domesday Book of 1086 and the poll tax of the year 1377. Estimates of plague victims are usually extrapolated from figures for the clergy. Mathematical modelling is used to match the spreading patterns and the means of transmission . In 2018 researchers suggested an alternative model in which "the disease was spread from human fleas and body lice to other people". The second model claims to better fit the trends of the plague's death toll, as the rat-flea-human hypothesis would have produced a delayed but very high spike in deaths, contradicting historical death data. Lars Walløe argued that these authors "take it for granted that Simond's infection model, black rat → rat flea → human, which was developed to explain the spread of plague in India, is the only way an epidemic of Yersinia pestis infection could spread". Similarly, Monica Green has argued that greater attention is needed to the range of (especially non- commensal ) animals that might be involved in the transmission of plague. Archaeologist Barney Sloane has argued that there is insufficient evidence of the extinction of numerous rats in the archaeological record of the medieval waterfront in London, and that the disease spread too quickly to support the thesis that Y. pestis was spread from fleas on rats; he argues that transmission must have been person to person. This theory is supported by research in 2018 which suggested transmission was more likely by body lice and fleas during the second plague pandemic . Academic debate continues, but no single alternative explanation for the plague's spread has achieved widespread acceptance. Many scholars arguing for Y. pestis as the major agent of the pandemic suggest that its extent and symptoms can be explained by a combination of bubonic plague with other diseases, including typhus , smallpox and respiratory infections . In addition to the bubonic infection, others point to additional septicemic and pneumonic forms of plague, which lengthen the duration of outbreaks throughout the seasons and help account for its high mortality rate and additional recorded symptoms. In 2014, Public Health England announced the results of an examination of 25 bodies exhumed in the Clerkenwell area of London, as well as of wills registered in London during the period, which supported the pneumonic hypothesis. Currently, while osteoarcheologists have conclusively verified the presence of Y. pestis bacteria in burial sites across northern Europe through examination of bones and dental pulp , no other epidemic pathogen has been discovered to bolster the alternative explanations. The importance of hygiene was not recognized until the 19th century and the germ theory of disease . Until then streets were usually unhygienic, with live animals and human parasites facilitating the spread of transmissible disease . By the early 14th century, so much filth had collected inside urban Europe that French and Italian cities were naming streets after human waste. In medieval Paris, several street names were inspired by merde, the French word for "shit". There were rue Merdeux, rue Merdelet, rue Merdusson, rue des Merdons and rue Merdiere—as well as a rue du Pipi. Pigs, cattle, chickens, geese, goats and horses roamed the streets of medieval London and Paris. Medieval homeowners were supposed to police their housefronts, including removing animal dung, but most urbanites were careless. William E. Cosner, a resident of the London suburb of Farringdon Without, received a complaint alleging that "men could not pass [by his house] for the stink [of] . . . horse dung and horse piss." One irate Londoner complained that the runoff from the local slaughterhouse had made his garden "stinking and putrid", while another charged that the blood from slain animals flooded nearby streets and lanes, "making a foul corruption and abominable sight to all dwelling near." In much of medieval Europe, sanitation legislation consisted of an ordinance requiring homeowners to shout, "Look out below!" three times before dumping a full chamber pot into the street. Early Christians considered bathing a temptation. With this danger in mind, St. Benedict declared, "To those who are well, and especially to the young, bathing shall seldom be permitted." St. Agnes took the injunction to heart and died without ever bathing. According to a team of medical geneticists led by Mark Achtman , Yersinia pestis "evolved in or near China" over 2,600 years ago. Later research by a team led by Galina Eroshenko placed its origins more specifically in the Tian Shan mountains on the border between Kyrgyzstan and China. However more recent research notes that the previous sampling contained East Asian bias and that sampling since then has discovered strains of Y. pestis in the Caucasus region previously thought to be restricted to China. There is also no physical or specific textual evidence of the Black Death in 14th century China. As a result, China's place in the sequence of the plague's spread is still debated to this day. According to Charles Creighton, records of epidemics in 14th century China suggest nothing more than typhus and major Chinese outbreaks of epidemic disease post-date the European epidemic by several years. The earliest Chinese descriptions of the bubonic plague do not appear until the 1640s. Nestorian gravesites dating from 1338 to 1339 near Issyk-Kul have inscriptions referring to plague, which has led some historians and epidemiologists to think they mark the outbreak of the epidemic ; this is supported by recent direct findings of Y. pestis DNA in teeth samples from graves in the area with inscriptions referring to "pestilence" as the cause of death. Epidemics killed an estimated 25 million across Asia during the fifteen years before the Black Death reached Constantinople in 1347. The evidence does not suggest, at least at present, that these mortality crises were caused by plague. Although some scholars, including McNeill and Cao, see the 1333 outbreak as a prelude to the outbreaks in Europe from the late 1340s to the early 1350s, scholars of the Yuan and Ming periods remain skeptical about such an interpretation. Nonetheless, the remarkably high mortality rates during the Datong mortality should discourage us from rejecting the possibility of localized/regional outbreaks of plague in different parts of China, albeit differing in scale from, and unrelated to, the pandemic mortality of the Black Death. What we lack is any indication of a plague pandemic that engulfed vast territories of the Yuan Empire and later moved into western Eurasia through Central Asia. According to John Norris, evidence from Issyk-Kul indicates a small sporadic outbreak characteristic of transmission from rodents to humans with no wide-scale impact. According to Achtman, the dating of the plague suggests that it was not carried along the Silk Road , and its widespread appearance in that region probably postdates the European outbreak. Additionally, the Silk Road had already been heavily disrupted before the spread of the Black Death; Western and Middle Eastern traders found it difficult to trade on the Silk Road by 1325 and impossible by 1340, making its role in the spread of plague less likely. There are no records of the symptoms of the Black Death from Mongol sources or writings from travelers east of the Black Sea prior to the Crimean outbreak in 1346. Others still favor an origin in China. The theory of Chinese origin implicates the Silk Road, the disease possibly spreading alongside Mongol armies and traders, or possibly arriving via ship—however, this theory is still contested. It is speculated that rats aboard Zheng He 's ships in the 15th century may have carried the plague to Southeast Asia , India and Africa. Research on the Delhi Sultanate and the Yuan Dynasty shows no evidence of any serious epidemic in fourteenth-century India and no specific evidence of plague in fourteenth-century China, suggesting that the Black Death may not have reached these regions. Ole Benedictow argues that since the first clear reports of the Black Death come from Kaffa , the Black Death most likely originated in the nearby plague focus on the northwestern shore of the Caspian Sea . Demographic historians estimate that China's population fell by at least 15 per cent, and perhaps as much as a third, between 1340 and 1370. This population loss coincided with the Black Death that ravaged Europe and much of the Islamic world in 1347–52. However, there is a conspicuous lack of evidence for pandemic disease on the scale of the Black Death in China at this time. War and famine – and the diseases that typically accompanied them – probably were the main causes of mortality in the final decades of Mongol rule. Monica H. Green suggests that other parts of Eurasia outside the west do not contain the same evidence of the Black Plague, because there were actually four strains of Yersinia pestis that became predominant in different parts of the world. Mongol records of illness such as food poisoning may have been referring to the Black Plague. Another theory is that the plague originated near Europe and cycled through the Mediterranean, Northern Europe and Russia before making its way to China. Other historians, such as John Norris and Ole Benedictaw, believe the plague likely originated in Europe or the Middle East, and never reached China. Norris specifically argues for an origin in Kurdistan rather than Central Asia. The seventh year after it began, it came to England and first began in the towns and ports joining on the seacoasts, in Dorsetshire , where, as in other counties, it made the country quite void of inhabitants so that there were almost none left alive. ... But at length it came to Gloucester , yea even to Oxford and to London, and finally it spread over all England and so wasted the people that scarce the tenth person of any sort was left alive. Geoffrey the Baker , Chronicon Angliae Plague was reportedly first introduced to Europe via Genoese traders from their port city of Kaffa in the Crimea in 1347. During a protracted siege of the city in 1345–1346, the Mongol Golden Horde army of Jani Beg —whose mainly Tatar troops were suffering from the disease— catapulted infected corpses over the city walls of Kaffa to infect the inhabitants, though it is also likely that infected rats travelled across the siege lines to spread the epidemic to the inhabitants. As the disease took hold, Genoese traders fled across the Black Sea to Constantinople , where the disease first arrived in Europe in summer 1347. The epidemic there killed the 13-year-old son of the Byzantine emperor , John VI Kantakouzenos , who wrote a description of the disease modelled on Thucydides 's account of the 5th century BCE Plague of Athens , noting the spread of the Black Death by ship between maritime cities. Nicephorus Gregoras , while writing to Demetrios Kydones , described the rising death toll, the futility of medicine, and the panic of the citizens. The first outbreak in Constantinople lasted a year, but the disease recurred ten times before 1400. Carried by twelve Genoese galleys, plague arrived by ship in Sicily in October 1347; the disease spread rapidly all over the island. Galleys from Kaffa reached Genoa and Venice in January 1348, but it was the outbreak in Pisa a few weeks later that was the entry point into northern Italy. Towards the end of January, one of the galleys expelled from Italy arrived in Marseilles . From Italy , the disease spread northwest across Europe, striking France , Spain , Portugal, and England by June 1348, then spreading east and north through Germany , Scotland and Scandinavia from 1348 to 1350. It was introduced into Norway in 1349 when a ship landed at Askøy , then spread to Bjørgvin (modern Bergen ). Finally, it spread to northwestern Russia in 1351. Plague was less common in parts of Europe with less-established trade relations, including the majority of the Basque Country , isolated parts of Belgium and the Netherlands , and isolated Alpine villages throughout the continent. According to some epidemiologists, periods of unfavorable weather decimated plague-infected rodent populations, forcing their fleas onto alternative hosts, inducing plague outbreaks which often peaked in the hot summers of the Mediterranean and during the cool autumn months of the southern Baltic region . [lower-alpha 4] Among many other culprits of plague contagiousness, pre-existing malnutrition weakened the immune response, contributing to an immense decline in European population. The disease struck various regions in the Middle East and North Africa during the pandemic , leading to serious depopulation and permanent change in both economic and social structures. By autumn 1347, plague had reached Alexandria in Egypt, transmitted by sea from Constantinople via a single merchant ship carrying slaves. By late summer 1348 it reached Cairo, capital of the Mamluk Sultanate , cultural center of the Islamic world , and the largest city in the Mediterranean Basin ; the Bahriyya child sultan an-Nasir Hasan fled and more than a third of the 600,000 residents died. The Nile was choked with corpses despite Cairo having a medieval hospital, the late 13th century bimaristan of the Qalawun complex . The historian al-Maqrizi described the abundant work for grave-diggers and practitioners of funeral rites ; plague recurred in Cairo more than fifty times over the following one and a half centuries. During 1347, the disease travelled eastward to Gaza by April; by July it had reached Damascus , and in October plague had broken out in Aleppo . That year, in the territory of modern Lebanon , Syria , Israel and Palestine , the cities of Ascalon , Acre , Jerusalem , Sidon and Homs were all infected. In 1348–1349, the disease reached Antioch . The city's residents fled to the north, but most of them ended up dying during the journey. Within two years, the plague had spread throughout the Islamic world, from Arabia across North Africa. [ page needed ] The pandemic spread westwards from Alexandria along the African coast, while in April 1348 Tunis was infected by ship from Sicily. Tunis was then under attack by an army from Morocco; this army dispersed in 1348 and brought the contagion with them to Morocco, whose epidemic may also have been seeded from the Islamic city of Almería in al-Andalus . Mecca became infected in 1348 by pilgrims performing the Hajj . In 1351 or 1352, the Rasulid sultan of the Yemen , al-Mujahid Ali , was released from Mamluk captivity in Egypt and carried plague with him on his return home. During 1349, records show the city of Mosul suffered a massive epidemic, and the city of Baghdad experienced a second round of the disease. The importance of hygiene was not recognized until the 19th century and the germ theory of disease . Until then streets were usually unhygienic, with live animals and human parasites facilitating the spread of transmissible disease . By the early 14th century, so much filth had collected inside urban Europe that French and Italian cities were naming streets after human waste. In medieval Paris, several street names were inspired by merde, the French word for "shit". There were rue Merdeux, rue Merdelet, rue Merdusson, rue des Merdons and rue Merdiere—as well as a rue du Pipi. Pigs, cattle, chickens, geese, goats and horses roamed the streets of medieval London and Paris. Medieval homeowners were supposed to police their housefronts, including removing animal dung, but most urbanites were careless. William E. Cosner, a resident of the London suburb of Farringdon Without, received a complaint alleging that "men could not pass [by his house] for the stink [of] . . . horse dung and horse piss." One irate Londoner complained that the runoff from the local slaughterhouse had made his garden "stinking and putrid", while another charged that the blood from slain animals flooded nearby streets and lanes, "making a foul corruption and abominable sight to all dwelling near." In much of medieval Europe, sanitation legislation consisted of an ordinance requiring homeowners to shout, "Look out below!" three times before dumping a full chamber pot into the street. Early Christians considered bathing a temptation. With this danger in mind, St. Benedict declared, "To those who are well, and especially to the young, bathing shall seldom be permitted." St. Agnes took the injunction to heart and died without ever bathing. According to a team of medical geneticists led by Mark Achtman , Yersinia pestis "evolved in or near China" over 2,600 years ago. Later research by a team led by Galina Eroshenko placed its origins more specifically in the Tian Shan mountains on the border between Kyrgyzstan and China. However more recent research notes that the previous sampling contained East Asian bias and that sampling since then has discovered strains of Y. pestis in the Caucasus region previously thought to be restricted to China. There is also no physical or specific textual evidence of the Black Death in 14th century China. As a result, China's place in the sequence of the plague's spread is still debated to this day. According to Charles Creighton, records of epidemics in 14th century China suggest nothing more than typhus and major Chinese outbreaks of epidemic disease post-date the European epidemic by several years. The earliest Chinese descriptions of the bubonic plague do not appear until the 1640s. Nestorian gravesites dating from 1338 to 1339 near Issyk-Kul have inscriptions referring to plague, which has led some historians and epidemiologists to think they mark the outbreak of the epidemic ; this is supported by recent direct findings of Y. pestis DNA in teeth samples from graves in the area with inscriptions referring to "pestilence" as the cause of death. Epidemics killed an estimated 25 million across Asia during the fifteen years before the Black Death reached Constantinople in 1347. The evidence does not suggest, at least at present, that these mortality crises were caused by plague. Although some scholars, including McNeill and Cao, see the 1333 outbreak as a prelude to the outbreaks in Europe from the late 1340s to the early 1350s, scholars of the Yuan and Ming periods remain skeptical about such an interpretation. Nonetheless, the remarkably high mortality rates during the Datong mortality should discourage us from rejecting the possibility of localized/regional outbreaks of plague in different parts of China, albeit differing in scale from, and unrelated to, the pandemic mortality of the Black Death. What we lack is any indication of a plague pandemic that engulfed vast territories of the Yuan Empire and later moved into western Eurasia through Central Asia. According to John Norris, evidence from Issyk-Kul indicates a small sporadic outbreak characteristic of transmission from rodents to humans with no wide-scale impact. According to Achtman, the dating of the plague suggests that it was not carried along the Silk Road , and its widespread appearance in that region probably postdates the European outbreak. Additionally, the Silk Road had already been heavily disrupted before the spread of the Black Death; Western and Middle Eastern traders found it difficult to trade on the Silk Road by 1325 and impossible by 1340, making its role in the spread of plague less likely. There are no records of the symptoms of the Black Death from Mongol sources or writings from travelers east of the Black Sea prior to the Crimean outbreak in 1346. Others still favor an origin in China. The theory of Chinese origin implicates the Silk Road, the disease possibly spreading alongside Mongol armies and traders, or possibly arriving via ship—however, this theory is still contested. It is speculated that rats aboard Zheng He 's ships in the 15th century may have carried the plague to Southeast Asia , India and Africa. Research on the Delhi Sultanate and the Yuan Dynasty shows no evidence of any serious epidemic in fourteenth-century India and no specific evidence of plague in fourteenth-century China, suggesting that the Black Death may not have reached these regions. Ole Benedictow argues that since the first clear reports of the Black Death come from Kaffa , the Black Death most likely originated in the nearby plague focus on the northwestern shore of the Caspian Sea . Demographic historians estimate that China's population fell by at least 15 per cent, and perhaps as much as a third, between 1340 and 1370. This population loss coincided with the Black Death that ravaged Europe and much of the Islamic world in 1347–52. However, there is a conspicuous lack of evidence for pandemic disease on the scale of the Black Death in China at this time. War and famine – and the diseases that typically accompanied them – probably were the main causes of mortality in the final decades of Mongol rule. Monica H. Green suggests that other parts of Eurasia outside the west do not contain the same evidence of the Black Plague, because there were actually four strains of Yersinia pestis that became predominant in different parts of the world. Mongol records of illness such as food poisoning may have been referring to the Black Plague. Another theory is that the plague originated near Europe and cycled through the Mediterranean, Northern Europe and Russia before making its way to China. Other historians, such as John Norris and Ole Benedictaw, believe the plague likely originated in Europe or the Middle East, and never reached China. Norris specifically argues for an origin in Kurdistan rather than Central Asia. The seventh year after it began, it came to England and first began in the towns and ports joining on the seacoasts, in Dorsetshire , where, as in other counties, it made the country quite void of inhabitants so that there were almost none left alive. ... But at length it came to Gloucester , yea even to Oxford and to London, and finally it spread over all England and so wasted the people that scarce the tenth person of any sort was left alive. Geoffrey the Baker , Chronicon Angliae Plague was reportedly first introduced to Europe via Genoese traders from their port city of Kaffa in the Crimea in 1347. During a protracted siege of the city in 1345–1346, the Mongol Golden Horde army of Jani Beg —whose mainly Tatar troops were suffering from the disease— catapulted infected corpses over the city walls of Kaffa to infect the inhabitants, though it is also likely that infected rats travelled across the siege lines to spread the epidemic to the inhabitants. As the disease took hold, Genoese traders fled across the Black Sea to Constantinople , where the disease first arrived in Europe in summer 1347. The epidemic there killed the 13-year-old son of the Byzantine emperor , John VI Kantakouzenos , who wrote a description of the disease modelled on Thucydides 's account of the 5th century BCE Plague of Athens , noting the spread of the Black Death by ship between maritime cities. Nicephorus Gregoras , while writing to Demetrios Kydones , described the rising death toll, the futility of medicine, and the panic of the citizens. The first outbreak in Constantinople lasted a year, but the disease recurred ten times before 1400. Carried by twelve Genoese galleys, plague arrived by ship in Sicily in October 1347; the disease spread rapidly all over the island. Galleys from Kaffa reached Genoa and Venice in January 1348, but it was the outbreak in Pisa a few weeks later that was the entry point into northern Italy. Towards the end of January, one of the galleys expelled from Italy arrived in Marseilles . From Italy , the disease spread northwest across Europe, striking France , Spain , Portugal, and England by June 1348, then spreading east and north through Germany , Scotland and Scandinavia from 1348 to 1350. It was introduced into Norway in 1349 when a ship landed at Askøy , then spread to Bjørgvin (modern Bergen ). Finally, it spread to northwestern Russia in 1351. Plague was less common in parts of Europe with less-established trade relations, including the majority of the Basque Country , isolated parts of Belgium and the Netherlands , and isolated Alpine villages throughout the continent. According to some epidemiologists, periods of unfavorable weather decimated plague-infected rodent populations, forcing their fleas onto alternative hosts, inducing plague outbreaks which often peaked in the hot summers of the Mediterranean and during the cool autumn months of the southern Baltic region . [lower-alpha 4] Among many other culprits of plague contagiousness, pre-existing malnutrition weakened the immune response, contributing to an immense decline in European population. The disease struck various regions in the Middle East and North Africa during the pandemic , leading to serious depopulation and permanent change in both economic and social structures. By autumn 1347, plague had reached Alexandria in Egypt, transmitted by sea from Constantinople via a single merchant ship carrying slaves. By late summer 1348 it reached Cairo, capital of the Mamluk Sultanate , cultural center of the Islamic world , and the largest city in the Mediterranean Basin ; the Bahriyya child sultan an-Nasir Hasan fled and more than a third of the 600,000 residents died. The Nile was choked with corpses despite Cairo having a medieval hospital, the late 13th century bimaristan of the Qalawun complex . The historian al-Maqrizi described the abundant work for grave-diggers and practitioners of funeral rites ; plague recurred in Cairo more than fifty times over the following one and a half centuries. During 1347, the disease travelled eastward to Gaza by April; by July it had reached Damascus , and in October plague had broken out in Aleppo . That year, in the territory of modern Lebanon , Syria , Israel and Palestine , the cities of Ascalon , Acre , Jerusalem , Sidon and Homs were all infected. In 1348–1349, the disease reached Antioch . The city's residents fled to the north, but most of them ended up dying during the journey. Within two years, the plague had spread throughout the Islamic world, from Arabia across North Africa. [ page needed ] The pandemic spread westwards from Alexandria along the African coast, while in April 1348 Tunis was infected by ship from Sicily. Tunis was then under attack by an army from Morocco; this army dispersed in 1348 and brought the contagion with them to Morocco, whose epidemic may also have been seeded from the Islamic city of Almería in al-Andalus . Mecca became infected in 1348 by pilgrims performing the Hajj . In 1351 or 1352, the Rasulid sultan of the Yemen , al-Mujahid Ali , was released from Mamluk captivity in Egypt and carried plague with him on his return home. During 1349, records show the city of Mosul suffered a massive epidemic, and the city of Baghdad experienced a second round of the disease. Symptoms of the plague include fever of 38–41 °C (100–106 °F) , headaches, painful aching joints , nausea and vomiting, and a general feeling of malaise . Left untreated, 80% of victims die within eight days. Contemporary accounts of the pandemic are varied and often imprecise. The most commonly noted symptom was the appearance of buboes (or gavocciolos ) in the groin, neck and armpits, which oozed pus and bled when opened. Boccaccio 's description: In men and women alike it first betrayed itself by the emergence of certain tumours in the groin or armpits, some of which grew as large as a common apple, others as an egg ... From the two said parts of the body this deadly gavocciolo soon began to propagate and spread itself in all directions indifferently; after which the form of the malady began to change, black spots or livid making their appearance in many cases on the arm or the thigh or elsewhere, now few and large, now minute and numerous. As the gavocciolo had been and still was an infallible token of approaching death, such also were these spots on whomsoever they showed themselves. [lower-alpha 5] This was followed by acute fever and vomiting of blood . Most people died two to seven days after initial infection. Freckle-like spots and rashes, which may have been caused by flea-bites , were identified as another potential sign of plague. Lodewijk Heyligen , whose master Cardinal Colonna died of plague in 1348, noted a distinct form of the disease, pneumonic plague , that infected the lungs and led to respiratory problems. Symptoms include fever, cough and blood-tinged sputum . As the disease progresses, sputum becomes free-flowing and bright red. Pneumonic plague has a mortality rate of 90–95%. Septicemic plague is the least common of the three forms, with a mortality rate near 100%. Symptoms are high fevers and purple skin patches ( purpura due to disseminated intravascular coagulation ). In cases of pneumonic and particularly septicemic plague, the progress of the disease is so rapid that there would often be no time for the development of the enlarged lymph nodes that were noted as buboes. Symptoms of the plague include fever of 38–41 °C (100–106 °F) , headaches, painful aching joints , nausea and vomiting, and a general feeling of malaise . Left untreated, 80% of victims die within eight days. Contemporary accounts of the pandemic are varied and often imprecise. The most commonly noted symptom was the appearance of buboes (or gavocciolos ) in the groin, neck and armpits, which oozed pus and bled when opened. Boccaccio 's description: In men and women alike it first betrayed itself by the emergence of certain tumours in the groin or armpits, some of which grew as large as a common apple, others as an egg ... From the two said parts of the body this deadly gavocciolo soon began to propagate and spread itself in all directions indifferently; after which the form of the malady began to change, black spots or livid making their appearance in many cases on the arm or the thigh or elsewhere, now few and large, now minute and numerous. As the gavocciolo had been and still was an infallible token of approaching death, such also were these spots on whomsoever they showed themselves. [lower-alpha 5] This was followed by acute fever and vomiting of blood . Most people died two to seven days after initial infection. Freckle-like spots and rashes, which may have been caused by flea-bites , were identified as another potential sign of plague.Lodewijk Heyligen , whose master Cardinal Colonna died of plague in 1348, noted a distinct form of the disease, pneumonic plague , that infected the lungs and led to respiratory problems. Symptoms include fever, cough and blood-tinged sputum . As the disease progresses, sputum becomes free-flowing and bright red. Pneumonic plague has a mortality rate of 90–95%. Septicemic plague is the least common of the three forms, with a mortality rate near 100%. Symptoms are high fevers and purple skin patches ( purpura due to disseminated intravascular coagulation ). In cases of pneumonic and particularly septicemic plague, the progress of the disease is so rapid that there would often be no time for the development of the enlarged lymph nodes that were noted as buboes. There are no exact figures for the death toll; the rate varied widely by locality. Urban centers with higher populations suffered longer periods of abnormal mortality. Some estimate that it may have killed between 75,000,000 and 200,000,000 people in Eurasia. [ better source needed ] A study published in 2022 of pollen samples across Europe from 1250 to 1450 was used to estimate changes in agricultural output before and after the Black Death. The authors found great variability in different regions, with evidence for high mortality in areas of Scandinavia, France, western Germany, Greece and central Italy, but uninterrupted agricultural growth in central and eastern Europe, Iberia and Ireland. The authors concluded that "the pandemic was immensely destructive in some areas, but in others it had a far lighter touch ... [the study methodology] invalidates histories of the Black Death that assume Y. pestis was uniformly prevalent, or nearly so, across Europe and that the pandemic had a devastating demographic impact everywhere." The Black Death killed, by various estimations, from 25 to 60% of Europe's population. Robert S. Gottfried writes that as early as 1351, "agents for Pope Clement VI calculated the number of dead in Christian Europe at 23,840,000. With a preplague population of about 75 million, Clement's figure accounts for mortality of 31%-a rate about midway between the 50% mortality estimated for East Anglia, Tuscany, and parts of Scandinavia, and the less-than-15% morbidity for Bohemia and Galicia. And it is unerringly close to Froissart's claim that "a third of the world died," a measurement probably drawn from St. John's figure of mortality from plague in the Book of Revelation , a favorite medieval source of information." Ole J. Benedictow proposes 60% mortality rate for Europe as a whole based on available data, with up to 80% based on poor nutritional conditions in the 14th century. [lower-alpha 6] According to medieval historian Philip Daileader , it is likely that over four years, 45–50% of the European population died of plague. [lower-alpha 7] The mortality rate of the Black Death in the 14th century was far greater than the worst 20th-century outbreaks of Y. pestis plague, which occurred in India and killed as much as 3% of the population of certain cities. The overwhelming number of deceased bodies produced by the Black Death caused the necessity of mass burial sites in Europe, sometimes including up to several hundred or several thousand skeletons. The mass burial sites that have been excavated have allowed archaeologists to continue interpreting and defining the biological, sociological, historical and anthropological implications of the Black Death. In 1348, the disease spread so rapidly that nearly a third of the European population perished before any physicians or government authorities had time to reflect upon its origins. In crowded cities, it was not uncommon for as much as 50% of the population to die. Half of Paris' population of 100,000 people died. In Italy, the population of Florence was reduced from between 110,000 and 120,000 inhabitants in 1338 to 50,000 in 1351. At least 60% of the population of Hamburg and Bremen perished, and a similar percentage of Londoners may have died from the disease as well, leaving a death toll of approximately 62,000 between 1346 and 1353. [lower-alpha 8] Florence's tax records suggest that 80% of the city's population died within four months in 1348. Before 1350, there were about 170,000 settlements in Germany, and this was reduced by nearly 40,000 by 1450. The disease bypassed some areas, with the most isolated areas being less vulnerable to contagion . Plague did not appear in Flanders until the turn of the 15th century, and the impact was less severe on the populations of Hainaut , Finland , northern Germany and areas of Poland. Monks, nuns and priests were especially hard-hit since they cared for people ill with the plague. In 1382 the physician to the Avignon Papacy , Raimundo Chalmel de Vinario ( Latin : Magister Raimundus , lit. ' Master Raymond ' ), observed the decreasing mortality rate of successive outbreaks of plague in 1347–1348, 1362, 1371 and 1382 in his treatise On Epidemics ( De epidemica ). In the first outbreak, two thirds of the population contracted the illness and most patients died; in the next, half the population became ill but only some died; by the third, a tenth were affected and many survived; while by the fourth occurrence, only one in twenty people were sickened and most of them survived. By the 1380s in Europe, the plague predominantly affected children. Chalmel de Vinario recognised that bloodletting was ineffective (though he continued to prescribe bleeding for members of the Roman Curia , whom he disliked), and said that all true cases of plague were caused by astrological factors and were incurable; he was never able to effect a cure. The populations of some Italian cities, notably Florence , did not regain their pre-14th century size until the 19th century. The most widely accepted estimate for the Middle East, including Iraq, Iran and Syria, during this time, is for a death toll of about a third of the population. The Black Death killed about 40% of Egypt's population. In Cairo, with a population numbering as many as 600,000, and possibly the largest city west of China, between one third and 40% of the inhabitants died within eight months. By the 18th century, the population of Cairo was halved from its numbers in 1347. Italian chronicler Agnolo di Tura recorded his experience from Siena , where plague arrived in May 1348: Father abandoned child, wife husband, one brother another; for this illness seemed to strike through the breath and sight. And so they died. And none could be found to bury the dead for money or friendship. Members of a household brought their dead to a ditch as best they could, without priest, without divine offices ... great pits were dug and piled deep with the multitude of dead. And they died by the hundreds both day and night ... And as soon as those ditches were filled more were dug ... And I, Agnolo di Tura ... buried my five children with my own hands. And there were also those who were so sparsely covered with earth that the dogs dragged them forth and devoured many bodies throughout the city. There was no one who wept for any death, for all awaited death. And so many died that all believed it was the end of the world. It has been suggested that the Black Plague, like other outbreaks through history, disproportionately affected the poorest people and those already in worse physical condition than the wealthier citizens. But along with population decline from the pandemic, wages soared in response to a subsequent labor shortage. Many laborers, artisans and craftsmen—those living from money-wages alone—suffered a reduction in real incomes owing to rampant inflation. Landowners were also pushed to substitute monetary rents for labor services in an effort to keep tenants. The trade disruptions in the Mongol Empire caused by the Black Death was one of the reasons for its collapse. A study performed by Thomas Van Hoof of the Utrecht University suggests that the innumerable deaths brought on by the pandemic cooled the climate by freeing up land and triggering reforestation . This may have led to the Little Ice Age . Renewed religious fervor and fanaticism increased in the wake of the Black Death. Some Europeans targeted "various groups such as Jews , friars , foreigners, beggars, pilgrims ", lepers and Romani , blaming them for the crisis. Lepers , and others with skin diseases such as acne or psoriasis , were killed throughout Europe. Because 14th-century healers and governments were at a loss to explain or stop the disease, Europeans turned to astrological forces, earthquakes and the poisoning of wells by Jews as possible reasons for outbreaks. Many believed the epidemic was a punishment by God for their sins, and could be relieved by winning God's forgiveness . There were many attacks against Jewish communities. In the Strasbourg massacre of February 1349, about 2,000 Jews were murdered. In August 1349, the Jewish communities in Mainz and Cologne were annihilated. By 1351, 60 major and 150 smaller Jewish communities had been destroyed. During this period many Jews relocated to Poland , where they received a welcome from King Casimir the Great . One theory that has been advanced is that the Black Death's devastation of Florence , between 1348 and 1350, resulted in a shift in the world view of people in 14th-century Italy that ultimately led to the Renaissance . Italy was particularly badly hit by the pandemic, and the resulting familiarity with death may have caused thinkers to dwell more on their lives on Earth, rather than on spirituality and the afterlife . [lower-alpha 9] It has also been argued that the Black Death prompted a new wave of piety, manifested in the sponsorship of religious works of art. This does not fully explain why the Renaissance occurred in Italy in the 14th century; the Renaissance's emergence was most likely the result of the complex interaction of the above factors, in combination with an influx of Greek scholars after the fall of the Byzantine Empire . As a result of the drastic reduction in the populace the value of the working class increased, and commoners came to enjoy more freedom. To answer the increased need for labor, workers travelled in search of the most favorable position economically. [ better source needed ] Prior to the emergence of the Black Death, the continent was considered a feudalistic society, composed of fiefs and city-states frequently managed by the Catholic Church. The pandemic completely restructured both religion and political forces; survivors began to turn to other forms of spirituality and the power dynamics of the fiefs and city-states crumbled. The survivors of the pandemic found not only that the prices of food were lower but also that lands were more abundant, and many of them inherited property from their dead relatives, and this probably contributed to the destabilization of feudalism . The word " quarantine " has its roots in this period, though the practice of isolating people to prevent the spread of disease is older. In the city-state of Ragusa (modern Dubrovnik , Croatia), a thirty-day isolation period was implemented in 1377 for new arrivals to the city from plague-affected areas. The isolation period was later extended to forty days, and given the name "quarantino" from the Italian word for "forty". There are no exact figures for the death toll; the rate varied widely by locality. Urban centers with higher populations suffered longer periods of abnormal mortality. Some estimate that it may have killed between 75,000,000 and 200,000,000 people in Eurasia. [ better source needed ] A study published in 2022 of pollen samples across Europe from 1250 to 1450 was used to estimate changes in agricultural output before and after the Black Death. The authors found great variability in different regions, with evidence for high mortality in areas of Scandinavia, France, western Germany, Greece and central Italy, but uninterrupted agricultural growth in central and eastern Europe, Iberia and Ireland. The authors concluded that "the pandemic was immensely destructive in some areas, but in others it had a far lighter touch ... [the study methodology] invalidates histories of the Black Death that assume Y. pestis was uniformly prevalent, or nearly so, across Europe and that the pandemic had a devastating demographic impact everywhere." The Black Death killed, by various estimations, from 25 to 60% of Europe's population. Robert S. Gottfried writes that as early as 1351, "agents for Pope Clement VI calculated the number of dead in Christian Europe at 23,840,000. With a preplague population of about 75 million, Clement's figure accounts for mortality of 31%-a rate about midway between the 50% mortality estimated for East Anglia, Tuscany, and parts of Scandinavia, and the less-than-15% morbidity for Bohemia and Galicia. And it is unerringly close to Froissart's claim that "a third of the world died," a measurement probably drawn from St. John's figure of mortality from plague in the Book of Revelation , a favorite medieval source of information." Ole J. Benedictow proposes 60% mortality rate for Europe as a whole based on available data, with up to 80% based on poor nutritional conditions in the 14th century. [lower-alpha 6] According to medieval historian Philip Daileader , it is likely that over four years, 45–50% of the European population died of plague. [lower-alpha 7] The mortality rate of the Black Death in the 14th century was far greater than the worst 20th-century outbreaks of Y. pestis plague, which occurred in India and killed as much as 3% of the population of certain cities. The overwhelming number of deceased bodies produced by the Black Death caused the necessity of mass burial sites in Europe, sometimes including up to several hundred or several thousand skeletons. The mass burial sites that have been excavated have allowed archaeologists to continue interpreting and defining the biological, sociological, historical and anthropological implications of the Black Death. In 1348, the disease spread so rapidly that nearly a third of the European population perished before any physicians or government authorities had time to reflect upon its origins. In crowded cities, it was not uncommon for as much as 50% of the population to die. Half of Paris' population of 100,000 people died. In Italy, the population of Florence was reduced from between 110,000 and 120,000 inhabitants in 1338 to 50,000 in 1351. At least 60% of the population of Hamburg and Bremen perished, and a similar percentage of Londoners may have died from the disease as well, leaving a death toll of approximately 62,000 between 1346 and 1353. [lower-alpha 8] Florence's tax records suggest that 80% of the city's population died within four months in 1348. Before 1350, there were about 170,000 settlements in Germany, and this was reduced by nearly 40,000 by 1450. The disease bypassed some areas, with the most isolated areas being less vulnerable to contagion . Plague did not appear in Flanders until the turn of the 15th century, and the impact was less severe on the populations of Hainaut , Finland , northern Germany and areas of Poland. Monks, nuns and priests were especially hard-hit since they cared for people ill with the plague. In 1382 the physician to the Avignon Papacy , Raimundo Chalmel de Vinario ( Latin : Magister Raimundus , lit. ' Master Raymond ' ), observed the decreasing mortality rate of successive outbreaks of plague in 1347–1348, 1362, 1371 and 1382 in his treatise On Epidemics ( De epidemica ). In the first outbreak, two thirds of the population contracted the illness and most patients died; in the next, half the population became ill but only some died; by the third, a tenth were affected and many survived; while by the fourth occurrence, only one in twenty people were sickened and most of them survived. By the 1380s in Europe, the plague predominantly affected children. Chalmel de Vinario recognised that bloodletting was ineffective (though he continued to prescribe bleeding for members of the Roman Curia , whom he disliked), and said that all true cases of plague were caused by astrological factors and were incurable; he was never able to effect a cure. The populations of some Italian cities, notably Florence , did not regain their pre-14th century size until the 19th century. The most widely accepted estimate for the Middle East, including Iraq, Iran and Syria, during this time, is for a death toll of about a third of the population. The Black Death killed about 40% of Egypt's population. In Cairo, with a population numbering as many as 600,000, and possibly the largest city west of China, between one third and 40% of the inhabitants died within eight months. By the 18th century, the population of Cairo was halved from its numbers in 1347. Italian chronicler Agnolo di Tura recorded his experience from Siena , where plague arrived in May 1348: Father abandoned child, wife husband, one brother another; for this illness seemed to strike through the breath and sight. And so they died. And none could be found to bury the dead for money or friendship. Members of a household brought their dead to a ditch as best they could, without priest, without divine offices ... great pits were dug and piled deep with the multitude of dead. And they died by the hundreds both day and night ... And as soon as those ditches were filled more were dug ... And I, Agnolo di Tura ... buried my five children with my own hands. And there were also those who were so sparsely covered with earth that the dogs dragged them forth and devoured many bodies throughout the city. There was no one who wept for any death, for all awaited death. And so many died that all believed it was the end of the world. It has been suggested that the Black Plague, like other outbreaks through history, disproportionately affected the poorest people and those already in worse physical condition than the wealthier citizens. But along with population decline from the pandemic, wages soared in response to a subsequent labor shortage. Many laborers, artisans and craftsmen—those living from money-wages alone—suffered a reduction in real incomes owing to rampant inflation. Landowners were also pushed to substitute monetary rents for labor services in an effort to keep tenants. The trade disruptions in the Mongol Empire caused by the Black Death was one of the reasons for its collapse. A study performed by Thomas Van Hoof of the Utrecht University suggests that the innumerable deaths brought on by the pandemic cooled the climate by freeing up land and triggering reforestation . This may have led to the Little Ice Age . Renewed religious fervor and fanaticism increased in the wake of the Black Death. Some Europeans targeted "various groups such as Jews , friars , foreigners, beggars, pilgrims ", lepers and Romani , blaming them for the crisis. Lepers , and others with skin diseases such as acne or psoriasis , were killed throughout Europe. Because 14th-century healers and governments were at a loss to explain or stop the disease, Europeans turned to astrological forces, earthquakes and the poisoning of wells by Jews as possible reasons for outbreaks. Many believed the epidemic was a punishment by God for their sins, and could be relieved by winning God's forgiveness . There were many attacks against Jewish communities. In the Strasbourg massacre of February 1349, about 2,000 Jews were murdered. In August 1349, the Jewish communities in Mainz and Cologne were annihilated. By 1351, 60 major and 150 smaller Jewish communities had been destroyed. During this period many Jews relocated to Poland , where they received a welcome from King Casimir the Great . One theory that has been advanced is that the Black Death's devastation of Florence , between 1348 and 1350, resulted in a shift in the world view of people in 14th-century Italy that ultimately led to the Renaissance . Italy was particularly badly hit by the pandemic, and the resulting familiarity with death may have caused thinkers to dwell more on their lives on Earth, rather than on spirituality and the afterlife . [lower-alpha 9] It has also been argued that the Black Death prompted a new wave of piety, manifested in the sponsorship of religious works of art. This does not fully explain why the Renaissance occurred in Italy in the 14th century; the Renaissance's emergence was most likely the result of the complex interaction of the above factors, in combination with an influx of Greek scholars after the fall of the Byzantine Empire . As a result of the drastic reduction in the populace the value of the working class increased, and commoners came to enjoy more freedom. To answer the increased need for labor, workers travelled in search of the most favorable position economically. [ better source needed ] Prior to the emergence of the Black Death, the continent was considered a feudalistic society, composed of fiefs and city-states frequently managed by the Catholic Church. The pandemic completely restructured both religion and political forces; survivors began to turn to other forms of spirituality and the power dynamics of the fiefs and city-states crumbled. The survivors of the pandemic found not only that the prices of food were lower but also that lands were more abundant, and many of them inherited property from their dead relatives, and this probably contributed to the destabilization of feudalism . The word " quarantine " has its roots in this period, though the practice of isolating people to prevent the spread of disease is older. In the city-state of Ragusa (modern Dubrovnik , Croatia), a thirty-day isolation period was implemented in 1377 for new arrivals to the city from plague-affected areas. The isolation period was later extended to forty days, and given the name "quarantino" from the Italian word for "forty". The plague repeatedly returned to haunt Europe and the Mediterranean throughout the 14th to 17th centuries. According to Jean-Noël Biraben, the plague was present somewhere in Europe in every year between 1346 and 1671 (although some researchers have cautions about the uncritical use of Biraben's data). The second pandemic was particularly widespread in the following years: 1360–1363; 1374; 1400; 1438–1439; 1456–1457; 1464–1466; 1481–1485; 1500–1503; 1518–1531; 1544–1548; 1563–1566; 1573–1588; 1596–1599; 1602–1611; 1623–1640; 1644–1654; and 1664–1667. Subsequent outbreaks, though severe, marked the plague's retreat from most of Europe (18th century) and northern Africa (19th century). Historian George Sussman argued that the plague had not occurred in East Africa until the 1900s. However, other sources suggest that the Second pandemic did indeed reach Sub-Saharan Africa. According to historian Geoffrey Parker , "France alone lost almost a million people to the plague in the epidemic of 1628–31." In the first half of the 17th century, a plague killed some 1.7 million people in Italy. More than 1.25 million deaths resulted from the extreme incidence of plague in 17th-century Spain . The Black Death ravaged much of the Islamic world . Plague could be found in the Islamic world almost every year between 1500 and 1850. Sometimes the outbreaks affected small areas, while other outbreaks affected multiple regions. Plague repeatedly struck the cities of North Africa. Algiers lost 30,000–50,000 inhabitants to it in 1620–21, and again in 1654–57, 1665, 1691 and 1740–42. Cairo suffered more than fifty plague epidemics within 150 years from the plague's first appearance, with the final outbreak of the second pandemic there in the 1840s. Plague remained a major event in Ottoman society until the second quarter of the 19th century. Between 1701 and 1750, thirty-seven larger and smaller epidemics were recorded in Constantinople , and an additional thirty-one between 1751 and 1800. Baghdad has suffered severely from visitations of the plague, and sometimes two-thirds of its population had died. The third plague pandemic (1855–1859) started in China in the mid-19th century, spreading to all inhabited continents and killing 10 million people in India alone. The investigation of the pathogen that caused the 19th-century plague was begun by teams of scientists who visited Hong Kong in 1894, among whom was the French-Swiss bacteriologist Alexandre Yersin , for whom the pathogen was named. Twelve plague outbreaks in Australia between 1900 and 1925 resulted in over 1,000 deaths, chiefly in Sydney. This led to the establishment of a Public Health Department there which undertook some leading-edge research on plague transmission from rat fleas to humans via the bacillus Yersinia pestis . The first North American plague epidemic was the San Francisco plague of 1900–1904 , followed by another outbreak in 1907–1908. Modern treatment methods include insecticides , the use of antibiotics , and a plague vaccine . It is feared that the plague bacterium could develop drug resistance and again become a major health threat. One case of a drug-resistant form of the bacterium was found in Madagascar in 1995. Another outbreak in Madagascar was reported in November 2014. In October 2017, the deadliest outbreak of the plague in modern times hit Madagascar, killing 170 people and infecting thousands. An estimate of the case fatality rate for the modern plague , after the introduction of antibiotics , is 11%, although it may be higher in underdeveloped regions. The plague repeatedly returned to haunt Europe and the Mediterranean throughout the 14th to 17th centuries. According to Jean-Noël Biraben, the plague was present somewhere in Europe in every year between 1346 and 1671 (although some researchers have cautions about the uncritical use of Biraben's data). The second pandemic was particularly widespread in the following years: 1360–1363; 1374; 1400; 1438–1439; 1456–1457; 1464–1466; 1481–1485; 1500–1503; 1518–1531; 1544–1548; 1563–1566; 1573–1588; 1596–1599; 1602–1611; 1623–1640; 1644–1654; and 1664–1667. Subsequent outbreaks, though severe, marked the plague's retreat from most of Europe (18th century) and northern Africa (19th century). Historian George Sussman argued that the plague had not occurred in East Africa until the 1900s. However, other sources suggest that the Second pandemic did indeed reach Sub-Saharan Africa. According to historian Geoffrey Parker , "France alone lost almost a million people to the plague in the epidemic of 1628–31." In the first half of the 17th century, a plague killed some 1.7 million people in Italy. More than 1.25 million deaths resulted from the extreme incidence of plague in 17th-century Spain . The Black Death ravaged much of the Islamic world . Plague could be found in the Islamic world almost every year between 1500 and 1850. Sometimes the outbreaks affected small areas, while other outbreaks affected multiple regions. Plague repeatedly struck the cities of North Africa. Algiers lost 30,000–50,000 inhabitants to it in 1620–21, and again in 1654–57, 1665, 1691 and 1740–42. Cairo suffered more than fifty plague epidemics within 150 years from the plague's first appearance, with the final outbreak of the second pandemic there in the 1840s. Plague remained a major event in Ottoman society until the second quarter of the 19th century. Between 1701 and 1750, thirty-seven larger and smaller epidemics were recorded in Constantinople , and an additional thirty-one between 1751 and 1800. Baghdad has suffered severely from visitations of the plague, and sometimes two-thirds of its population had died. The third plague pandemic (1855–1859) started in China in the mid-19th century, spreading to all inhabited continents and killing 10 million people in India alone. The investigation of the pathogen that caused the 19th-century plague was begun by teams of scientists who visited Hong Kong in 1894, among whom was the French-Swiss bacteriologist Alexandre Yersin , for whom the pathogen was named. Twelve plague outbreaks in Australia between 1900 and 1925 resulted in over 1,000 deaths, chiefly in Sydney. This led to the establishment of a Public Health Department there which undertook some leading-edge research on plague transmission from rat fleas to humans via the bacillus Yersinia pestis . The first North American plague epidemic was the San Francisco plague of 1900–1904 , followed by another outbreak in 1907–1908. Modern treatment methods include insecticides , the use of antibiotics , and a plague vaccine . It is feared that the plague bacterium could develop drug resistance and again become a major health threat. One case of a drug-resistant form of the bacterium was found in Madagascar in 1995. Another outbreak in Madagascar was reported in November 2014. In October 2017, the deadliest outbreak of the plague in modern times hit Madagascar, killing 170 people and infecting thousands. An estimate of the case fatality rate for the modern plague , after the introduction of antibiotics , is 11%, although it may be higher in underdeveloped regions.

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Bubonic plague

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Plague (disease)

Plague is an infectious disease caused by the bacterium Yersinia pestis . Symptoms include fever , weakness and headache . Usually this begins one to seven days after exposure. There are three forms of plague, each affecting a different part of the body and causing associated symptoms. Pneumonic plague infects the lungs, causing shortness of breath, coughing and chest pain; bubonic plague affects the lymph nodes , making them swell; and septicemic plague infects the blood and can cause tissues to turn black and die . The bubonic and septicemic forms are generally spread by flea bites or handling an infected animal, whereas pneumonic plague is generally spread between people through the air via infectious droplets. Diagnosis is typically by finding the bacterium in fluid from a lymph node, blood or sputum . Those at high risk may be vaccinated . Those exposed to a case of pneumonic plague may be treated with preventive medication. If infected, treatment is with antibiotics and supportive care . Typically antibiotics include a combination of gentamicin and a fluoroquinolone . The risk of death with treatment is about 10% while without it is about 70%. Globally, about 600 cases are reported a year. In 2017, the countries with the most cases include the Democratic Republic of the Congo , Madagascar and Peru . In the United States, infections occasionally occur in rural areas, where the bacteria are believed to circulate among rodents . It has historically occurred in large outbreaks , with the best known being the Black Death in the 14th century, which resulted in more than 50 million deaths in Europe. There are several different clinical manifestations of plague. The most common form is bubonic plague, followed by septicemic and pneumonic plague. Other clinical manifestations include plague meningitis, plague pharyngitis, and ocular plague. General symptoms of plague include fever, chills, headaches, and nausea. Many people experience swelling in their lymph nodes if they have bubonic plague. For those with pneumonic plague, symptoms may (or may not) include a cough, pain in the chest, and haemoptysis. When a flea bites a human and contaminates the wound with regurgitated blood, the plague-causing bacteria are passed into the tissue. Y. pestis can reproduce inside cells, so even if phagocytosed , they can still survive. Once in the body, the bacteria can enter the lymphatic system , which drains interstitial fluid . Plague bacteria secrete several toxins , one of which is known to cause beta-adrenergic blockade . Y. pestis spreads through the lymphatic vessels of the infected human until it reaches a lymph node , where it causes acute lymphadenitis . The swollen lymph nodes form the characteristic buboes associated with the disease, and autopsies of these buboes have revealed them to be mostly hemorrhagic or necrotic . If the lymph node is overwhelmed, the infection can pass into the bloodstream, causing secondary septicemic plague and if the lungs are seeded, it can cause secondary pneumonic plague . Lymphatics ultimately drain into the bloodstream, so the plague bacteria may enter the blood and travel to almost any part of the body. In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), causing tiny clots throughout the body and possibly ischemic necrosis (tissue death due to lack of circulation/perfusion to that tissue) from the clots. DIC results in depletion of the body's clotting resources so that it can no longer control bleeding. Consequently, there is bleeding into the skin and other organs, which can cause red and/or black patchy rash and hemoptysis/hematemesis (coughing up/ vomiting of blood). There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the centre. Untreated, the septicemic plague is usually fatal. Early treatment with antibiotics reduces the mortality rate to between 4 and 15 per cent. The pneumonic form of plague arises from infection of the lungs . It causes coughing and thereby produces airborne droplets that contain bacterial cells and are likely to infect anyone inhaling them. The incubation period for pneumonic plague is short, usually two to four days, but sometimes just a few hours. The initial signs are indistinguishable from several other respiratory illnesses; they include headache, weakness, and spitting or vomiting of blood. The course of the disease is rapid; unless diagnosed and treated soon enough, typically within a few hours, death may follow in one to six days; in untreated cases, mortality is nearly 100%. When a flea bites a human and contaminates the wound with regurgitated blood, the plague-causing bacteria are passed into the tissue. Y. pestis can reproduce inside cells, so even if phagocytosed , they can still survive. Once in the body, the bacteria can enter the lymphatic system , which drains interstitial fluid . Plague bacteria secrete several toxins , one of which is known to cause beta-adrenergic blockade . Y. pestis spreads through the lymphatic vessels of the infected human until it reaches a lymph node , where it causes acute lymphadenitis . The swollen lymph nodes form the characteristic buboes associated with the disease, and autopsies of these buboes have revealed them to be mostly hemorrhagic or necrotic . If the lymph node is overwhelmed, the infection can pass into the bloodstream, causing secondary septicemic plague and if the lungs are seeded, it can cause secondary pneumonic plague . Lymphatics ultimately drain into the bloodstream, so the plague bacteria may enter the blood and travel to almost any part of the body. In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), causing tiny clots throughout the body and possibly ischemic necrosis (tissue death due to lack of circulation/perfusion to that tissue) from the clots. DIC results in depletion of the body's clotting resources so that it can no longer control bleeding. Consequently, there is bleeding into the skin and other organs, which can cause red and/or black patchy rash and hemoptysis/hematemesis (coughing up/ vomiting of blood). There are bumps on the skin that look somewhat like insect bites; these are usually red, and sometimes white in the centre. Untreated, the septicemic plague is usually fatal. Early treatment with antibiotics reduces the mortality rate to between 4 and 15 per cent. The pneumonic form of plague arises from infection of the lungs . It causes coughing and thereby produces airborne droplets that contain bacterial cells and are likely to infect anyone inhaling them. The incubation period for pneumonic plague is short, usually two to four days, but sometimes just a few hours. The initial signs are indistinguishable from several other respiratory illnesses; they include headache, weakness, and spitting or vomiting of blood. The course of the disease is rapid; unless diagnosed and treated soon enough, typically within a few hours, death may follow in one to six days; in untreated cases, mortality is nearly 100%. Transmission of Y. pestis to an uninfected individual is possible by any of the following means: droplet contact – coughing or sneezing on another person Direct physical contact;– touching an infected person, including sexual contact indirect contact – usually by touching soil contamination or a contaminated surface airborne transmission – if the microorganism can remain in the air for long periods fecal-oral transmission – usually from contaminated food or water sources vector borne transmission – carried by insects or other animals. Yersinia pestis circulates in animal reservoirs, particularly in rodents, in the natural foci of infection found on all continents except Australia. The natural foci of plague are situated in a broad belt in the tropical and sub-tropical latitudes and the warmer parts of the temperate latitudes around the globe, between the parallels 55° N and 40° S. Contrary to popular belief, rats did not directly start the spread of the bubonic plague. It is mainly a disease in the fleas ( Xenopsylla cheopis ) that infested the rats, making the rats themselves the first victims of the plague. Rodent-borne infection in a human occurs when a person is bitten by a flea that has been infected by biting a rodent that itself has been infected by the bite of a flea carrying the disease. The bacteria multiply inside the flea, sticking together to form a plug that blocks its stomach and causes it to starve. The flea then bites a host and continues to feed, even though it cannot quell its hunger, and consequently, the flea vomits blood tainted with the bacteria back into the bite wound. The bubonic plague bacterium then infects a new person and the flea eventually dies from starvation. Serious outbreaks of plague are usually started by other disease outbreaks in rodents or a rise in the rodent population. A 21st-century study of a 1665 outbreak of plague in the village of Eyam in England's Derbyshire Dales – which isolated itself during the outbreak, facilitating modern study – found that three-quarters of cases are likely to have been due to human-to-human transmission, especially within families, a much bigger proportion than previously thought. Symptoms of plague are usually non-specific and to definitively diagnose plague, laboratory testing is required. Y. pestis can be identified through both a microscope and by culturing a sample and this is used as a reference standard to confirm that a person has a case of plague. The sample can be obtained from the blood, mucus ( sputum ), or aspirate extracted from inflamed lymph nodes ( buboes ). If a person is administered antibiotics before a sample is taken or if there is a delay in transporting the person's sample to a laboratory and/or a poorly stored sample, there is a possibility for false negative results. Polymerase chain reaction (PCR) may also be used to diagnose plague, by detecting the presence of bacterial genes such as the pla gene (plasmogen activator) and caf1 gene, (F1 capsule antigen). PCR testing requires a very small sample and is effective for both alive and dead bacteria. For this reason, if a person receives antibiotics before a sample is collected for laboratory testing, they may have a false negative culture and a positive PCR result. Blood tests to detect antibodies against Y. pestis can also be used to diagnose plague, however, this requires taking blood samples at different periods to detect differences between the acute and convalescent phases of F1 antibody titres. In 2020, a study about rapid diagnostic tests that detect the F1 capsule antigen (F1RDT) by sampling sputum or bubo aspirate was released. Results show rapid diagnostic F1RDT test can be used for people who have suspected pneumonic and bubonic plague but cannot be used in asymptomatic people. F1RDT may be useful in providing a fast result for prompt treatment and fast public health response as studies suggest that F1RDT is highly sensitive for both pneumonic and bubonic plague. However, when using the rapid test, both positive and negative results need to be confirmed to establish or reject the diagnosis of a confirmed case of plague and the test result needs to be interpreted within the epidemiological context as study findings indicate that although 40 out of 40 people who had the plague in a population of 1000 were correctly diagnosed, 317 people were diagnosed falsely as positive. Bacteriologist Waldemar Haffkine developed the first plague vaccine in 1897. He conducted a massive inoculation program in British India , and it is estimated that 26 million doses of Haffkine's anti-plague vaccine were sent out from Bombay between 1897 and 1925, reducing the plague mortality by 50–85%. Since human plague is rare in most parts of the world as of 2023, routine vaccination is not needed other than for those at particularly high risk of exposure, nor for people living in areas with enzootic plague, meaning it occurs at regular, predictable rates in populations and specific areas, such as the western United States. It is not even indicated for most travellers to countries with known recent reported cases, particularly if their travel is limited to urban areas with modern hotels. The United States CDC thus only recommends vaccination for (1) all laboratory and field personnel who are working with Y. pestis organisms resistant to antimicrobials: (2) people engaged in aerosol experiments with Y. pestis ; and (3) people engaged in field operations in areas with enzootic plague where preventing exposure is not possible (such as some disaster areas). A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine. Diagnosing plague early leads to a decrease in transmission or spread of the disease. Pre-exposure prophylaxis for first responders and health care providers who will care for patients with pneumonic plague is not considered necessary as long as standard and droplet precautions can be maintained. In cases of surgical mask shortages, patient overcrowding, poor ventilation in hospital wards, or other crises, pre-exposure prophylaxis might be warranted if sufficient supplies of antimicrobials are available. Postexposure prophylaxis should be considered for people who had close (<6 feet), sustained contact with a patient with pneumonic plague and were not wearing adequate personal protective equipment. Antimicrobial postexposure prophylaxis also can be considered for laboratory workers accidentally exposed to infectious materials and people who had close (<6 feet) or direct contact with infected animals, such as veterinary staff, pet owners, and hunters. Specific recommendations on pre- and post-exposure prophylaxis are available in the clinical guidelines on treatment and prophylaxis of plague published in 2021. Bacteriologist Waldemar Haffkine developed the first plague vaccine in 1897. He conducted a massive inoculation program in British India , and it is estimated that 26 million doses of Haffkine's anti-plague vaccine were sent out from Bombay between 1897 and 1925, reducing the plague mortality by 50–85%. Since human plague is rare in most parts of the world as of 2023, routine vaccination is not needed other than for those at particularly high risk of exposure, nor for people living in areas with enzootic plague, meaning it occurs at regular, predictable rates in populations and specific areas, such as the western United States. It is not even indicated for most travellers to countries with known recent reported cases, particularly if their travel is limited to urban areas with modern hotels. The United States CDC thus only recommends vaccination for (1) all laboratory and field personnel who are working with Y. pestis organisms resistant to antimicrobials: (2) people engaged in aerosol experiments with Y. pestis ; and (3) people engaged in field operations in areas with enzootic plague where preventing exposure is not possible (such as some disaster areas). A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine. Diagnosing plague early leads to a decrease in transmission or spread of the disease. Pre-exposure prophylaxis for first responders and health care providers who will care for patients with pneumonic plague is not considered necessary as long as standard and droplet precautions can be maintained. In cases of surgical mask shortages, patient overcrowding, poor ventilation in hospital wards, or other crises, pre-exposure prophylaxis might be warranted if sufficient supplies of antimicrobials are available. Postexposure prophylaxis should be considered for people who had close (<6 feet), sustained contact with a patient with pneumonic plague and were not wearing adequate personal protective equipment. Antimicrobial postexposure prophylaxis also can be considered for laboratory workers accidentally exposed to infectious materials and people who had close (<6 feet) or direct contact with infected animals, such as veterinary staff, pet owners, and hunters. Specific recommendations on pre- and post-exposure prophylaxis are available in the clinical guidelines on treatment and prophylaxis of plague published in 2021. If diagnosed in time, the various forms of plague are usually highly responsive to antibiotic therapy. The antibiotics often used are streptomycin , chloramphenicol and tetracycline . Amongst the newer generation of antibiotics, gentamicin and doxycycline have proven effective in monotherapeutic treatment of plague. Guidelines on treatment and prophylaxis of plague were published by the Centers for Disease Control and Prevention in 2021. The plague bacterium could develop drug resistance and again become a major health threat. One case of a drug-resistant form of the bacterium was found in Madagascar in 1995. Further outbreaks in Madagascar were reported in November 2014 and October 2017. Globally about 600 cases are reported a year. In 2017, the countries with the most cases include the Democratic Republic of the Congo , Madagascar and Peru . It has historically occurred in large outbreaks , with the best known being the Black Death in the 14th century which resulted in more than 50 million dead. In recent years, cases have been distributed between small seasonal outbreaks which occur primarily in Madagascar, and sporadic outbreaks or isolated cases in endemic areas. In 2022 the possible origin of all modern strands of Yersinia pestis DNA was found in human remains in three graves located in Kyrgyzstan , dated to 1338 and 1339. The siege of Caffa in Crimea in 1346, is known to have been the first plague outbreak with following strands, later to spread over Europe. Sequencing DNA compared to other ancient and modern strands paints a family tree of the bacteria. Bacteria today affecting marmots in Kyrgyzstan, are closest to the strand found in the graves, suggesting this is also the location where plague transferred from animals to humans. The plague has a long history as a biological weapon . Historical accounts from ancient China and medieval Europe details the use of infected animal carcasses, such as cows or horses, and human carcasses, by the Xiongnu / Huns , Mongols , Turks and other groups, to contaminate enemy water supplies. Han dynasty general Huo Qubing is recorded to have died of such contamination while engaging in warfare against the Xiongnu. Plague victims were also reported to have been tossed by catapult into cities under siege. In 1347, the Genoese possession of Caffa , a great trade emporium on the Crimean peninsula , came under siege by an army of Mongol warriors of the Golden Horde under the command of Jani Beg . After a protracted siege during which the Mongol army was reportedly withering from the disease, they decided to use the infected corpses as a biological weapon. The corpses were catapulted over the city walls, infecting the inhabitants. This event might have led to the transfer of the Black Death via their ships into the south of Europe , possibly explaining its rapid spread. During World War II , the Japanese Army developed weaponized plague, based on the breeding and release of large numbers of fleas. During the Japanese occupation of Manchuria , Unit 731 deliberately infected Chinese , Korean and Manchurian civilians and prisoners of war with the plague bacterium. These subjects, termed "maruta" or "logs", were then studied by dissection , others by vivisection while still conscious. Members of the unit such as Shiro Ishii were exonerated from the Tokyo tribunal by Douglas MacArthur but 12 of them were prosecuted in the Khabarovsk War Crime Trials in 1949 during which some admitted having spread bubonic plague within a 36-kilometre (22 mi) radius around the city of Changde . Ishii innovated bombs containing live mice and fleas, with very small explosive loads, to deliver the weaponized microbes, overcoming the problem of the explosive killing the infected animal and insect by the use of a ceramic, rather than metal, casing for the warhead. While no records survive of the actual usage of the ceramic shells, prototypes exist and are believed to have been used in experiments during WWII. After World War II, both the United States and the Soviet Union developed means of weaponising pneumonic plague. Experiments included various delivery methods, vacuum drying, sizing the bacterium, developing strains resistant to antibiotics, combining the bacterium with other diseases (such as diphtheria ), and genetic engineering. Scientists who worked in USSR bio-weapons programs have stated that the Soviet effort was formidable and that large stocks of weaponised plague bacteria were produced. Information on many of the Soviet and US projects is largely unavailable. Aerosolized pneumonic plague remains the most significant threat. The plague can be easily treated with antibiotics. Some countries, such as the United States, have large supplies on hand if such an attack should occur, making the threat less severe.

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Bubonic plague

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List of epidemics and pandemics

This is a list of the largest known epidemics and pandemics caused by an infectious disease . Widespread non-communicable diseases such as cardiovascular disease and cancer are not included. An epidemic is the rapid spread of disease to a large number of people in a given population within a short period of time; in meningococcal infections , an attack rate in excess of 15 cases per 100,000 people for two consecutive weeks is considered an epidemic. Due to the long time spans, the first plague pandemic (6th century – 8th century) and the second plague pandemic (14th century – early 19th century) are shown by individual outbreaks, such as the Plague of Justinian (first pandemic) and the Black Death (second pandemic). Infectious diseases with high prevalence are listed separately (sometimes in addition to their epidemics), such as malaria , which may have killed 50–60 billion people throughout history, or about half of all humans that have ever lived. Ongoing epidemics and pandemics are in boldface . For a given epidemic or pandemic, the average of its estimated death toll range is used for ranking. If the death toll averages of two or more epidemics or pandemics are equal, then the smaller the range, the higher the rank. For the historical records of major changes in the world population, see world population . Not included in the above table are many waves of deadly diseases brought by Europeans to the Americas and Caribbean. Western Hemisphere populations were ravaged mostly by smallpox , but also typhus , measles , influenza , bubonic plague , cholera , malaria , tuberculosis , mumps , yellow fever , and pertussis . The lack of written records in many places and the destruction of many native societies by disease, war, and colonization make estimates uncertain. Deaths probably numbered in the tens or perhaps over a hundred million, with perhaps 90% of the population dead in the worst-hit areas. Lack of scientific knowledge about microorganisms and lack of surviving medical records for many areas makes attribution of specific numbers to specific diseases uncertain. There have been various major infectious diseases with high prevalence worldwide, but they are currently not listed in the above table as epidemics/pandemics due to the lack of definite data, such as time span and death toll.Ongoing epidemics and pandemics are in boldface . For a given epidemic or pandemic, the average of its estimated death toll range is used for ranking. If the death toll averages of two or more epidemics or pandemics are equal, then the smaller the range, the higher the rank. For the historical records of major changes in the world population, see world population . Not included in the above table are many waves of deadly diseases brought by Europeans to the Americas and Caribbean. Western Hemisphere populations were ravaged mostly by smallpox , but also typhus , measles , influenza , bubonic plague , cholera , malaria , tuberculosis , mumps , yellow fever , and pertussis . The lack of written records in many places and the destruction of many native societies by disease, war, and colonization make estimates uncertain. Deaths probably numbered in the tens or perhaps over a hundred million, with perhaps 90% of the population dead in the worst-hit areas. Lack of scientific knowledge about microorganisms and lack of surviving medical records for many areas makes attribution of specific numbers to specific diseases uncertain.There have been various major infectious diseases with high prevalence worldwide, but they are currently not listed in the above table as epidemics/pandemics due to the lack of definite data, such as time span and death toll.Events in boldface are ongoing.

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Bubonic plague

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Pneumonic plague

Pneumonic plague is a severe lung infection caused by the bacterium Yersinia pestis . Symptoms include fever , headache, shortness of breath , chest pain , and coughing. They typically start about three to seven days after exposure. It is one of three forms of plague , the other two being septicemic plague and bubonic plague . The pneumonic form may occur following an initial bubonic or septicemic plague infection. It may also result from breathing in airborne droplets from another person or animal infected with pneumonic plague. The difference between the forms of plague is the location of infection; in pneumonic plague the infection is in the lungs, in bubonic plague the lymph nodes , and in septicemic plague within the blood. Diagnosis is by testing the blood, sputum, or fluid from a lymph node. While vaccines are being developed, in most countries they are not yet commercially available. Prevention is by avoiding contact with infected rodents, people, or cats. It is recommended that those infected be isolated from others. Treatment of pneumonic plague is with antibiotics . Plague is present among rodents in Africa, the Americas, and Asia. Pneumonic plague is more serious and less common than bubonic plague. The total reported number of cases of all types of plague in 2013 was 783. Left untreated, pneumonic plague is always fatal. Some hypothesize that the pneumonic version of the plague was mainly responsible for the Black Death that resulted in approximately 75 - 200 million deaths in the 1300s. The most apparent symptom of pneumonic plague is coughing, often with hemoptysis (coughing up blood). With pneumonic plague, the first signs of illness are fever, headache, weakness and rapidly developing pneumonia with shortness of breath, chest pain, cough and sometimes bloody or watery sputum . The pneumonia progresses for two to four days and may cause respiratory failure and shock . Patients will die without early treatment, some within 36 hours. [ citation needed ] Initial pneumonic plague symptoms can often include the following: [ citation needed ] Rapidly developing pneumonia with: [ citation needed ]Pneumonic plague can be caused in two ways: primary, which results from the inhalation of aerosolized plague bacteria , or secondary, when septicemic plague spreads into lung tissue from the bloodstream. Pneumonic plague is not exclusively vector-borne like bubonic plague; instead, it can be spread from person to person. There have been cases of pneumonic plague resulting from the dissection or handling of contaminated animal tissue. This is one of the types of plague formerly known as the Black Death . Pneumonic plague is a very aggressive infection requiring early treatment, which must be given within 24 hours of first symptoms to reduce the risk of death. Streptomycin , gentamicin , tetracyclines and chloramphenicol are all able to kill the causative bacterium. [ citation needed ] Antibiotic treatment for seven days will protect people who have had direct, close contact with infected patients. Wearing a close-fitting surgical mask also protects against infection. The mortality rate from untreated pneumonic plague approaches 100%. Since 2002, the World Health Organization (WHO) has reported seven plague outbreaks, though some may go unreported because they often happen in remote areas. Between 1998 and 2009, nearly 24,000 cases have been reported, including about 2,000 deaths, in Africa, Asia, the Americas, and Eastern Europe. Ninety-eight percent of the world's cases occur in Africa. Two outbreaks occurred in the Democratic Republic of the Congo in 2005 and 2006. The outbreak in 2005 was only detected by looking back at blood samples. The total death toll was 111. In September 1994, India experienced an outbreak of plague that killed 50 and caused travel to New Delhi by air to be suspended until the outbreak was brought under control. The outbreak was feared to be much worse because the plague superficially resembles other common diseases such as influenza and bronchitis; over 200 people that had been quarantined were released when they did not test positive for the plague. All but two of the deaths occurred around the city of Surat . [ citation needed ] A major outbreak of the pneumonic plague occurred in Manchuria from 1910 to 1911, in what became known as the Manchurian plague , killing around 60,000 people. The Qing court dispatched Wu Lien-teh , a doctor educated at Cambridge University , to oversee disease control and treatment efforts. He made the novel observation that the disease was transmitted by air , and developed prototypical respirators to help prevent its spread. A second, less deadly outbreak occurred in 1920–21, killing approximately 9,300 people. The People's Republic of China has eradicated pneumonic plague from most parts of the country, but still reports occasional cases in remote western areas, where the disease is carried by rats and the marmots that live across the Himalayan plateau . Outbreaks can be caused when a person eats an infected marmot or comes into contact with fleas carried by rats. A 2006 WHO report from an international meeting on plague cited a Chinese government disease expert as saying that most cases of the plague in China's northwest occur when hunters are contaminated while skinning infected animals. The expert said at the time that, due to the region's remoteness, the disease killed more than half the infected people. The report also said that since the 1990s, there was a rise in plague cases in humans—from fewer than 10 in the 1980s to nearly 100 cases in 1996 and 254 in 2000. In September 2008, two people in East Tibet died of pneumonic plague. An outbreak of the disease in China began in August 2009 in Ziketan Town located in Qinghai Province . The town was sealed off and several people died as a result of the disease. According to spokesperson Vivian Tan of the WHO office in Beijing , "In cases like this [in August 2009], we encourage the authorities to identify cases, to investigate any suspicious symptoms among close contacts, and to treat confirmed cases as soon as possible. So far, they have done exactly that. There have been sporadic cases reported around the country in the last few years so the authorities do have the experience to deal with this." In September 2010, five cases of pneumonic plague were reported in Tibet. In July 2014, Chinese media reported one case found in Gansu. On 12 November 2019, It was announced that two people from the Chinese province of Inner Mongolia were diagnosed with pneumonic plague. They received treatment in Chaoyang District, Beijing , and authorities implemented preventative control measures. Later in November, a third case of plague was confirmed. A 55-year-old man was diagnosed with bubonic plague after eating wild rabbit in Inner Mongolia. The region's health commission says it has no evidence to suggest that this case is linked to the previous two. By the end of November, a fourth case was confirmed. Chinese health authorities reported a fresh case of bubonic plague in the country's northern Inner Mongolia region, bringing the total number of reported plague cases originating from Inner Mongolia to four. In August 2010, Peru's health minister Oscar Ugarte announced that an outbreak of plague had killed a 14-year-old boy and had infected at least 31 people in a northern coastal province. The boy died of bubonic plague on 26 July 2010. Ugarte stated that authorities were screening sugar and fish meal exports from Ascope Province , located about 325 miles (520 km) northwest of Lima , not far from the popular Chicama beach . Most of the infections in Peru were bubonic plague, with four cases of pneumonic plague. The first recorded plague outbreak in Peru was in 1903. Prior to the above case, the last known outbreak was in 1994, killing 35 people. In November 2013, an outbreak of plague occurred in the African island nation of Madagascar . As of 16 December, at least 89 people were infected, with 39 deaths with at least two cases involving pneumonic plague. However, as many as 90% of cases were later reported to have involved pneumonic plague. From 23 August to 30 September 2017, a total of 73 suspected, probable, and confirmed cases of pneumonic plague, including 17 deaths, were reported in Madagascar. The diagnosis was confirmed by the Institut Pasteur de Madagascar by a polymerase chain reaction test, while field health workers used a Rapid Diagnostic Test. The WHO and Institut Pasteur de Madagascar were both involved in administering antibiotic compounds and attempting to stop the spread of the disease. By mid-October, there were an estimated 684 confirmed cases of plague with 474 pneumonic, 156 bubonic and one septicemic. The remainder were not classified. At least 74 deaths have been ascribed to pneumonic plague. The outbreak officially ended on 26 November 2017 with 2,348 cases and 202 deaths officially reported. In the fall of 1924, an outbreak occurred in Los Angeles that killed 30 people. On 2 November 2007, wildlife biologist Eric York died of pneumonic plague in Grand Canyon National Park . York was exposed to the bacteria while conducting a necropsy on a cougar carcass. In 2014, the Colorado Department of Public Health and Environment confirmed that a Colorado man had been diagnosed with pneumonic plague, the first confirmed human case in Colorado in more than 10 years, and one of only 60 cases since 1957. The man was found to have the disease after the family dog died unexpectedly and a necropsy revealed that the disease was the cause. Three additional pneumonic plague cases were confirmed in Colorado before the outbreak ended. Two outbreaks occurred in the Democratic Republic of the Congo in 2005 and 2006. The outbreak in 2005 was only detected by looking back at blood samples. The total death toll was 111.In September 1994, India experienced an outbreak of plague that killed 50 and caused travel to New Delhi by air to be suspended until the outbreak was brought under control. The outbreak was feared to be much worse because the plague superficially resembles other common diseases such as influenza and bronchitis; over 200 people that had been quarantined were released when they did not test positive for the plague. All but two of the deaths occurred around the city of Surat . [ citation needed ]A major outbreak of the pneumonic plague occurred in Manchuria from 1910 to 1911, in what became known as the Manchurian plague , killing around 60,000 people. The Qing court dispatched Wu Lien-teh , a doctor educated at Cambridge University , to oversee disease control and treatment efforts. He made the novel observation that the disease was transmitted by air , and developed prototypical respirators to help prevent its spread. A second, less deadly outbreak occurred in 1920–21, killing approximately 9,300 people. The People's Republic of China has eradicated pneumonic plague from most parts of the country, but still reports occasional cases in remote western areas, where the disease is carried by rats and the marmots that live across the Himalayan plateau . Outbreaks can be caused when a person eats an infected marmot or comes into contact with fleas carried by rats. A 2006 WHO report from an international meeting on plague cited a Chinese government disease expert as saying that most cases of the plague in China's northwest occur when hunters are contaminated while skinning infected animals. The expert said at the time that, due to the region's remoteness, the disease killed more than half the infected people. The report also said that since the 1990s, there was a rise in plague cases in humans—from fewer than 10 in the 1980s to nearly 100 cases in 1996 and 254 in 2000. In September 2008, two people in East Tibet died of pneumonic plague. An outbreak of the disease in China began in August 2009 in Ziketan Town located in Qinghai Province . The town was sealed off and several people died as a result of the disease. According to spokesperson Vivian Tan of the WHO office in Beijing , "In cases like this [in August 2009], we encourage the authorities to identify cases, to investigate any suspicious symptoms among close contacts, and to treat confirmed cases as soon as possible. So far, they have done exactly that. There have been sporadic cases reported around the country in the last few years so the authorities do have the experience to deal with this." In September 2010, five cases of pneumonic plague were reported in Tibet. In July 2014, Chinese media reported one case found in Gansu. On 12 November 2019, It was announced that two people from the Chinese province of Inner Mongolia were diagnosed with pneumonic plague. They received treatment in Chaoyang District, Beijing , and authorities implemented preventative control measures. Later in November, a third case of plague was confirmed. A 55-year-old man was diagnosed with bubonic plague after eating wild rabbit in Inner Mongolia. The region's health commission says it has no evidence to suggest that this case is linked to the previous two. By the end of November, a fourth case was confirmed. Chinese health authorities reported a fresh case of bubonic plague in the country's northern Inner Mongolia region, bringing the total number of reported plague cases originating from Inner Mongolia to four. In August 2010, Peru's health minister Oscar Ugarte announced that an outbreak of plague had killed a 14-year-old boy and had infected at least 31 people in a northern coastal province. The boy died of bubonic plague on 26 July 2010. Ugarte stated that authorities were screening sugar and fish meal exports from Ascope Province , located about 325 miles (520 km) northwest of Lima , not far from the popular Chicama beach . Most of the infections in Peru were bubonic plague, with four cases of pneumonic plague. The first recorded plague outbreak in Peru was in 1903. Prior to the above case, the last known outbreak was in 1994, killing 35 people. In November 2013, an outbreak of plague occurred in the African island nation of Madagascar . As of 16 December, at least 89 people were infected, with 39 deaths with at least two cases involving pneumonic plague. However, as many as 90% of cases were later reported to have involved pneumonic plague. From 23 August to 30 September 2017, a total of 73 suspected, probable, and confirmed cases of pneumonic plague, including 17 deaths, were reported in Madagascar. The diagnosis was confirmed by the Institut Pasteur de Madagascar by a polymerase chain reaction test, while field health workers used a Rapid Diagnostic Test. The WHO and Institut Pasteur de Madagascar were both involved in administering antibiotic compounds and attempting to stop the spread of the disease. By mid-October, there were an estimated 684 confirmed cases of plague with 474 pneumonic, 156 bubonic and one septicemic. The remainder were not classified. At least 74 deaths have been ascribed to pneumonic plague. The outbreak officially ended on 26 November 2017 with 2,348 cases and 202 deaths officially reported. In the fall of 1924, an outbreak occurred in Los Angeles that killed 30 people. On 2 November 2007, wildlife biologist Eric York died of pneumonic plague in Grand Canyon National Park . York was exposed to the bacteria while conducting a necropsy on a cougar carcass. In 2014, the Colorado Department of Public Health and Environment confirmed that a Colorado man had been diagnosed with pneumonic plague, the first confirmed human case in Colorado in more than 10 years, and one of only 60 cases since 1957. The man was found to have the disease after the family dog died unexpectedly and a necropsy revealed that the disease was the cause. Three additional pneumonic plague cases were confirmed in Colorado before the outbreak ended.

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Bubonic plague

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Plague of Justinian

The plague of Justinian or Justinianic plague (AD 541–549) was an epidemic that afflicted the entire Mediterranean Basin, Europe, and the Near East, severely affecting the Sasanian Empire and the Byzantine Empire , especially Constantinople . The plague is named for the Byzantine Emperor Justinian I (r. 527–565), who according to his court historian Procopius contracted the disease and recovered in 542, at the height of the epidemic which killed about a fifth of the population in the imperial capital. The contagion arrived in Roman Egypt in 541, spread around the Mediterranean Sea until 544, and persisted in Northern Europe and the Arabian Peninsula until 549. By 543, the plague had spread to every corner of the empire. As the first episode of the first plague pandemic , it had profound economic, social, and political effects across Europe and the Near East and cultural and religious impact on Eastern Roman society. In 2013, researchers confirmed earlier speculation that the cause of the plague of Justinian was Yersinia pestis , the same bacterium responsible for the Black Death (1346–1353). Ancient and modern Yersinia pestis strains are closely related to the ancestor of the Justinian plague strain that has been found in the Tian Shan , a system of mountain ranges on the borders of Kyrgyzstan , Kazakhstan , and China , suggesting that the Justinian plague originated in or near that region. However, there would appear to be no mention of bubonic plague in China until the year 610. The Byzantine historian Procopius first reported the epidemic in 541 from the port of Pelusium , near Suez in Egypt. Two other first hand reports of the plague's ravages were by the Syriac church historian John of Ephesus and Evagrius Scholasticus , who was a child in Antioch at the time and later became a church historian. Evagrius was afflicted with the buboes associated with the disease but survived. During the disease's four returns in his lifetime, he lost his wife, a daughter and her child, other children, most of his servants and people from his country estate. According to contemporary sources, the outbreak in Constantinople was thought to have been carried to the city by infected rats on grain ships arriving from Egypt. To feed its citizens, the city and outlying communities imported large amounts of grain, mostly from Egypt. The rat population in Egypt thrived on feeding from the large granaries maintained by the government, and the fleas thrived as well. [ citation needed ] Procopius, in a passage closely modelled on Thucydides , recorded that at its peak the plague was killing 10,000 people in Constantinople daily, but the accuracy of the figure is in question, and the true number will probably never be known. He noted that because there was no room to bury the dead, bodies were left stacked in the open. Funeral rites were often left unattended to, and the entire city smelled like the dead. Given such circumstances, it is highly probable that a sudden increase in mortality rates may not have been as accurately recorded, hence why the overall death toll is based on an estimate. In his Secret History , he records the devastation in the countryside and reports the ruthless response by the hard-pressed Justinian: When pestilence swept through the whole known world and notably the Roman Empire, wiping out most of the farming community and of necessity leaving a trail of desolation in its wake, Justinian showed no mercy towards the ruined freeholders. Even then, he did not refrain from demanding the annual tax, not only the amount at which he assessed each individual, but also the amount for which his deceased neighbors were liable. As a result of the plague in the countryside, farmers could not take care of crops and the price of grain rose in Constantinople. Justinian had expended huge amounts of money for wars against the Vandals in the region of Carthage and the Ostrogoths ' kingdom in Italy . He had invested heavily in the construction of great churches, such as Hagia Sophia . As the empire tried to fund the projects, the plague caused tax revenues to decline through the massive number of deaths and the disruption of agriculture and trade. Justinian swiftly enacted new legislation to deal more efficiently with the glut of inheritance suits being brought as a result of victims dying intestate . The plague's long-term effects on European and Christian history were enormous. As the disease spread to port cities around the Mediterranean, the struggling Goths were reinvigorated and their conflict with Constantinople entered a new phase. The plague weakened the Byzantine Empire at a critical point, when Justinian's armies had nearly retaken all of Italy and the western Mediterranean coast; the evolving conquest would have reunited the core of the Western Roman Empire with the Eastern Roman Empire. Although the conquest occurred in 554, the reunification did not last long. In 568, the Lombards invaded Northern Italy , defeated the small Byzantine army that had been left behind and established the Kingdom of the Lombards . Gaul is known to have suffered severely from the plague, and plague victims at an early Anglo-Saxon burial site at Edix Hill near Cambridge show that it also reached Britain. The Plague of Justinian is the first and the best known outbreak of the first plague pandemic, which continued to recur until the middle of the 8th century. Some historians believe the first plague pandemic was one of the deadliest pandemics in history , resulting in the deaths of an estimated 15–100 million people during two centuries of recurrence, a death toll equivalent to 25–60% of Europe's population at the time of the first outbreak. Research published in 2019 argued that the 200-year-long pandemic's death toll and social effects have been exaggerated, comparing it to the modern third plague pandemic (1855–1960s). Furthermore, historians seek to play down the effects of the late-antique bubonic plague, arguing that our eyewitness accounts of the disease are hysterical in tone and misleading in effect. The Plague of Justinian is the first and the best known outbreak of the first plague pandemic, which continued to recur until the middle of the 8th century. Some historians believe the first plague pandemic was one of the deadliest pandemics in history , resulting in the deaths of an estimated 15–100 million people during two centuries of recurrence, a death toll equivalent to 25–60% of Europe's population at the time of the first outbreak. Research published in 2019 argued that the 200-year-long pandemic's death toll and social effects have been exaggerated, comparing it to the modern third plague pandemic (1855–1960s). Furthermore, historians seek to play down the effects of the late-antique bubonic plague, arguing that our eyewitness accounts of the disease are hysterical in tone and misleading in effect. The plague of Justinian is generally regarded as the first historically recorded epidemic of Yersinia pestis . This conclusion is based on historical descriptions of the clinical manifestations of the disease and the detection of Y. pestis DNA from human remains at ancient grave sites dated to that period. Genetic studies of modern and ancient Yersinia pestis DNA suggest that the origin of the Justinian plague was in Central Asia . The most basal or root level existing strains of the Yersinia pestis as a whole species are found in Qinghai , China . Other scholars contest that, rather than Central Asia, the specific strain that composed the Justinian plague began in sub-Saharan Africa, and that the plague was spread to the Mediterranean by merchants from the Kingdom of Aksum in East Africa. This point of origin aligns more with the general south–north spread of the disease from Egypt into the rest of the Mediterranean world. It also explains why Sassanid Persia saw a later development of the outbreak despite stronger trade links with Central Asia. After samples of DNA from Yersinia pestis were isolated from skeletons of Justinian plague victims in Germany, it was found that modern strains currently found in the Tian Shan mountain range system are most basal known in comparison with the Justinian plague strain. Additionally, a skeleton found in Tian Shan dating to around 180 AD and identified as an "early Hun" was found to contain DNA from Yersinia pestis closely related to the Tian Shan strain basal ancestor of the Justinian plague strain German samples. This finding suggests that the expansion of nomadic peoples who moved across the Eurasian steppe , such as the Xiongnu and the later Huns , had a role in spreading plague to West Eurasia from an origin in Central Asia. Earlier samples of Yersinia pestis DNA have been found in skeletons dating from 3000 to 800 BC, across West and East Eurasia. The strain of Yersinia pestis responsible for the Black Death , the devastating pandemic of bubonic plague , does not appear to be a direct descendant of the Justinian plague strain. However, the spread of Justinian plague may have caused the evolutionary radiation that gave rise to the currently extant 0ANT.1 clade of strains. The number of deaths is uncertain. Some modern scholars believe that the plague killed up to 5,000 people per day in Constantinople at the peak of the pandemic. According to one view, the initial plague ultimately killed perhaps 40% of the city's inhabitants and caused the deaths of up to a quarter of the human population of the Eastern Mediterranean . Frequent subsequent waves of the plague continued to strike throughout the 6th, 7th and 8th centuries, with the disease becoming more localized and less virulent. [ citation needed ] A revisionist view expressed by scholars such as Lee Mordechai and Merle Eisenberg argues that the mortality of the Justinian Plague was far lower than previously believed. They say that the plague might have caused high mortality in specific places, but it did not cause widespread demographic decline or decimate Mediterranean populations. According to them, any direct mid-to-long term effects of plague were minor. However, their position has been the subject of a concerted critique by Peter Sarris. Sarris challenged both their core methodology and their handling of the sources. Sarris also provides up-to-date discussion of the genetic evidence, including the suggestion that the plague may have entered Western Eurasia via more than one route, and perhaps struck England before Constantinople. The plague of Justinian is generally regarded as the first historically recorded epidemic of Yersinia pestis . This conclusion is based on historical descriptions of the clinical manifestations of the disease and the detection of Y. pestis DNA from human remains at ancient grave sites dated to that period. Genetic studies of modern and ancient Yersinia pestis DNA suggest that the origin of the Justinian plague was in Central Asia . The most basal or root level existing strains of the Yersinia pestis as a whole species are found in Qinghai , China . Other scholars contest that, rather than Central Asia, the specific strain that composed the Justinian plague began in sub-Saharan Africa, and that the plague was spread to the Mediterranean by merchants from the Kingdom of Aksum in East Africa. This point of origin aligns more with the general south–north spread of the disease from Egypt into the rest of the Mediterranean world. It also explains why Sassanid Persia saw a later development of the outbreak despite stronger trade links with Central Asia. After samples of DNA from Yersinia pestis were isolated from skeletons of Justinian plague victims in Germany, it was found that modern strains currently found in the Tian Shan mountain range system are most basal known in comparison with the Justinian plague strain. Additionally, a skeleton found in Tian Shan dating to around 180 AD and identified as an "early Hun" was found to contain DNA from Yersinia pestis closely related to the Tian Shan strain basal ancestor of the Justinian plague strain German samples. This finding suggests that the expansion of nomadic peoples who moved across the Eurasian steppe , such as the Xiongnu and the later Huns , had a role in spreading plague to West Eurasia from an origin in Central Asia. Earlier samples of Yersinia pestis DNA have been found in skeletons dating from 3000 to 800 BC, across West and East Eurasia. The strain of Yersinia pestis responsible for the Black Death , the devastating pandemic of bubonic plague , does not appear to be a direct descendant of the Justinian plague strain. However, the spread of Justinian plague may have caused the evolutionary radiation that gave rise to the currently extant 0ANT.1 clade of strains. The number of deaths is uncertain. Some modern scholars believe that the plague killed up to 5,000 people per day in Constantinople at the peak of the pandemic. According to one view, the initial plague ultimately killed perhaps 40% of the city's inhabitants and caused the deaths of up to a quarter of the human population of the Eastern Mediterranean . Frequent subsequent waves of the plague continued to strike throughout the 6th, 7th and 8th centuries, with the disease becoming more localized and less virulent. [ citation needed ] A revisionist view expressed by scholars such as Lee Mordechai and Merle Eisenberg argues that the mortality of the Justinian Plague was far lower than previously believed. They say that the plague might have caused high mortality in specific places, but it did not cause widespread demographic decline or decimate Mediterranean populations. According to them, any direct mid-to-long term effects of plague were minor. However, their position has been the subject of a concerted critique by Peter Sarris. Sarris challenged both their core methodology and their handling of the sources. Sarris also provides up-to-date discussion of the genetic evidence, including the suggestion that the plague may have entered Western Eurasia via more than one route, and perhaps struck England before Constantinople.

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Bubonic plague

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Bombay plague epidemic

The Bombay plague epidemic was a bubonic plague epidemic that struck the city of Bombay (present-day Mumbai) in the late nineteenth century. The plague killed thousands, and many fled the city, leading to a drastic fall in the population of the city. In September 1896, Bombay's municipal administration declared the presence of bubonic plague in the city. The administration of ineffective protocols furthered the spread. By January 1897, half the population fled to the countryside.The bubonic plague's arrival in Bombay in the summer of 1896 was part of a deadly pandemic that had originated in China in the 1850s and continued to afflict many parts of the globe until the 1950s. Bombay was made vulnerable by the rapid growth of the city's commerce, which led to a large influx of workers. In the 1891 census, the population of Bombay was counted to be 820,000. Most of the immigrant workers (over 70%) lived in chawls . The city services were not geared towards the well-being of the working class and various diseases were endemic to the slums. Workers in cotton mills, as one of the major social fractions within the city, and as the bedrock of its trade, played a major role in the making of this crisis. The difficulties of sanitary administration arise from the rapidity of decomposition of organic matter, the density of population, and the primitive habits of the people, which have never been brought in line with the necessities of a closely inhabited town having in certain wards a density of 700 per acre.In September 1896, the first case of bubonic plague was detected in Mandvi by Dr. Acacio Gabriel Viegas . It spread rapidly to other parts of the city, and the death toll was estimated at 1,900 people per week through the rest of the year. By March 1897, municipal authorities believed around 20,000 people had died. The epidemic peaked in early 1897, and had a mortality rate of 75–85%. Many people fled from Bombay at this time, and in the census of 1901, the population had actually fallen to 780,000. Viegas correctly diagnosed the disease as bubonic plague and tended to patients at great personal risk. He then launched a vociferous campaign to clean up slums and exterminate rats, the carriers of the fleas which spread the plague bacterium. To confirm Viegas' findings, four teams of independent experts were brought in. With his diagnosis proving to be correct, the Governor of Bombay invited W M Haffkine , who had earlier formulated a vaccine for cholera , to do the same for the epidemic. Those who could afford it tried to avoid the plague by moving out of the city. Jamsetji Tata tried to open up the northern suburbs to accommodate such people. The brunt of the plague was borne by mill workers. The anti-plague activities of the health department involved police searches, isolation of the sick, detention in camps of travellers and forced evacuation of residents in parts of the city. These measures were widely regarded as offensive and alarming. The extent of this outrage was demonstrated with the murder of W.C. Rand , British chairman of the Special Plague Committee. He was murdered by the Chapekar brothers , two Indian revolutionaries angered by the intrusive methods employed by the British to combat the plague in Pune . In 1900, the mortality rate from plague was about 22 per thousand. In the same year, the corresponding rates from tuberculosis were 12 per thousand, from cholera about 14 per thousand, and about 22 per thousand from various other illnesses classified as "fevers". The plague was fearsome only because it was apparently contagious. More mundane diseases took a larger toll. In the city of Bombay, the epidemic had caused 10,606 deaths in the winter of 1896.Authorities in Bombay, working to British Governor William Mansfield, were initially reluctant to acknowledge that the plague had reached their city, and may have been motivated by wanting to preserve Bombay's status as a trading hub. Viceroy of India, Lord Elgin, feared that harsh medical measures may cause a violent backlash against the British authorities. But as the plague worsened, Lord Hamilton, Secretary of State for India, challenged Viceroy Elgin's cautious approach. By the spring of 1897, it was agreed that strict rules would be put in place to curb the epidemic. Brigadier General William Gatacre of the Indian Army was put in charge, and given martial authority in the city. The British Parliament also passed legislation, including the Epidemic Diseases Act, which gave Gatacre license for draconian actions. In the first year of the plague, a research laboratory was set up at the JJ Hospital . It moved in 1899 to the Government House in Parel under the directorship of Haffkine. This was the beginning of the Haffkine Institute . During the plague epidemic 1897 in Bombay a medical commission of the Austrian Academy of Sciences carried out clinical, pathologic-anatomical, -histological and bacteriological investigations. On 9 December 1898, the City of Bombay Improvement Trust (BIT) was created. The Trust was tasked with "making new streets, opening out crowded localities, reclaiming lands from the sea to provide room for the expansion of the city, and the construction of sanitary dwellings for the poor." It was entrusted with the job of creating a healthier city. One of the measures taken by the CIT was the building of roads, like Princess Street and Sydenham Road (now Mohammedali Road), which would channel the sea air into the more crowded parts of the city. The Trust also implemented anti-epidemic building regulations, such as the "63.5 degree light angle rule," which determined the distance between a building and its boundary wall to allow improved light and ventilation. Many of the iconic Art Deco-style buildings that adorn present-day Mumbai's streets were built in accordance with these plague regulations.

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Bubonic plague

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Great Plague of London

The Great Plague of London , lasting from 1665 to 1666, was the last major epidemic of the bubonic plague to occur in England . It happened within the centuries-long Second Pandemic , a period of intermittent bubonic plague epidemics that originated in Central Asia in 1331 (the first year of the Black Death ), and included related diseases such as pneumonic plague and septicemic plague , which lasted until 1750. The Great Plague killed an estimated 100,000 people—almost a quarter of London's population—in 18 months. The plague was caused by the Yersinia pestis bacterium , which is usually transmitted to a human by the bite of a flea or louse. The 1665–66 epidemic was on a much smaller scale than the earlier Black Death pandemic . It became known afterwards as the "great" plague mainly because it was the last widespread outbreak of bubonic plague in England during the 400-year Second Pandemic. The plague was endemic in 17th-century London, as it was in other European cities at the time. The disease periodically erupted into massive epidemics. There were 30,000 deaths due to the plague in 1603, 35,000 in 1625, 10,000 in 1636, and smaller numbers in other years. In late 1664, a bright comet was seen in the sky, and the people of London became fearful, wondering what evil event it portended. London at that time was a city of about 448 acres surrounded by a city wall that had originally been built to keep out raiding bands, and, in the south, by the River Thames . There were gates in the wall at Ludgate , Newgate , Aldersgate , Cripplegate , Moorgate , Bishopsgate and Aldgate , and the Thames was crossable at London Bridge . In the poorer parts of the city, filled with overcrowded tenements and garrets, hygiene was impossible to maintain. There was no sanitation, and open drains flowed along the centre of winding streets. The cobbles were slippery with animal droppings, rubbish and the slops thrown out of the houses; they were muddy and buzzing with flies in summer, and awash with sewage in winter. The City Corporation employed "rakers" to remove the worst of the filth, and it was transported to mounds outside the walls, where it accumulated and continued to decompose. The stench was overwhelming, and people walked around with handkerchiefs or nosegays pressed against their nostrils. Some of the city's necessities, such as coal, arrived by barge , but most came by road. Carts, carriages, horses and pedestrians were crowded together, and the gateways in the wall formed bottlenecks through which it was difficult to progress. The nineteen-arch London Bridge was even more congested. Those who were better-off used hackney carriages and sedan chairs to get to their destinations without getting filthy. The poor walked, and might be drenched by water tossed up by wheeled vehicles, slops thrown into the street, or water pouring off overhanging roofs. Another hazard was the choking black smoke belching forth from soap factories, breweries , iron smelters and about 15,000 households that were burning coal to heat their homes. Outside the city walls, shanty towns with wooden shacks and no sanitation had sprung up, providing homes for the craftsmen and tradespeople who had flocked to the already overcrowded city. The government had tried to limit the development of these "suburbs", but had failed: Over a quarter of a million people lived in them. When Royalists had fled the country during the Commonwealth , they had left many fine town houses vacant, and some immigrants to London had crowded into them, converting them into tenements that housed different families in every room. These properties were soon vandalised and became rat-infested. The City of London proper was administered by the Lord Mayor, the Aldermen and the common councillors, but some parts of the greater metropolitan area were not legally part of the city. Some of these areas, both inside the City walls and outside its boundaries, had long been organised into districts of various sizes, called " liberties ", that had historically been granted rights to self-government. (Many had originally been associated with the religious institutions that were abolished in the Dissolution of the Monasteries , whereupon their historic rights and property had been transferred to secular owners.) By 1665, the walled City was surrounded by a ring of liberties which had come under its authority, and these had come to be referred to collectively as 'the City and Liberties'. However, this area was surrounded by additional suburbs with other independent administrations. For example, Westminster was an independent town with its own liberties, joined to London by urban development, and the Tower of London was an independent liberty. Areas that were not part of any of these various independent administrations came under the authority of the county of Middlesex if they were north of the river, and under the authority of Surrey if they were south of the river. At that time, bubonic plague was a much feared disease, but its cause was not understood. Many mistakenly blamed emanations from the earth, "pestilential effluvia", unusual weather, sickness in livestock, abnormal behaviour of animals or an increase in the numbers of moles, frogs, mice or flies. It was not until 1894 that its causal agent, the bacterium Yersinia pestis , was identified by Alexandre Yersin , and its transmission by rat fleas became known. Although the Great Plague in London was long assumed to be bubonic plague, caused by Yersinia pestis , this was only confirmed (by DNA analysis) in 2016. It is now believed that human body lice also played a key role in causing infections, perhaps more so than rats. In order to judge the severity of an epidemic, it is first necessary to know how big the population was in which it occurred. There was no official census of the population to provide this figure, and the best contemporary count comes from the work of John Graunt (1620–1674), who was one of the earliest Fellows of the Royal Society and one of the first demographers , bringing a scientific approach to the collection of statistics. In 1662, he estimated that 384,000 people lived in the City of London, the Liberties, Westminster and the out-parishes, based on figures in the Bills of Mortality published each week in the capital. These different districts with different administrations constituted the officially recognized extent of London as a whole. In 1665, he revised his estimate to "not above 460,000". Other contemporaries put the figure higher (the French Ambassador, for example, suggested 600,000), but with no mathematical basis to support their estimates. The next largest city in the kingdom was Norwich , with a population of 30,000. There was no duty to report a death to anyone in authority. Instead, each parish appointed two or more " searchers of the dead ", whose duty was to inspect a corpse and determine the cause of death. A searcher was entitled to charge a small fee from relatives for each death they reported, and so habitually the parish would appoint someone to the post who would otherwise be destitute and would be receiving support from the parish poor rate. Typically, this meant searchers would be old women who were illiterate, might know little about identifying diseases and who would be open to dishonesty. Searchers would typically learn about a death either from the local sexton who had been asked to dig a grave or from the tolling of a church bell. Anyone who did not report a death to their local church, such as Quakers , Anabaptists , other non-Anglican Christians or Jews , frequently did not get included in the official records. Searchers during times of plague were required to live apart from the community, avoid other people and carry a white stick to warn of their occupation when outdoors, and stay indoors except when performing their duties, to avoid spreading the diseases. Searchers reported to the Parish Clerk, who made a return each week to the Company of Parish Clerks in Brode Lane. Figures were then passed to the Lord Mayor and then to the Minister of State once plague became a matter of national concern. The reported figures were used to compile the Bills of Mortality, which listed total deaths in each parish and whether by the plague. The system of Searchers to report the cause of death continued until 1836. Graunt recorded the incompetence of the Searchers at identifying true causes of death, remarking on the frequent recording of 'consumption' rather than other diseases which were recognized then by physicians. He suggested a cup of ale and a doubling of their fee to two groats rather than one was sufficient for Searchers to change the cause of death to one more convenient for the householders. No one wished to be known as having had a death by plague in their household, and Parish Clerks, too, connived in covering up cases of plague in their official returns. Analysis of the Bills of Mortality during the months plague took hold shows a rise in deaths other than by plague well above the average death rate, a tell-tale sign of misrepresentation of the true cause of death. As plague spread, a system of quarantine was introduced, whereby any house where someone had died from plague would be locked up and no one allowed to enter or leave for 40 days. This frequently led to the deaths of the other inhabitants, by neglect if not from the plague, and provided ample incentive not to report the disease. The official returns record 68,596 cases of plague, but a reasonable estimate suggests this figure is 30,000 short of the true total. A plague house was marked with a red cross on the door with the words "Lord have mercy upon us", and a watchman stood guard outside. Reports of plague around Europe began to reach England in the 1660s, causing the Privy Council to consider what steps might be taken to prevent it crossing to England. Quarantining (isolation) of ships had been used during previous outbreaks and was again introduced for ships coming to London in November 1663, following outbreaks in Amsterdam and Hamburg . Two naval ships were assigned to intercept any vessels entering the Thames estuary. Ships from infected ports were required to moor at Hole Haven on Canvey Island for a trentine – period of 30 days – before being allowed to travel up-river. Ships from ports free of plague or completing their isolation period were given a certificate of health and allowed to travel on. A second inspection line was established between the forts on opposite banks of the Thames at Tilbury and Gravesend with instructions to pass only ships with a certificate. The isolation period was increased to forty days – a quarantine – in May 1664 as the continental plague worsened, and the areas subject to quarantine changed with the news of the spread of plague to include all of Holland , Zeeland and Friesland (all regions of the Dutch Republic ); restrictions on Hamburg were removed in November. Quarantine measures against ships coming from the Dutch Republic were put in place in 29 other ports from May, starting with Great Yarmouth . The Dutch ambassador objected at the constraint of trade with his country, but England responded that it had been one of the last countries introducing such restrictions. Regulations were enforced quite strictly, so that people or houses where voyagers had come ashore without serving their quarantine were also subjected to 40 days of quarantine. Plague was one of the hazards of life in Britain from its dramatic appearance in 1348 with the Black Death. The Bills of Mortality began to be published regularly in 1603, in which year 33,347 deaths were recorded from plague. Between then and 1665, only four years had no recorded cases. In 1563, a thousand people were reportedly dying in London each week. In 1593, there were 15,003 deaths, 1625 saw 41,313 dead, between 1640 and 1646 came 11,000 deaths, culminating in 3,597 for 1647. The 1625 outbreak was recorded at the time as the 'Great Plague', until deaths from the plague of 1665 surpassed it. These official figures are likely to under-report actual numbers. Plague was sufficiently uncommon that medical practitioners might have had no personal experience of seeing the disease; medical training varied from those who had attended the college of physicians, to apothecaries who also acted as doctors, to charlatans. Other diseases abounded, such as an outbreak of smallpox the year before, and these uncertainties all added to difficulties identifying the true start of the epidemic. Contemporary accounts suggest cases of plague occurred through the winter of 1664–65, some of which were fatal but a number of which did not display the virulence of the later epidemic. The winter was cold, the ground frozen from December to March, river traffic on the Thames twice blocked by ice, and it may be that the cold weather held back its spread. This outbreak of bubonic plague in England is thought to have spread from the Netherlands, where the disease had been occurring intermittently since 1599. It is unclear exactly where the disease first struck but the initial contagion may have arrived with Dutch trading ships carrying bales of cotton from Amsterdam , which was ravaged by the disease in 1663–64, with a mortality given of 50,000. The first areas to be struck are believed to be the dock areas just outside London, and the parish of St Giles . In both of these localities, poor workers were crowded into ill-kept structures. Two suspicious deaths were recorded in St Giles parish in 1664 and another in February 1665. These did not appear as plague deaths on the Bills of Mortality, so no control measures were taken by the authorities, but the total number of people dying in London during the first four months of 1665 showed a marked increase. By the end of April, only four plague deaths had been recorded, two in the parish of St. Giles, but total deaths per week had risen from around 290 to 398. There had been three official cases in April, a level of plague which in earlier years had not induced any official response, but the Privy Council now acted to introduce household quarantine. Justices of the Peace in Middlesex were instructed to investigate any suspected cases and to shut up the house if it was confirmed. Shortly after, a similar order was issued by the King's Bench to the City and Liberties. A riot broke out in St. Giles when the first house was sealed up; the crowd broke down the door and released the inhabitants. Rioters caught were punished severely. Instructions were given to build pest-houses, which were essentially isolation hospitals built away from other people where the sick could be cared for (or stay until they died). This official activity suggests that despite the few recorded cases, the government was already aware that this was a serious outbreak of plague. With the arrival of warmer weather, the disease began to take a firmer hold. In the week 2–9 May, there were three recorded deaths in the parish of St Giles, four in neighbouring St Clement Danes and one each in St Andrew Holborn and St Mary Woolchurch Haw . Only the last was actually inside the city walls. A Privy Council committee was formed to investigate methods to best prevent the spread of plague, and measures were introduced to close some of the ale houses in affected areas and limit the number of lodgers allowed in a household. In the city, the Lord Mayor issued a proclamation that all householders must diligently clean the streets outside their property, which was a householder's responsibility, not a state one (the city employed scavengers and rakers to remove the worst of the mess). Matters just became worse, and Aldermen were instructed to find and punish those failing their duty. As cases in St. Giles began to rise, an attempt was made to quarantine the area and constables were instructed to inspect everyone wishing to travel and contain inside vagrants or suspect persons. People began to be alarmed. Samuel Pepys , who had an important position at the Admiralty , stayed in London and provided a contemporary account of the plague through his diary. On 30 April he wrote: "Great fears of the sickness here in the City it being said that two or three houses are already shut up. God preserve us all!" Another source of information on the time is A Journal of the Plague Year , which was written by Daniel Defoe and published in 1722. He had been only five when the plague struck but made use of his family's recollections (his uncle was a saddler in East London and his father a butcher in Cripplegate ), interviews with survivors and sight of such official records as were available. The onset of the disease was recalled two years later by Puritan minister Thomas Vincent : It was in the month of May that the Plague was first taken notice of; our Bill of Mortality did let us know but of three which died of the disease in the whole year before; but in the beginning of May the bill tells us of nine...fear quickly begins to creep upon peoples hearts; great thoughts and discourse there is in Town about the Plague, and they cast in their minds whether they should go if the Plague should increase. Yet when the next weeks Bill signifieth to them the disease from nine to three their minds are something appeased; discourse of that subject cools; fears are hushed, and hopes take place, that the black cloud did but threaten, and give a few drops; but the wind would drive it away. But when in the next Bill the number of the dead by the Plague is mounted from three to fourteen, and in the next to seventeen, and in the next to forty-three, and the disease begins so much to increase, and disperse. Now secure sinners begin to be startled, and those who would have slept at quiet still in their nests, are unwillingly awakened. By July 1665, plague was rampant in the City of London. The rich ran away, including King Charles II of England , his family and his court, who left the city for Salisbury , moving on to Oxford in September when some cases of plague occurred in Salisbury. The aldermen and most of the other city authorities opted to stay at their posts. The Lord Mayor of London , Sir John Lawrence , also decided to stay in the city. Businesses were closed when merchants and professionals fled. Defoe wrote "Nothing was to be seen but wagons and carts, with goods, women, servants, children, coaches filled with people of the better sort, and horsemen attending them, and all hurrying away". As the plague raged throughout the summer, only a small number of clergymen , physicians and apothecaries remained to cope with an increasingly large number of victims. Ellen Cotes, author of London's Dreadful Visitation , expressed the hope that "Neither the Physicians of our Souls or Bodies may hereafter in such great numbers forsake us". The poorer people were also alarmed by the contagion and some left the city, but it was not easy for them to abandon their accommodation and livelihoods for an uncertain future elsewhere. Before exiting through the city gates, they were required to possess a certificate of good health signed by the Lord Mayor and these became increasingly difficult to obtain. As time went by and the numbers of plague victims rose, people living in the villages outside London began to resent this exodus and were no longer prepared to accept townsfolk from London, with or without a certificate. The refugees were turned back, were not allowed to pass through towns and had to travel across country, and were forced to live rough on what they could steal or scavenge from the fields. Many died in wretched circumstances of starvation and dehydration in the hot summer that was to follow. In the last week of July, the London Bill of Mortality showed 3,014 deaths, of which 2,020 had died from the plague. The number of deaths as a result of plague may have been underestimated, as deaths in other years in the same period were much lower, at around 300. As the number of victims affected mounted up, burial grounds became overfull, and pits were dug to accommodate the dead. Drivers of dead-carts travelled the streets calling "Bring out your dead" and carted away piles of bodies. The authorities became concerned that the number of deaths might cause public alarm and ordered that body removal and interment should take place only at night. As time went on, there were too many victims, and too few drivers, to remove the bodies which began to be stacked up against the walls of houses. Daytime collection was resumed and the plague pits became mounds of decomposing corpses. In the parish of Aldgate, a great hole was dug near the churchyard, fifty feet long and twenty feet wide. Digging was continued by labourers at one end while the dead-carts tipped in corpses at the other. When there was no room for further extension it was dug deeper until ground water was reached at twenty feet. When finally covered with earth it housed 1,114 corpses. Plague doctors traversed the streets diagnosing victims, many of them without formal medical training. Several public health efforts were attempted. Physicians were hired by city officials and burial details were carefully organized, but panic spread through the city and, out of the fear of contagion, bodies were hastily buried in overcrowded pits. The means of transmission of the disease were not known but thinking they might be linked to the animals, the City Corporation ordered a cull of dogs and cats. This decision may have affected the length of the epidemic since those animals could have helped keep in check the rat population carrying the fleas which transmitted the disease. Thinking bad air was involved in transmission, the authorities ordered giant bonfires to be burned in the streets and house fires to be kept burning night and day, in the hope that the air would be cleansed. Tobacco was thought to be a prophylactic and it was later said that no London tobacconist had died from the plague during the epidemic. Trade and business had dried up, and the streets were empty of people except for the dead-carts and the dying victims, as witnessed and recorded by Samuel Pepys in his diary: "Lord! How empty the streets are and how melancholy, so many poor sick people in the streets full of sores… in Westminster, there is never a physician and but one apothecary left, all being dead." That people did not starve was down to the foresight of Sir John Lawrence and the Corporation of London who arranged for a commission of one farthing to be paid above the normal price for every quarter of corn landed in the Port of London. Another food source was the villages around London which, denied of their usual sales in the capital, left vegetables in specified market areas, negotiated their sale by shouting, and collected their payment after the money had been left submerged in a bucket of vinegar to "disinfect" the coins. Records state that plague deaths in London and the suburbs crept up over the summer from 2,000 people per week to over 7,000 per week in September. These figures are likely to be a considerable underestimate. Many of the sextons and parish clerks who kept the records themselves died. Quakers refused to co-operate and many of the poor were just dumped into mass graves unrecorded. It is not clear how many people caught the disease and made a recovery because only deaths were recorded and many records were destroyed in the Great Fire of London the following year. In the few districts where intact records remain, plague deaths varied between 30% and over 50% of the total population. Vincent wrote: it was very dismal to behold the red crosses, and read in great letters "LORD, HAVE MERCY UPON US" on the doors, and watchmen standing before them with halberds...people passing by them so gingerly, and with such fearful looks as if they had been lined with enemies in ambush to destroy them...a man at the corner of Artillery-wall, that as I judge, through the dizziness of his head with the disease, which seized upon him there, had dasht his face against the wall; and when I came by, he lay hanging with his bloody face over the rails, and bleeding upon the ground...I went and spoke to him; he could make no answer, but rattled in the throat, and as I was informed, within half an hour died in the place. It would be endless to speak of what we have seen and heard, of some in their frenzy, rising out of their beds, and leaping about their rooms; others crying and roaring at their windows; some coming forth almost naked, and running into the streets...scarcely a day passed over my head for, I think, a month or more together, but I should hear of the death of some one or more that I knew. The first day that they were smitten, the next day some hopes of recovery, and the third day, that they were dead. The outbreak was concentrated in London, but it affected other areas as well. Perhaps the best known example occurred in the village of Eyam in Derbyshire . The plague allegedly arrived with a merchant carrying a parcel of cloth sent from London. The villagers imposed a quarantine on themselves to stop the further spread of the disease. This prevented the disease from moving into surrounding areas, but around 33% of the village's inhabitants died over a period of fourteen months. Other places hit hard included Derby and Norwich . In Bristol strenuous efforts by the City Council seems to have limited the death rate to c.0.6 per cent during an outbreak lasting from April to September 1666. Plague was sufficiently uncommon that medical practitioners might have had no personal experience of seeing the disease; medical training varied from those who had attended the college of physicians, to apothecaries who also acted as doctors, to charlatans. Other diseases abounded, such as an outbreak of smallpox the year before, and these uncertainties all added to difficulties identifying the true start of the epidemic. Contemporary accounts suggest cases of plague occurred through the winter of 1664–65, some of which were fatal but a number of which did not display the virulence of the later epidemic. The winter was cold, the ground frozen from December to March, river traffic on the Thames twice blocked by ice, and it may be that the cold weather held back its spread. This outbreak of bubonic plague in England is thought to have spread from the Netherlands, where the disease had been occurring intermittently since 1599. It is unclear exactly where the disease first struck but the initial contagion may have arrived with Dutch trading ships carrying bales of cotton from Amsterdam , which was ravaged by the disease in 1663–64, with a mortality given of 50,000. The first areas to be struck are believed to be the dock areas just outside London, and the parish of St Giles . In both of these localities, poor workers were crowded into ill-kept structures. Two suspicious deaths were recorded in St Giles parish in 1664 and another in February 1665. These did not appear as plague deaths on the Bills of Mortality, so no control measures were taken by the authorities, but the total number of people dying in London during the first four months of 1665 showed a marked increase. By the end of April, only four plague deaths had been recorded, two in the parish of St. Giles, but total deaths per week had risen from around 290 to 398. There had been three official cases in April, a level of plague which in earlier years had not induced any official response, but the Privy Council now acted to introduce household quarantine. Justices of the Peace in Middlesex were instructed to investigate any suspected cases and to shut up the house if it was confirmed. Shortly after, a similar order was issued by the King's Bench to the City and Liberties. A riot broke out in St. Giles when the first house was sealed up; the crowd broke down the door and released the inhabitants. Rioters caught were punished severely. Instructions were given to build pest-houses, which were essentially isolation hospitals built away from other people where the sick could be cared for (or stay until they died). This official activity suggests that despite the few recorded cases, the government was already aware that this was a serious outbreak of plague. With the arrival of warmer weather, the disease began to take a firmer hold. In the week 2–9 May, there were three recorded deaths in the parish of St Giles, four in neighbouring St Clement Danes and one each in St Andrew Holborn and St Mary Woolchurch Haw . Only the last was actually inside the city walls. A Privy Council committee was formed to investigate methods to best prevent the spread of plague, and measures were introduced to close some of the ale houses in affected areas and limit the number of lodgers allowed in a household. In the city, the Lord Mayor issued a proclamation that all householders must diligently clean the streets outside their property, which was a householder's responsibility, not a state one (the city employed scavengers and rakers to remove the worst of the mess). Matters just became worse, and Aldermen were instructed to find and punish those failing their duty. As cases in St. Giles began to rise, an attempt was made to quarantine the area and constables were instructed to inspect everyone wishing to travel and contain inside vagrants or suspect persons. People began to be alarmed. Samuel Pepys , who had an important position at the Admiralty , stayed in London and provided a contemporary account of the plague through his diary. On 30 April he wrote: "Great fears of the sickness here in the City it being said that two or three houses are already shut up. God preserve us all!" Another source of information on the time is A Journal of the Plague Year , which was written by Daniel Defoe and published in 1722. He had been only five when the plague struck but made use of his family's recollections (his uncle was a saddler in East London and his father a butcher in Cripplegate ), interviews with survivors and sight of such official records as were available. The onset of the disease was recalled two years later by Puritan minister Thomas Vincent : It was in the month of May that the Plague was first taken notice of; our Bill of Mortality did let us know but of three which died of the disease in the whole year before; but in the beginning of May the bill tells us of nine...fear quickly begins to creep upon peoples hearts; great thoughts and discourse there is in Town about the Plague, and they cast in their minds whether they should go if the Plague should increase. Yet when the next weeks Bill signifieth to them the disease from nine to three their minds are something appeased; discourse of that subject cools; fears are hushed, and hopes take place, that the black cloud did but threaten, and give a few drops; but the wind would drive it away. But when in the next Bill the number of the dead by the Plague is mounted from three to fourteen, and in the next to seventeen, and in the next to forty-three, and the disease begins so much to increase, and disperse. Now secure sinners begin to be startled, and those who would have slept at quiet still in their nests, are unwillingly awakened. By July 1665, plague was rampant in the City of London. The rich ran away, including King Charles II of England , his family and his court, who left the city for Salisbury , moving on to Oxford in September when some cases of plague occurred in Salisbury. The aldermen and most of the other city authorities opted to stay at their posts. The Lord Mayor of London , Sir John Lawrence , also decided to stay in the city. Businesses were closed when merchants and professionals fled. Defoe wrote "Nothing was to be seen but wagons and carts, with goods, women, servants, children, coaches filled with people of the better sort, and horsemen attending them, and all hurrying away". As the plague raged throughout the summer, only a small number of clergymen , physicians and apothecaries remained to cope with an increasingly large number of victims. Ellen Cotes, author of London's Dreadful Visitation , expressed the hope that "Neither the Physicians of our Souls or Bodies may hereafter in such great numbers forsake us". The poorer people were also alarmed by the contagion and some left the city, but it was not easy for them to abandon their accommodation and livelihoods for an uncertain future elsewhere. Before exiting through the city gates, they were required to possess a certificate of good health signed by the Lord Mayor and these became increasingly difficult to obtain. As time went by and the numbers of plague victims rose, people living in the villages outside London began to resent this exodus and were no longer prepared to accept townsfolk from London, with or without a certificate. The refugees were turned back, were not allowed to pass through towns and had to travel across country, and were forced to live rough on what they could steal or scavenge from the fields. Many died in wretched circumstances of starvation and dehydration in the hot summer that was to follow. In the last week of July, the London Bill of Mortality showed 3,014 deaths, of which 2,020 had died from the plague. The number of deaths as a result of plague may have been underestimated, as deaths in other years in the same period were much lower, at around 300. As the number of victims affected mounted up, burial grounds became overfull, and pits were dug to accommodate the dead. Drivers of dead-carts travelled the streets calling "Bring out your dead" and carted away piles of bodies. The authorities became concerned that the number of deaths might cause public alarm and ordered that body removal and interment should take place only at night. As time went on, there were too many victims, and too few drivers, to remove the bodies which began to be stacked up against the walls of houses. Daytime collection was resumed and the plague pits became mounds of decomposing corpses. In the parish of Aldgate, a great hole was dug near the churchyard, fifty feet long and twenty feet wide. Digging was continued by labourers at one end while the dead-carts tipped in corpses at the other. When there was no room for further extension it was dug deeper until ground water was reached at twenty feet. When finally covered with earth it housed 1,114 corpses. Plague doctors traversed the streets diagnosing victims, many of them without formal medical training. Several public health efforts were attempted. Physicians were hired by city officials and burial details were carefully organized, but panic spread through the city and, out of the fear of contagion, bodies were hastily buried in overcrowded pits. The means of transmission of the disease were not known but thinking they might be linked to the animals, the City Corporation ordered a cull of dogs and cats. This decision may have affected the length of the epidemic since those animals could have helped keep in check the rat population carrying the fleas which transmitted the disease. Thinking bad air was involved in transmission, the authorities ordered giant bonfires to be burned in the streets and house fires to be kept burning night and day, in the hope that the air would be cleansed. Tobacco was thought to be a prophylactic and it was later said that no London tobacconist had died from the plague during the epidemic. Trade and business had dried up, and the streets were empty of people except for the dead-carts and the dying victims, as witnessed and recorded by Samuel Pepys in his diary: "Lord! How empty the streets are and how melancholy, so many poor sick people in the streets full of sores… in Westminster, there is never a physician and but one apothecary left, all being dead." That people did not starve was down to the foresight of Sir John Lawrence and the Corporation of London who arranged for a commission of one farthing to be paid above the normal price for every quarter of corn landed in the Port of London. Another food source was the villages around London which, denied of their usual sales in the capital, left vegetables in specified market areas, negotiated their sale by shouting, and collected their payment after the money had been left submerged in a bucket of vinegar to "disinfect" the coins. Records state that plague deaths in London and the suburbs crept up over the summer from 2,000 people per week to over 7,000 per week in September. These figures are likely to be a considerable underestimate. Many of the sextons and parish clerks who kept the records themselves died. Quakers refused to co-operate and many of the poor were just dumped into mass graves unrecorded. It is not clear how many people caught the disease and made a recovery because only deaths were recorded and many records were destroyed in the Great Fire of London the following year. In the few districts where intact records remain, plague deaths varied between 30% and over 50% of the total population. Vincent wrote: it was very dismal to behold the red crosses, and read in great letters "LORD, HAVE MERCY UPON US" on the doors, and watchmen standing before them with halberds...people passing by them so gingerly, and with such fearful looks as if they had been lined with enemies in ambush to destroy them...a man at the corner of Artillery-wall, that as I judge, through the dizziness of his head with the disease, which seized upon him there, had dasht his face against the wall; and when I came by, he lay hanging with his bloody face over the rails, and bleeding upon the ground...I went and spoke to him; he could make no answer, but rattled in the throat, and as I was informed, within half an hour died in the place. It would be endless to speak of what we have seen and heard, of some in their frenzy, rising out of their beds, and leaping about their rooms; others crying and roaring at their windows; some coming forth almost naked, and running into the streets...scarcely a day passed over my head for, I think, a month or more together, but I should hear of the death of some one or more that I knew. The first day that they were smitten, the next day some hopes of recovery, and the third day, that they were dead. The outbreak was concentrated in London, but it affected other areas as well. Perhaps the best known example occurred in the village of Eyam in Derbyshire . The plague allegedly arrived with a merchant carrying a parcel of cloth sent from London. The villagers imposed a quarantine on themselves to stop the further spread of the disease. This prevented the disease from moving into surrounding areas, but around 33% of the village's inhabitants died over a period of fourteen months. Other places hit hard included Derby and Norwich . In Bristol strenuous efforts by the City Council seems to have limited the death rate to c.0.6 per cent during an outbreak lasting from April to September 1666. By late autumn, the death toll in London and the suburbs began to slow until, in February 1666, it was considered safe enough for the King and his entourage to come back to the city. With the return of the monarch, others began to return: The gentry returned in their carriages accompanied by carts piled high with their belongings. The judges moved back from Windsor to sit in Westminster Hall ; Parliament , which had been prorogued in April 1665, did not reconvene until September 1666. Trade recommenced and businesses and workshops opened up. London was the goal of a new wave of people who flocked to the city in expectation of making their fortunes. Writing at the end of March 1666, Lord Clarendon , the Lord Chancellor , stated "... the streets were as full, the Exchange as much crowded, the people in all places as numerous as they had ever been seen ...". Plague cases continued to occur sporadically at a modest rate until mid-1666. That September, the Great Fire of London destroyed much of the City of London, and some people believed that the fire put an end to the epidemic. It is now thought that the plague had largely subsided before the fire took place. Most of the later cases of plague were found in the suburbs, and it was the City of London that was destroyed by the fire. According to the Bills of Mortality, there were in total 68,596 deaths in London from the plague in 1665. Lord Clarendon estimated that the true number of mortalities was probably twice that figure. 1666 saw further deaths in other cities but on a lesser scale. Dr Thomas Gumble , chaplain to the Duke of Albemarle , both of whom had stayed in London for the whole of the epidemic, estimated that the total death count for the country from plague during 1665 and 1666 was about 200,000. Among the more notable death victims were Samuel Fisher , John Godwin , John Lewger and George Starkey . The Great Plague of 1665/1666 was the last major outbreak of bubonic plague in Great Britain. The last recorded death from plague came in 1679, and it was removed as a specific category in the Bills of Mortality after 1703. It spread to other towns in East Anglia and the southeast of England but fewer than ten per cent of parishes outside London had a higher than average death rate during those years. Urban areas were more affected than rural ones; Norwich, Ipswich, Colchester, Southampton and Winchester were badly affected, while the west of England and areas of the English Midlands escaped altogether. The population of England in 1650 was approximately 5.25 million, which declined to about 4.9 million by 1680, recovering to just over 5 million by 1700. Other diseases, such as smallpox, took a high toll on the population without the contribution by plague. The higher death rate in cities, both generally and specifically from the plague, was made up by continuous immigration, from small towns to larger ones and from the countryside to the towns. There were no contemporary censuses of London's population, but available records suggest that the population returned to its previous level within a couple of years. Burials in 1667 had returned to 1663 levels, Hearth Tax returns had recovered, and John Graunt contemporarily analysed baptism records and concluded they represented a recovered population. Part of this could be accounted for by the return of wealthy households, merchants and manufacturing industries, all of which needed to replace losses among their staff and took steps to bring in necessary people. Colchester had suffered more severe depopulation, but manufacturing records for cloth suggested that production had recovered or even increased by 1669, and the total population had nearly returned to pre-plague levels by 1674. Other towns did less well: Ipswich was affected less than Colchester, but in 1674, its population had dropped by 18%, more than could be accounted for by the plague deaths alone. [ dubious – discuss ] As a proportion of the population who died, the London death toll was less severe than in some other towns. The total of deaths in London was greater than in any previous outbreak for 100 years, though as a proportion of the population, the epidemics in 1563, 1603 and 1625 were comparable or greater. Perhaps around 2.5% of the English population died. The plague in London largely affected the poor, as the rich were able to leave the city by either retiring to their country estates or residing with kin in other parts of the country. The subsequent Great Fire of London ruined many city merchants and property owners. As a result of these events, London was largely rebuilt and Parliament enacted the Rebuilding of London Act 1666 . The street plan of the capital remained relatively unchanged, but some improvements were made: streets were widened, pavements were created, open sewers abolished, wooden buildings and overhanging gables forbidden, and the design and construction of buildings controlled. The use of brick or stone was mandatory and many gracious buildings were constructed. Not only was the capital rejuvenated, but it became a healthier environment in which to live. Londoners had a greater sense of community after they had overcome the great adversities of 1665 and 1666. Rebuilding took over ten years and was supervised by Robert Hooke as Surveyor of London. The architect Sir Christopher Wren was involved in the rebuilding of St Paul's Cathedral and more than fifty London churches . King Charles II did much to foster the rebuilding work. He was a patron of the arts and sciences and founded the Royal Observatory and supported the Royal Society , a scientific group whose early members included Robert Hooke, Robert Boyle and Sir Isaac Newton . In fact, out of the fire and pestilence flowed a renaissance in the arts and sciences in England. Plague pits have been archaeologically excavated during underground construction work. Between 2011 and 2015, 3,500 burials from the ' New Churchyard ' or 'Bethlam burial ground' were discovered during the construction of the Crossrail railway at Liverpool Street. Yersinia pestis DNA was found in the teeth of individuals found buried in pits at the site, confirming they had died of bubonic plague.

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Bubonic plague

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Plague doctor

A plague doctor was a physician who treated victims of bubonic plague during epidemics mainly in the 16th and 17th centuries. These physicians were hired by cities to treat infected patients regardless of income, especially the poor, who could not afford to pay. Plague doctors had a mixed reputation, with some citizens seeing their presence as a warning to leave the area or that death was near. Some plague doctors were said to charge patients and their families additional fees for special treatments or false cures. In many cases, these doctors were not experienced and trained physicians or surgeons , instead being volunteers, second-rate doctors, or young doctors just starting a career. In one case, a plague doctor was a fruit salesman before his employment as a physician. Plague doctors rarely cured patients, instead serving to record death tolls and the number of infected people for demographic purposes. In France and the Netherlands, plague doctors often lacked medical training and were referred to as " empirics ". Plague doctors were known as municipal or "community plague doctors", whereas "general practitioners" were separate doctors and both might be in the same European city or town at the same time. An early reference to plague doctors wearing masks is in 1373 when Johannes Jacobi recommends the use of masks, but offers no physical description of the masks themselves. According to Michel Tibayrenc's Encyclopedia of Infectious Diseases , the first mention of the iconic plague doctor is found during the 1619 plague outbreak in Paris, in a biography of royal physician Charles de Lorme , serving King Louis XIII of France at the time. After De Lorme, German engraver Gerhart Altzenbach published a famous illustration in 1656, which publisher Paulus Fürst's iconic Doctor Schnabel von Rom (1656) is based upon. In this satirical work, Fürst describes how the doctor does nothing but terrify people and take money from the dead and dying. The city of Orvieto hired Matteo fu Angelo as a plague doctor in 1348 for four times at a normal doctor's rate of 50 florins per year. Pope Clement VI hired several extra plague doctors during the Black Death plague to tend to the sick people of Avignon . Of eighteen doctors in Venice , only one was left by 1348: five had died of the plague, and twelve were missing and may have fled. Plague doctors practiced bloodletting and other remedies such as putting frogs or leeches on the buboes to "rebalance the humors ." A plague doctor's principal task, besides treating people with the plague, was to compile public records of plague deaths. In certain European cities like Florence and Perugia , plague doctors were requested to do autopsies to help determine the cause of death and how the plague affected the people. Plague doctors also sometimes took patients' last will and testament during times of plague epidemics, and gave advice to their patients about their conduct before death. This advice varied depending on the patient, and after the Middle Ages , the nature of the relationship between doctor and patient was governed by an increasingly complex ethical code. Some plague doctors wore a special costume consisting of an ankle-length overcoat and a bird-like beak mask. As an attempt to purify the air they breathed (it was believed that good smells would 'cancel out' the diseases , and people would often walk around with a flower under their nose), the wearer would fill the mask with herbs and spices (commonly lavender ). The plague doctors would also wear gloves, boots, a wide-brimmed hat, a linen hood, and an outer over-clothing garment. However, the costume was not worn by all medieval and early modern physicians studying and treating plague patients. The exact origins of the Plague costumes are unclear but have been dated back to Italy and France. Plague doctors wore a mask of some form since at least 1373. Most depictions come from satirical writings and political cartoons. The beaked plague doctor inspired costumes in Italian theatre as a symbol of general horror and death, though some historians insist that the plague doctor was originally fictional and inspired the real plague doctors later. Depictions of the beaked plague doctor rose in response to superstition and fear about the unknown source of the plague. Often, these plague doctors were the last thing a patient would see before death; therefore, the doctors were seen as a foreboding of death. It appears that the only contemporary sources which claim witness to this infamous costume are based in Italy during the 17th century. Later sources based in other areas do claim that this costume was in use in their country (most specifically during the Black Death); however, it is possible that these sources were influenced by theatre and other works of fiction. The typical mask had glass openings for the eyes and a curved leather beak, shaped like a bird's beak, with straps that held the beak in front of the doctor's nose. The mask had two small nose holes and was a type of respirator which contained aromatic items. The first known observation of the herbal-stuffed beak was during the 1656–1658 epidemic in Rome. The beak could hold dried flowers (like roses and carnations ), herbs (like lavender and peppermint ), camphor , or a vinegar sponge, as well as juniper berry , ambergris , cloves , labdanum , myrrh , and storax . The herbs right up against the nose inside the beak allowed for the doctor to have both of their hands free in order to examine the patient or corpse. The purpose of the mask was to keep away bad smells such as decaying bodies and the smell taken with the most caution was known as miasma , a noxious form of "bad air". This was thought to be the principal cause of the disease. Doctors believed the herbs would counter the "evil" smells of the plague and prevent them from becoming infected. The wide-brimmed leather hat indicated their profession, they used wooden canes in order to point out areas needing attention and to examine patients without touching them. The canes were also used to keep people away and to remove clothing from plague victims without having to touch them. The doctor's long robe was made from linen because it was said germs did not stick to linen as easily as other materials. The robe was also sometimes made from goat skin, which was said to be stronger against the plague than linen because of its small pores and polished texture. It was heard of for the robe to be sealed with oil or wax for an extra layer of protection so the "bad air" could not seep through the holes of the linen material. Though contemporary theories about the plague's nature were incorrect, it is likely that the costume actually did afford the wearer some protection. The garments covered the body, shielding against splattered blood, lymph and cough droplets, and the waxed robe prevented fleas (the true carriers of the plague) from touching the body or clinging to the linen. The costume of the plague doctor is one of the earliest examples of a hazmat suit . This well known costume now is used as common costume in festivals mainly in Europe and within the art of theatre. A plague doctor's contract was an agreement between a town's administrators and a doctor to treat bubonic plague patients. These contracts are present in European city archives. Their contractual responsibility was to treat plague patients, and no other type of patient, to prevent spreading the disease to the uninfected. A plague doctor had to serve a long quarantine after seeing a plague patient. The doctor was regarded as a "contact" who by agreement had to live in isolation to be quarantined. The bargaining which always preceded the final contract often consisted of serious negotiations. For example, the town administrators of Turin in 1630 were considering the terms of an agreement requested by one Dr. Maletto to become their plague doctor. After much negotiating, they instructed their broker representatives to make a fair and prompt deal as soon as possible with Dr. Maletto. They were told to get the best possible deal for their city, but to be careful not to lose the opportunity of hiring this plague doctor, as it would be difficult to find someone else to perform these dangerous duties at such a low rate. As an example of the tough negotiating that went on between plague doctors and infected European towns, there is in Pavia an original agreement between one Giovanni de Ventura and the city in their archives that shows a sixteen clause contract that was further amended after it was originally written. Clause one originally showed 30 florins per month for pay but was later modified to be net of living expenses. Clause two was originally that the pay was to be given two months in advance but later modified to monthly. Clause five provided originally a severance pay of two months but later modified that to one month's pay. Clause six stated that "the said master Giovanni shall not be bound nor held under obligation except only in attending the plague patients", which was later amplified with "...the doctor must treat all patients and visit infected places as it shall be found to be necessary." Clause seven had to do with full citizenship and the original text was modified with "according to how he shall behave himself." Bernardino di Francesco Rinaldi obtained a clause in his contract when he was hired as plague doctor by the city of Volterra in 1527 that said essentially that the city had the obligation to provide Bernardino with all and everything necessary for his life support (i.e. food, water), and for these living expenses to be paid through the city expenditures. In 1527, in the city of Prato , a plague doctor named Stefano Mezzettino was seen attending to other patients without a custodian. The rule in the plague doctor contract was that a custodian must always be with the plague doctor when he visits other patients. This created much danger for the public. He was fined for his illegal act and breaking the rule of the plague doctor contract. The bargaining which always preceded the final contract often consisted of serious negotiations. For example, the town administrators of Turin in 1630 were considering the terms of an agreement requested by one Dr. Maletto to become their plague doctor. After much negotiating, they instructed their broker representatives to make a fair and prompt deal as soon as possible with Dr. Maletto. They were told to get the best possible deal for their city, but to be careful not to lose the opportunity of hiring this plague doctor, as it would be difficult to find someone else to perform these dangerous duties at such a low rate. As an example of the tough negotiating that went on between plague doctors and infected European towns, there is in Pavia an original agreement between one Giovanni de Ventura and the city in their archives that shows a sixteen clause contract that was further amended after it was originally written. Clause one originally showed 30 florins per month for pay but was later modified to be net of living expenses. Clause two was originally that the pay was to be given two months in advance but later modified to monthly. Clause five provided originally a severance pay of two months but later modified that to one month's pay. Clause six stated that "the said master Giovanni shall not be bound nor held under obligation except only in attending the plague patients", which was later amplified with "...the doctor must treat all patients and visit infected places as it shall be found to be necessary." Clause seven had to do with full citizenship and the original text was modified with "according to how he shall behave himself." Bernardino di Francesco Rinaldi obtained a clause in his contract when he was hired as plague doctor by the city of Volterra in 1527 that said essentially that the city had the obligation to provide Bernardino with all and everything necessary for his life support (i.e. food, water), and for these living expenses to be paid through the city expenditures. In 1527, in the city of Prato , a plague doctor named Stefano Mezzettino was seen attending to other patients without a custodian. The rule in the plague doctor contract was that a custodian must always be with the plague doctor when he visits other patients. This created much danger for the public. He was fined for his illegal act and breaking the rule of the plague doctor contract.

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Bubonic plague

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Septicemic plague

Septicemic plague is one of the three forms of plague , and is caused by Yersinia pestis , a gram-negative species of bacterium . Septicemic plague is a systemic disease involving infection of the blood and is most commonly spread by bites from infected fleas. Septicemic plague can cause disseminated intravascular coagulation and is always fatal when untreated. The other varieties of the plague are bubonic plague and pneumonic plague . The usual symptoms are: Abdominal pain Bleeding under the skin due to blood clotting problems Bleeding from mouth, nose or rectum Gastrointestinal symptoms, including nausea, vomiting, which can be with blood , and diarrhea Fever Chills Low blood pressure Organ failure Shock Death of tissue ( gangrene ) in extremities, mostly fingers, nose, and toes Difficulty breathing Death These symptoms are common to many human illnesses and are not considered, in and of themselves, to signify infection with any form of plague. [ citation needed ] It is important to note that septicemic plague may be asymptomatic and may cause death absent of any symptoms. [ citation needed ]Human Yersinia infections most commonly result from the bite of an infected flea or occasionally an infected mammal, but like most bacterial systemic diseases , the disease may be transmitted through an opening in the skin or by inhaling infectious droplets of moisture from sneezes or coughs. In both cases septicemic plague need not be the result, and in particular, not the initial result, but it occasionally happens that bubonic plague for example leads to infection of the blood, and septicemic plague results. If the bacteria happen to enter the bloodstream rather than the lymph or lungs, they multiply in the blood, causing bacteremia and severe sepsis . In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), where tiny blood clots form throughout the body, commonly resulting in localised ischemic necrosis , tissue death from lack of circulation and perfusion . [ citation needed ] DIC results in depletion of the body's clotting resources, so that it can no longer control bleeding. Consequently, the unclotted blood bleeds into the skin and other organs, leading to a red or black patchy rash and to hematemesis (vomiting blood) or hemoptysis (coughing up blood). The rash may cause bumps on the skin that look somewhat like insect bites, usually red, sometimes white in the centre. [ citation needed ] Septicemic plague is caused by horizontal and direct transmission. Horizontal transmission is the transmitting of a disease from one individual to another regardless of blood relation. Direct transmission occurs from close physical contact with individuals, through common air usage, or from direct bite from a flea or an infected rodent. Most common rodents may carry the bacteria and so may Leporidae such as rabbits. The bacteria are cosmopolitan, mainly in rodents on all continents except Australia and Antarctica. The greatest frequency of human plague infections occurs in Africa. The bacteria most commonly appear in rural areas and wherever there is poor sanitation, overcrowding, and high rodent populations in urban areas. Outdoor activities such as hiking, camping, or hunting where plague-infected animals may be found, increase the risk of contracting septicemic plague, and so do certain occupations such as veterinary or other animal-related work. Human Yersinia infections most commonly result from the bite of an infected flea or occasionally an infected mammal, but like most bacterial systemic diseases , the disease may be transmitted through an opening in the skin or by inhaling infectious droplets of moisture from sneezes or coughs. In both cases septicemic plague need not be the result, and in particular, not the initial result, but it occasionally happens that bubonic plague for example leads to infection of the blood, and septicemic plague results. If the bacteria happen to enter the bloodstream rather than the lymph or lungs, they multiply in the blood, causing bacteremia and severe sepsis . In septicemic plague, bacterial endotoxins cause disseminated intravascular coagulation (DIC), where tiny blood clots form throughout the body, commonly resulting in localised ischemic necrosis , tissue death from lack of circulation and perfusion . [ citation needed ] DIC results in depletion of the body's clotting resources, so that it can no longer control bleeding. Consequently, the unclotted blood bleeds into the skin and other organs, leading to a red or black patchy rash and to hematemesis (vomiting blood) or hemoptysis (coughing up blood). The rash may cause bumps on the skin that look somewhat like insect bites, usually red, sometimes white in the centre. [ citation needed ] Septicemic plague is caused by horizontal and direct transmission. Horizontal transmission is the transmitting of a disease from one individual to another regardless of blood relation. Direct transmission occurs from close physical contact with individuals, through common air usage, or from direct bite from a flea or an infected rodent. Most common rodents may carry the bacteria and so may Leporidae such as rabbits. The bacteria are cosmopolitan, mainly in rodents on all continents except Australia and Antarctica. The greatest frequency of human plague infections occurs in Africa. The bacteria most commonly appear in rural areas and wherever there is poor sanitation, overcrowding, and high rodent populations in urban areas. Outdoor activities such as hiking, camping, or hunting where plague-infected animals may be found, increase the risk of contracting septicemic plague, and so do certain occupations such as veterinary or other animal-related work. A doctor or veterinarian will perform a physical exam which includes asking about the medical history and possible sources of exposure. The following possible test could include: Blood samples (detecting antibodies) Culture samples of body fluids (check for the bacteria Yersinia pestis ) Kidney and liver testing Checking lymphatic system for signs of infection Examining body fluids for abnormal signs Checking for swelling Checking for signs of dehydration Checking for fever Checking for lung infection The following steps and precautions should be used to avoid infection of the septicemic plague: Caregivers of infected patients should wear masks, gloves, goggles and gowns Take antibiotics if close contact with the infected patient has occurred Use insecticides throughout the house Avoid contact with dead rodents or sick cats Set traps if mice or rats are present around the house Do not allow family pets to roam in areas where plague is common Flea control and treatment for animals (especially rodents)Starting antibiotics early is the first step in treating septicemic plague in humans. One of the following antibiotics may be used: [ citation needed ] Lymph nodes may require draining and the patient will need close monitoring. In animals, antibiotics such as tetracycline or doxycycline can be used. Intravenous drip may be used to assist in dehydration scenarios. Flea treatment can also be used. In some cases, euthanasia may be the best option for treatment and to prevent further spreading. Untreated septicemic plague is almost always fatal. Early treatment with antibiotics reduces the mortality rate to between 4 and 15 per cent. Death is almost inevitable if treatment is delayed more than about 24 hours, and some people may even die on the same day they present with the disease. [ citation needed ]In 2015, Taylor Gaes, a 16-year-old in Larimer County in northern Colorado, contracted septicemic plague and subsequently died after being bitten by a flea that had bitten a rodent on his family's rural property. Only three people in Colorado had contracted the bacteria in the previous thirty years. The septicemic plague was the least common of the three plague varieties that occurred during the Black Death from 1348 to 1350 (the other two being bubonic plague and pneumonic plague ). Like the others, septicemic plague spread from East Asia through trade routes on the Black Sea and down to the Mediterranean Sea . [ citation needed ] Major port cities and trade centres such as Venice and Florence were hit the hardest. The massive loss of the working population in Europe following the Black Death, resulting in the increased economic bargaining power of the serf labour force, was a major precipitating factor for the Peasants' Revolt of 1381. [ citation needed ]Septicemic plague is a zoonosis , a disease that generally is acquired by humans from animals, such as rodents and carnivores. Goats, sheep and camels also may carry the bacteria. Cats rarely develop clinical signs but can be infected. Areas west of the Great Plains of North America are one region where plague-infected animals commonly occur. Plague-infested animals are found in many other countries as well, especially in developing countries where health controls are not effective. [ citation needed ] Animals that commonly carry plague bacteria are large rodents and Leporidae , but carnivores sometimes also become infected by their prey. Prey animals are not immune to the disease, and outbreaks of various strains of plague, such as sylvatic plague , have on occasion devastated populations of black-tailed prairie dogs and black-footed ferrets . Plague has been active in black-tailed prairie dog populations since the 1960s. In the United States outbreaks only occur in the western States and they are devastating, with mortality rates near 100% because the animals have no immunity to the plague. Survivors are the ones that happened not to become infected and colonies that recover from a plague outbreak remain at risk. Because black-footed ferrets prey on black-tailed prairie dogs, wild ferret populations also fall victim to sylvatic plague. An outbreak can kill nearly 100% of ferrets in a population, and surviving ferrets commonly face starvation because prairie dogs are their main prey. Spray-and-vaccinate campaigns have aimed at preventing the spread of the plague among these animals. Similar septicemic problems occur in many countries across the world, especially in developing countries where spending on health systems is very low and health controls are not effective. [ citation needed ]

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Bubonic plague

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First plague pandemic

The first plague pandemic was the first historically recorded Old World pandemic of plague , the contagious disease caused by the bacterium Yersinia pestis . Also called the early medieval pandemic , it began with the Plague of Justinian in 541 and continued until 750 or 767; at least fifteen or eighteen major waves of plague following the Justinianic plague have been identified from historical records. The pandemic affected the Mediterranean Basin most severely and most frequently, but also infected the Near East and Northern Europe , and potentially East Asia as well. The Roman emperor Justinian I 's name is sometimes applied to the whole series of plague epidemics in late Antiquity . The pandemic is best known from its first and last outbreaks: the Justinianic Plague of 541 – 549, described by the contemporary Roman historian Procopius , and the late 8th century plague of Naples described by Neapolitan historian John the Deacon in the following century (distinct from the much later Naples Plague ). Other accounts from contemporaries of the pandemic are included in the texts of Evagrius Scholasticus , John of Ephesus , Gregory of Tours , Paul the Deacon , and Theophanes the Confessor ; most seem to have believed plague was a divine punishment for human misdeeds. While Latin and Byzantine Greek texts treated the disease as a generic pestilence ( Ancient Greek: λοιμός , romanized: loimós , Latin: plaga ), only later did Arabic writers term the condition ṭāʿūn (to some extent interchangeable with wabāʾ , 'plague'). In Syriac , both bubonic plague and the buboes themselves are called sharʿūṭā . The Chronicle of Seert makes this term synonymous with Arabic ṭāʿūn . Often, however, Syriac writers referred to an outbreak simply as a pestilence or mortality, mawtānā , equivalent to Arabic wabāʾ . In Pseudo-Zacharias Rhetor 's Historia Miscellanea , the clarifying combined form mawtānā d sharʿūṭā (plague of tumors) is found. The Chronicle of 640 of Thomas the Presbyter dates the "first plague" ( mawtānā qadmayā ) to the year AG 854 (AD 542/3). Several sources attest the plague's origins in Africa. According to Jacob of Edessa (died 708), the "great plague ( mawtānā rabbā ) began in the region of Kush ( Nubia ), south of Egypt, in the year AG 853 (AD 541–542). Evagrius Scholasticus (died 594) and the Historia Miscellanea also place its origins in Aethiopia (Nubia) on the border of Egypt. Michael the Syrian , relying on the lost chronicle of John of Ephesus (died c. 590), says that it began in Kush on the border of Egypt and in Himyar (Yemen). An inscription dated to 543 records how Abraha , the Ethiopian ruler of Himyar, repaired the Maʾrib dam after sickness and death had struck the local community. The Chronicle of Seert records that Aksum ( al-Habasha ) was hit by the pandemic. Early Arabic sources record that plague was endemic in Nubia and Abyssinia. The testimony of Procopius , who says that the plague began in Pelusium in the east of the Nile Delta and then spread to Alexandria , is consistent with an introduction from the Red Sea region, possible via ship-borne rats if the Canal of the Pharaohs was still open. The plague could have originated in commercial links with India or in growing Roman religious links with Nubia and Aksum. A link with India is rendered less likely by the fact that the plague arrived in the Roman Empire before arriving in Persia or China, which had closer links with India. According to Peter Sarris, the "geopolitical context of the early sixth century," with an Aksumite–Roman alliance against Himyar and Persia, "was arguably the crucial prerequisite for the transmission of the plague from Africa to Byzantium." According to the bishop - chronicler of Tours in the late 6th century, Gregory of Tours , there were numerous epidemics of plague in the Kingdom of the Franks after the Justinianic Plague struck Arelate ( Arles ) and the surrounding region in the late 540s. Various portents were witnessed and to expiate them the inhabitants of affected areas resorted to processions , prayers , and vigils . Gregory records an epidemic in 571 in the Auvergne and in the cities of Divio ( Dijon ), Avaricum ( Bourges ), Cabillonum ( Chalon-sur-Saône ), and Lugdunum ( Lyon ). Gregory's description of the plague as causing wounds in the armpit or groin that he described as resembling snakebite and of patients dying delirious within two or three days allow identification of the disease as bubonic plague; the "wounds" are the characteristic buboes . In 582 Gregory of Tours reports an epidemic in Narbo Martius ( Narbonne ). According to him, the majority of the townsfolk at Albi in 584 died of an outbreak of plague. Massilia ( Marseille ) was hit by plague in 588; there the king Guntram of Francia recommended a strict diet of barley bread and water. Gregory blames a ship arriving from Hispania for being the source of the contagion, and the epidemic recurred several times thereafter. In 590 Gregory records another plague epidemic at Vivarium ( Viviers ) and at Avenio ( Avignon ) at the same time as the plague broke out in Rome under Pope Pelagius II . These plagues affected the Byzantine Empire , West Asia , Syria , and Mesopotamia and the Byzantine Empire, West Asia, and Africa respectively.In 610, Chao Yuanfang mentioned an endemic plague of "malignant bubo" described as "coming on abruptly with high fever together with the appearance of a bundle of nodes beneath the tissue." Sun Simo, who died in 652, also mentioned a "malignant bubo" and plague that was common in Lingnan ( Guangdong ). Ole Benedictow posits that it was an offshoot of the first plague pandemic that reached Chinese territory around 600. The historian Lester Little suggests that just as the Black Death led to the near disappearance of serfdom in western Europe, the first pandemic resulted in the end of ancient slavery , at least in Italy and Spain. A 2019 study, however, suggests that the first plague pandemic was not a major cause of the demographic, economic, political, and social changes across Europe and the Near East from the 6th to 8th centuries AD and that upper estimates of the pandemic's mortality are unsupported by historical, archaeological, genetic, and palynological evidence.

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Bubonic plague

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21st century Madagascar plague outbreaks

Madagascar has experienced several outbreaks of bubonic and pneumonic plague in the 21st century. In the outbreak beginning in 2014, 71 died; in 2017, 202 died. Smaller outbreaks occurred in January 2008 (18 deaths), and December 2013. An outbreak of plague in Madagascar in 2014 started on 31 August. On that day the first case, a man from Soamahamanina village in Tsiroanomandidy , was identified. The patient died on 3 September. The outbreak was in the form of bubonic and pneumonic plague . By 16 November 2014, a total of 119 cases had been confirmed, including 40 deaths. Two percent of reported cases were of the pneumonic form. By 21 November, in the capital Antananarivo there were two confirmed cases, including one death. On 4 November 2014, the Ministry of Health of Madagascar reported the outbreak to the World Health Organization . On 11 February 2015, the WHO and Madagascar Ministry of Health released a follow-up situation report the outbreak. The report stated the outbreak beginning in September 2014 peaked from November through end-December and had slowed down as of February 2015. The WHO report cited 263 cases and 71 deaths with a 27% fatality rate. Efficient identification and treatment with antibiotics were noted as critical to treatment efficacy, evidenced by fatality rates ranging from 15% - 60% depending on early identification and treatment. The report explained that Madagascar's plague "season" typically runs through April and stopped short of officially declaring the outbreak over. A more recent outbreak of plague in Madagascar began in August 2017 and expanded rapidly, with about two-thirds of cases transmitted person-to-person as pneumonic plague, the most dangerous form of the disease. The death toll of 124 by 20 October exceeded that of previous outbreaks. [ citation needed ] More than half of cases have been recorded in the capital of Antananarivo and the main port of Toamasina, the largest cities in Madagascar. Nine nearby countries were considered at high risk of a similar outbreak. The outbreak appeared to peak in mid-October with the number of new cases declining. Typically the annual plague outbreak peaks in December and runs until April. On 2 November, a ProMED-mail moderator expressed surprise at the considerable variation reported in numbers of cases and deaths, especially with the relatively low case-fatality rate considering that pneumonic plague is reported to account for over 60 percent of deaths. An article from the World Health Organization reported more than 1800 cases as of late October, while nearly 500 fewer had been reported in the week previously. In January 2018 the experts declared the outbreak over as no new cases had been reported since November 2017, although the World health organization stated that there was a "moderate" chance of re-occurrence. Malagasy Prime Minister Olivier Mahafaly Solonandrasana had declared the crisis over on 23 November 2017. The outbreak began in August 2017 with the death from pneumonic plague of a 31-year-old man who had been traveling in a crowded minibus toward the capital city of Antananarivo in the central highlands. The outbreak expanded rapidly, transmitted person-to-person in the pneumonic form of the disease, which accounted for more than 60 percent of cases. Scientists discovered three new strains of Y. pestis in Madagascar in 2017. Additionally, one strain of Y. pestis was found to be resistant to antibiotic treatment. Because of plague moving from rural to urban areas, there is increased risk of transmission to other countries. Urban areas that are major transportation hubs for shipping and recreation are at high risk for transmitting plague to nearby countries. The outbreak was initially recognized on 11 September by local authorities and confirmed by the Institut Pasteur de Madagascar . Authorities called the outbreak "quite worrisome" because the number of cases per day was growing rapidly, and many cases were in urban areas where there are more opportunities for contact between people. Panic was reported in the capital, with the main hospital overcrowded with cases. The death toll in this outbreak had by mid-October exceeded an outbreak in 2014 . Most cases were of the pneumonic form. The bubonic form, transmitted by the bites of fleas from rodents, is more usual in the annual outbreaks in Madagascar. The government announced they had "temporarily suspended gatherings to the general public in places where the traceability of the participants is difficult if not impossible (stadiums, sports palaces, gymnasiums …)". By 8 November, deaths had risen to 165 with infections totalling over 2000, however the rate of spread had slowed, raising hope that the outbreak was starting to come under control. Concerns continued to be raised that plague might still spread to neighboring countries, or mutate to a form that could be more difficult to treat. By 15 November, there had been 171 deaths and 2119 total cases of plague, however no new infections had been reported since 28 October. An outbreak of plague in Madagascar in 2014 started on 31 August. On that day the first case, a man from Soamahamanina village in Tsiroanomandidy , was identified. The patient died on 3 September. The outbreak was in the form of bubonic and pneumonic plague . By 16 November 2014, a total of 119 cases had been confirmed, including 40 deaths. Two percent of reported cases were of the pneumonic form. By 21 November, in the capital Antananarivo there were two confirmed cases, including one death. On 4 November 2014, the Ministry of Health of Madagascar reported the outbreak to the World Health Organization . On 11 February 2015, the WHO and Madagascar Ministry of Health released a follow-up situation report the outbreak. The report stated the outbreak beginning in September 2014 peaked from November through end-December and had slowed down as of February 2015. The WHO report cited 263 cases and 71 deaths with a 27% fatality rate. Efficient identification and treatment with antibiotics were noted as critical to treatment efficacy, evidenced by fatality rates ranging from 15% - 60% depending on early identification and treatment. The report explained that Madagascar's plague "season" typically runs through April and stopped short of officially declaring the outbreak over.A more recent outbreak of plague in Madagascar began in August 2017 and expanded rapidly, with about two-thirds of cases transmitted person-to-person as pneumonic plague, the most dangerous form of the disease. The death toll of 124 by 20 October exceeded that of previous outbreaks. [ citation needed ] More than half of cases have been recorded in the capital of Antananarivo and the main port of Toamasina, the largest cities in Madagascar. Nine nearby countries were considered at high risk of a similar outbreak. The outbreak appeared to peak in mid-October with the number of new cases declining. Typically the annual plague outbreak peaks in December and runs until April. On 2 November, a ProMED-mail moderator expressed surprise at the considerable variation reported in numbers of cases and deaths, especially with the relatively low case-fatality rate considering that pneumonic plague is reported to account for over 60 percent of deaths. An article from the World Health Organization reported more than 1800 cases as of late October, while nearly 500 fewer had been reported in the week previously. In January 2018 the experts declared the outbreak over as no new cases had been reported since November 2017, although the World health organization stated that there was a "moderate" chance of re-occurrence. Malagasy Prime Minister Olivier Mahafaly Solonandrasana had declared the crisis over on 23 November 2017. The outbreak began in August 2017 with the death from pneumonic plague of a 31-year-old man who had been traveling in a crowded minibus toward the capital city of Antananarivo in the central highlands. The outbreak expanded rapidly, transmitted person-to-person in the pneumonic form of the disease, which accounted for more than 60 percent of cases. Scientists discovered three new strains of Y. pestis in Madagascar in 2017. Additionally, one strain of Y. pestis was found to be resistant to antibiotic treatment. Because of plague moving from rural to urban areas, there is increased risk of transmission to other countries. Urban areas that are major transportation hubs for shipping and recreation are at high risk for transmitting plague to nearby countries. The outbreak was initially recognized on 11 September by local authorities and confirmed by the Institut Pasteur de Madagascar . Authorities called the outbreak "quite worrisome" because the number of cases per day was growing rapidly, and many cases were in urban areas where there are more opportunities for contact between people. Panic was reported in the capital, with the main hospital overcrowded with cases. The death toll in this outbreak had by mid-October exceeded an outbreak in 2014 . Most cases were of the pneumonic form. The bubonic form, transmitted by the bites of fleas from rodents, is more usual in the annual outbreaks in Madagascar. The government announced they had "temporarily suspended gatherings to the general public in places where the traceability of the participants is difficult if not impossible (stadiums, sports palaces, gymnasiums …)". By 8 November, deaths had risen to 165 with infections totalling over 2000, however the rate of spread had slowed, raising hope that the outbreak was starting to come under control. Concerns continued to be raised that plague might still spread to neighboring countries, or mutate to a form that could be more difficult to treat. By 15 November, there had been 171 deaths and 2119 total cases of plague, however no new infections had been reported since 28 October. The outbreak began in August 2017 with the death from pneumonic plague of a 31-year-old man who had been traveling in a crowded minibus toward the capital city of Antananarivo in the central highlands. The outbreak expanded rapidly, transmitted person-to-person in the pneumonic form of the disease, which accounted for more than 60 percent of cases. Scientists discovered three new strains of Y. pestis in Madagascar in 2017. Additionally, one strain of Y. pestis was found to be resistant to antibiotic treatment. Because of plague moving from rural to urban areas, there is increased risk of transmission to other countries. Urban areas that are major transportation hubs for shipping and recreation are at high risk for transmitting plague to nearby countries.The outbreak was initially recognized on 11 September by local authorities and confirmed by the Institut Pasteur de Madagascar . Authorities called the outbreak "quite worrisome" because the number of cases per day was growing rapidly, and many cases were in urban areas where there are more opportunities for contact between people. Panic was reported in the capital, with the main hospital overcrowded with cases. The death toll in this outbreak had by mid-October exceeded an outbreak in 2014 . Most cases were of the pneumonic form. The bubonic form, transmitted by the bites of fleas from rodents, is more usual in the annual outbreaks in Madagascar. The government announced they had "temporarily suspended gatherings to the general public in places where the traceability of the participants is difficult if not impossible (stadiums, sports palaces, gymnasiums …)". By 8 November, deaths had risen to 165 with infections totalling over 2000, however the rate of spread had slowed, raising hope that the outbreak was starting to come under control. Concerns continued to be raised that plague might still spread to neighboring countries, or mutate to a form that could be more difficult to treat. By 15 November, there had been 171 deaths and 2119 total cases of plague, however no new infections had been reported since 28 October. Plague is caused by the bacterium Yersinia pestis and is most commonly transmitted through infected fleas. There are three types of plague: bubonic, pneumonic and septicemic. Bubonic plague is the most well-known type. This type of plague results in swollen lymph nodes that are called buboes. This type of plague is treatable with antibiotics, but if not treated effectively, the infection can spread to different parts of the body. Pneumonic plague occurs when plague infects the lungs and is transmissible person to person through infected droplets. This form of plague is very deadly. Septicemic plague occurs when plague enters the blood. Skin and tissues turn black and die, and bleeding into skin and organs often occurs. This form of plague is also deadly. Pneumonic plague and septicemic plague often occur when bubonic plague goes untreated and are difficult to diagnose. Plague has endemically resided in Madagascar since it was first brought to the island from India in 1898, on the central high plateau of Madagascar , usually occurring every year as a seasonal upsurge during the rainy season. Plague resides in Madagascar similar to the way flu resides in the United States. "Plague season" is generally October through March, and mostly affects rural areas of Madagascar. Plague, although endemic, has been relatively dormant in Madagascar until 1990. Annually until then, there were about 20-30 cases reported a year. Recently, however, the annual number of cases has risen to typically between 800 and 1500 a year. All cases of plague must be reported to the Ministry of Health; however, cases often go underreported due to lack of quality epidemiologic resources in rural areas. Tests for plague used in these areas often have low sensitivity and are unreliable. In the past, cases of plague in Madagascar have been bubonic and not transmittable person to person. The increase in plague cases over the last 20 years have been largely due to an increase in pneumonic plague. Pneumonic plague is transmitted person to person via infected droplets. It is often difficult to diagnose and by the time it is diagnosed, cases are usually fatal. Case fatality rate of pneumonic plague in Madagascar is close to 75%. When an endemic disease, such as Ebola or plague, is introduced to a new geographic area that is densely populated with international shipping routes, it increases transmission rates and leads to severe outbreaks and potential pandemics. Although urban areas like Antananarivo and Mahajanga are more affluent, they are still impoverished in global comparison. Insufficient waste management, lack of clean water, and poor infrastructure are all issues that are breeding grounds for rats and fleas and therefore perpetuate plague transmission in urban areas. Furthermore, the rat-to-flea cycle of transmission has not changed since the first pandemic of plague. This type of consistency allows the organism to become more infectious. High rates of plague transmission have been associated with low rat abundance and high volume of flea vectors. Historically, rats who acted as hosts to the flea vector subsequently died once they were infected with plague. However, the organism evolved and scientists are now finding that rats are not dying from plague. This means that plague survives longer in the host and allows for the bacteria to live longer and potentially infect more people. The elevation of the mountains where most of the agriculture takes place, in addition to the ideal climate that allows rats and fleas to prosper, scientists have seen plague thrive in Madagascar's climate compared to other countries where there is endemic plague. Scientists discovered three new strains of Y. pestis in Madagascar in 2017. Additionally, one strain of Y. pestis was found to be resistant to antibiotic treatment. Because of plague moving from rural to urban areas, there is increased risk for transmission to other countries. Urban areas that are a major transportation hub for shipping and recreation are at high risk for transmitting plague to nearby countries. Plague in Madagascar is predominantly a rural disease related to agricultural activities. Plague "season" (October through April) coincides with the hot and rainy season in the agricultural highlands. Rats do not thrive in cold climate, and therefore are more prevalent during this time of year. Rice is a vital crop in Madagascar, and due to the high prevalence of fleas and rats in agricultural areas, plague bacteria often infects crops and soil. Many scientists have found that the plague bacteria Y. pestis can live in soil for months at a time. In addition to agricultural factors that increase prevalence of plague, burial practices in Madagascar also spread disease. Famadihana is a burial practice in Madagascar that is practiced among the Malagasy people. It is commonly known as "turning of the bones." Family members exhume their deceased family members from the family crypts and wrap them up in fresh cloth. Then, they dance around the crypt with the body to live music. This custom is based on a belief that the dead do not join the rest of their ancestors until their body reaches full decomposition with appropriate ceremonies. This process could take up to several years and involves direct contact with corpses. This burial practice perpetuates the spread of plague among other diseases. Plague is symptomatic of poverty. Rats and fleas thrive in rural and urban areas of Madagascar due to the impoverishment of the country. Lack of proper infrastructure, lack of sanitation and waste removal, little clean water, and scarce health facilities create a perfect breeding ground for rats and fleas to thrive. Although plague is prevalent in other countries, Madagascar has the highest fatality and accounts for 30% of all plague cases largely due to poverty and lack of health resources like antibiotics and proper testing. Furthermore, outbreaks of plague have become increasingly more severe due to bubonic plague going untreated and developing into pneumonic plague. Once plague becomes pneumonic, it is significantly more contagious and is transmittable person to person. Recently, plague outbreaks have become increasingly more severe. The most recent outbreak in August 2017 is the worst to date with over 1,800 confirmed cases of plague. Of these confirmed cases, 1,100 of them were cases of pneumonic plague. 114 districts of Madagascar were affected by the plague outbreak. Usually, endemic plague only affects around 20 rural districts. This outbreak was different in nature due to the fact that the plague shifted from rural geographic location to urban geographic location. Plague was found in major shipping ports like Mahajanga and in the capital Antananarivo. The capital alone is home to 2.7 million people. Plague moving into urban areas increased transmission rates due to the high volume of people living in these areas and the amount of trade traffic that occurs on a daily basis.Plague has endemically resided in Madagascar since it was first brought to the island from India in 1898, on the central high plateau of Madagascar , usually occurring every year as a seasonal upsurge during the rainy season. Plague resides in Madagascar similar to the way flu resides in the United States. "Plague season" is generally October through March, and mostly affects rural areas of Madagascar. Plague, although endemic, has been relatively dormant in Madagascar until 1990. Annually until then, there were about 20-30 cases reported a year. Recently, however, the annual number of cases has risen to typically between 800 and 1500 a year. All cases of plague must be reported to the Ministry of Health; however, cases often go underreported due to lack of quality epidemiologic resources in rural areas. Tests for plague used in these areas often have low sensitivity and are unreliable. In the past, cases of plague in Madagascar have been bubonic and not transmittable person to person. The increase in plague cases over the last 20 years have been largely due to an increase in pneumonic plague. Pneumonic plague is transmitted person to person via infected droplets. It is often difficult to diagnose and by the time it is diagnosed, cases are usually fatal. Case fatality rate of pneumonic plague in Madagascar is close to 75%. When an endemic disease, such as Ebola or plague, is introduced to a new geographic area that is densely populated with international shipping routes, it increases transmission rates and leads to severe outbreaks and potential pandemics. Although urban areas like Antananarivo and Mahajanga are more affluent, they are still impoverished in global comparison. Insufficient waste management, lack of clean water, and poor infrastructure are all issues that are breeding grounds for rats and fleas and therefore perpetuate plague transmission in urban areas. Furthermore, the rat-to-flea cycle of transmission has not changed since the first pandemic of plague. This type of consistency allows the organism to become more infectious. High rates of plague transmission have been associated with low rat abundance and high volume of flea vectors. Historically, rats who acted as hosts to the flea vector subsequently died once they were infected with plague. However, the organism evolved and scientists are now finding that rats are not dying from plague. This means that plague survives longer in the host and allows for the bacteria to live longer and potentially infect more people. The elevation of the mountains where most of the agriculture takes place, in addition to the ideal climate that allows rats and fleas to prosper, scientists have seen plague thrive in Madagascar's climate compared to other countries where there is endemic plague. Scientists discovered three new strains of Y. pestis in Madagascar in 2017. Additionally, one strain of Y. pestis was found to be resistant to antibiotic treatment. Because of plague moving from rural to urban areas, there is increased risk for transmission to other countries. Urban areas that are a major transportation hub for shipping and recreation are at high risk for transmitting plague to nearby countries. Plague in Madagascar is predominantly a rural disease related to agricultural activities. Plague "season" (October through April) coincides with the hot and rainy season in the agricultural highlands. Rats do not thrive in cold climate, and therefore are more prevalent during this time of year. Rice is a vital crop in Madagascar, and due to the high prevalence of fleas and rats in agricultural areas, plague bacteria often infects crops and soil. Many scientists have found that the plague bacteria Y. pestis can live in soil for months at a time. In addition to agricultural factors that increase prevalence of plague, burial practices in Madagascar also spread disease. Famadihana is a burial practice in Madagascar that is practiced among the Malagasy people. It is commonly known as "turning of the bones." Family members exhume their deceased family members from the family crypts and wrap them up in fresh cloth. Then, they dance around the crypt with the body to live music. This custom is based on a belief that the dead do not join the rest of their ancestors until their body reaches full decomposition with appropriate ceremonies. This process could take up to several years and involves direct contact with corpses. This burial practice perpetuates the spread of plague among other diseases. Plague is symptomatic of poverty. Rats and fleas thrive in rural and urban areas of Madagascar due to the impoverishment of the country. Lack of proper infrastructure, lack of sanitation and waste removal, little clean water, and scarce health facilities create a perfect breeding ground for rats and fleas to thrive. Although plague is prevalent in other countries, Madagascar has the highest fatality and accounts for 30% of all plague cases largely due to poverty and lack of health resources like antibiotics and proper testing. Furthermore, outbreaks of plague have become increasingly more severe due to bubonic plague going untreated and developing into pneumonic plague. Once plague becomes pneumonic, it is significantly more contagious and is transmittable person to person. When an endemic disease, such as Ebola or plague, is introduced to a new geographic area that is densely populated with international shipping routes, it increases transmission rates and leads to severe outbreaks and potential pandemics. Although urban areas like Antananarivo and Mahajanga are more affluent, they are still impoverished in global comparison. Insufficient waste management, lack of clean water, and poor infrastructure are all issues that are breeding grounds for rats and fleas and therefore perpetuate plague transmission in urban areas. Furthermore, the rat-to-flea cycle of transmission has not changed since the first pandemic of plague. This type of consistency allows the organism to become more infectious.High rates of plague transmission have been associated with low rat abundance and high volume of flea vectors. Historically, rats who acted as hosts to the flea vector subsequently died once they were infected with plague. However, the organism evolved and scientists are now finding that rats are not dying from plague. This means that plague survives longer in the host and allows for the bacteria to live longer and potentially infect more people. The elevation of the mountains where most of the agriculture takes place, in addition to the ideal climate that allows rats and fleas to prosper, scientists have seen plague thrive in Madagascar's climate compared to other countries where there is endemic plague.Scientists discovered three new strains of Y. pestis in Madagascar in 2017. Additionally, one strain of Y. pestis was found to be resistant to antibiotic treatment. Because of plague moving from rural to urban areas, there is increased risk for transmission to other countries. Urban areas that are a major transportation hub for shipping and recreation are at high risk for transmitting plague to nearby countries.Plague in Madagascar is predominantly a rural disease related to agricultural activities. Plague "season" (October through April) coincides with the hot and rainy season in the agricultural highlands. Rats do not thrive in cold climate, and therefore are more prevalent during this time of year. Rice is a vital crop in Madagascar, and due to the high prevalence of fleas and rats in agricultural areas, plague bacteria often infects crops and soil. Many scientists have found that the plague bacteria Y. pestis can live in soil for months at a time. In addition to agricultural factors that increase prevalence of plague, burial practices in Madagascar also spread disease. Famadihana is a burial practice in Madagascar that is practiced among the Malagasy people. It is commonly known as "turning of the bones." Family members exhume their deceased family members from the family crypts and wrap them up in fresh cloth. Then, they dance around the crypt with the body to live music. This custom is based on a belief that the dead do not join the rest of their ancestors until their body reaches full decomposition with appropriate ceremonies. This process could take up to several years and involves direct contact with corpses. This burial practice perpetuates the spread of plague among other diseases. Plague is symptomatic of poverty. Rats and fleas thrive in rural and urban areas of Madagascar due to the impoverishment of the country. Lack of proper infrastructure, lack of sanitation and waste removal, little clean water, and scarce health facilities create a perfect breeding ground for rats and fleas to thrive. Although plague is prevalent in other countries, Madagascar has the highest fatality and accounts for 30% of all plague cases largely due to poverty and lack of health resources like antibiotics and proper testing. Furthermore, outbreaks of plague have become increasingly more severe due to bubonic plague going untreated and developing into pneumonic plague. Once plague becomes pneumonic, it is significantly more contagious and is transmittable person to person. Recently, plague outbreaks have become increasingly more severe. The most recent outbreak in August 2017 is the worst to date with over 1,800 confirmed cases of plague. Of these confirmed cases, 1,100 of them were cases of pneumonic plague. 114 districts of Madagascar were affected by the plague outbreak. Usually, endemic plague only affects around 20 rural districts. This outbreak was different in nature due to the fact that the plague shifted from rural geographic location to urban geographic location. Plague was found in major shipping ports like Mahajanga and in the capital Antananarivo. The capital alone is home to 2.7 million people. Plague moving into urban areas increased transmission rates due to the high volume of people living in these areas and the amount of trade traffic that occurs on a daily basis.Madagascar proposed a National Plague Control Program, which is a surveillance program run by the government and the Ministry of Health that is based on immediate notification of every suspected case of plague. Every case reported to the National Plague Control Program is treated with antibiotics. In addition to this course of treatment, insecticide is brought to the home or work for flea control. Although the ideas and intentions of the National Plague Control Program are good and in theory could be very beneficial to treating and preventing outbreaks of plague, severe economic limitations make the execution of this program less than ideal. Furthermore, disparities in rural areas compared to urban areas make accessibility and testing in rural areas challenging. Economic resources need to be strengthened before this program can live up to its full potential. After the most recent, major outbreak, the WHO created a Crisis Emergency Committee to monitor the situation. They deployed epidemiologists, doctors, and risk management coordinators in order to coordinate surveillance, facilitate tracing contacts, oversee case management, administer isolation protocol, and distribute supplies. In addition to the new committee, Madagascar reallocated funds in order to help with isolation, treatment, and supplies. These solutions to the outbreak helped, as cases of plague declined and hospitalized patients decreased in volume.Twelve more cases of suspected plague appeared in the Seychelles days after the death of a 34-year-old male who had recently traveled to Madagascar and who was confirmed as having pneumonic plague on 10 October 2017. Air Seychelles suspended all flights to Madagascar. More sophisticated tests later showed that the infection was not plague. A South African basketball player who contracted plague while attending a tournament in Madagascar was successfully treated and returned home. The type of plague the player had was not reported, but one of the cases in the Seychelles who died of pneumonic plague was thought to have attended the same tournament. The World Health Organization warned that there was a high risk the disease could spread to nine other countries in Africa and the Indian Ocean (Ethiopia, Kenya, Tanzania, Mozambique, South Africa, Seychelles, Comoros, Reunion, and Mauritius) because of frequent trade and travel with Madagascar.

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Bubonic plague

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Bubo

A bubo (Greek Î²Î¿Ï Î²ÏŽÎ½, boubṓn , 'groin') is adenitis or inflammation of the lymph nodes and is an example of reactive infectious lymphadenopathy . Buboes are a symptom of bubonic plague and occur as painful swellings in the thighs, neck, groin or armpits. They are caused by Yersinia pestis bacteria spreading from flea bites through the bloodstream to the lymph nodes, where the bacteria replicate, causing the nodes to swell. Plague buboes may turn black and necrotic , rotting away the surrounding tissue, or they may rupture, discharging large amounts of pus . Infection can spread from buboes around the body, resulting in other forms of the disease such as pneumonic plague . Plague patients whose buboes swell to such a size that they burst tend to survive the disease. Before the discovery of antibiotics , doctors often drained buboes with leeches or heated rods to save patients. Buboes are also symptoms of other diseases, such as chancroid and lymphogranuloma venereum . In these conditions, a two-week course of antibiotics is the recommended treatment, and incision and drainage or excision of the swollen lymph nodes is best avoided. However, aspiration may sometimes be performed to prevent buboes from rupturing. Although incision and drainage yields better results in such cases—since usually no further intervention is necessary, whereas repeat aspirations may be required— incision and drainage wounds may heal more slowly, increasing the risk of secondary infection.

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Bubonic plague

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The Plague (novel)

The Plague ( French : La Peste ) is a 1947 absurdist novel by Albert Camus . It tells the story from the point of view of a narrator in the midst of a plague sweeping the French Algerian city of Oran . The narrator remains unknown until the beginning of the last chapter. The novel presents a snapshot into life in Oran as seen through the author's distinctive absurdist point of view. Camus used as source material the cholera epidemic that killed a large proportion of Oran's population in 1849, but set the novel in the 1940s. Oran and its surroundings were struck by disease several times before Camus published his novel. According to an academic study, Oran was decimated by the bubonic plague in 1556 and 1678, but all later outbreaks (in 1921: 185 cases; 1931: 76 cases; and 1944: 95 cases) were very far from the scale of the epidemic described in the novel. The Plague is considered an existentialist classic despite Camus' objection to the label. The novel stresses the powerlessness of the individual characters to affect their own destinies. The narrative tone is similar to Kafka 's, especially in The Trial , whose individual sentences potentially have multiple meanings; the material often pointedly resonating as stark allegory of phenomenal consciousness and the human condition .The Narrator : the narrator presents himself at the outset of the book as witness to the events and privy to documents, but does not identify himself until the ending of the novel. The Prefect : The Prefect believes at first that the talk of plague is a false alarm, but on the advice of his medical association, he authorizes limited measures to combat it. When they do not work, he attempts to avoid responsibility, saying he will ask the government for orders. He later takes responsibility for tightening up the regulations relating to the plague and issues the order to close the town. Dr. Castel : Dr. Castel is one of Rieux's medical colleagues and is much older than Rieux. He realizes after the first few cases that the disease is bubonic plague and is aware of the seriousness of the situation. He works hard to make an antiplague serum, but as the epidemic continues, he shows increasing signs of wear and tear. M. Othon : M. Othon is a magistrate in Oran. He is tall and thin, and Tarrou describes him as follows: "Two small eyes, round, and hard, a thin nose, a horizontal mouth give the air of a well-brought-up owl." Othon treats his wife and children unkindly, but after his son Philippe dies of the plague, his character softens. After he finishes his time at the isolation camp, where he was sent because his son is infected, he wants to return there because it would make him feel closer to his lost son. However, before Othon can do this, he contracts the plague and dies. Philippe Othon : Philippe Othon is M. Othon's young son. When he contracts the plague, he is the first to receive Dr. Castel's antiplague serum. The serum is ineffective, and Philippe Othon dies after a long and painful struggle. Mme. Rieux : Mme. Rieux is Dr. Rieux's mother, who comes to stay with him when his sick wife goes to the sanatorium. She is a serene woman who, after taking care of the housework, sits quietly in a chair. She says that at her age, there is nothing much left to fear. Dr. Richard : Dr. Richard is chairman of the Oran Medical Association. He is slow to recommend any action to combat the plague for fear of public alarm. He does not want even to admit that the disease is the plague, referring instead to "a fever that had inguinal complications". M. Michel : M. Michel is the concierge of the building in which Rieux lives. An old man, he is the first victim of the plague. Raoul : Raoul is the man who agrees, for a fee of ten thousand francs, to arrange for Rambert to escape. He introduces Rambert to Gonzales. Gonzales : Gonzales is the smuggler who makes the arrangements for Rambert's escape and bonds with him over football. Asthma Patient : the asthma patient receives regular visits from Dr. Rieux. He is a seventy-five-year-old Spaniard with a rugged face, who comments on events in Oran that he hears about on the radio and in the newspapers. He sits in his bed all day and measures the passing of time by putting chickpeas from one jug into another. Louis : Louis is one of the sentries who take part in the plan for Rambert to escape. Marcel : Marcel, Louis's brother, is also a sentry who is part of the escape plan for Rambert. Garcia : Garcia is a man who knows the group of smugglers in Oran. He introduces Rambert to Raoul.The book begins with an epigraph quoting Daniel Defoe , author of A Journal of the Plague Year : In the town of Oran, thousands of rats, initially unnoticed by the populace, begin to die in the streets. Hysteria develops soon afterward, causing the local newspapers to report the incident. Authorities responding to public pressure order the collection and cremation of the rats, unaware that the collection itself was the catalyst for the spread of the bubonic plague . The main character, Dr. Bernard Rieux, lives comfortably in an apartment building when strangely the building's concierge, M. Michel, a confidante, dies from a fever. Dr. Rieux consults his colleague, Dr. Castel, about the illness until they come to the conclusion that a plague is sweeping the town. They both approach fellow doctors and town authorities about their theory but are eventually dismissed on the basis of one death. However, as more deaths quickly ensue, it becomes apparent that there is an epidemic. Meanwhile, Rieux's wife has been sent to a sanatorium in another city, to be treated for an unrelated chronic illness. Authorities, including the Prefect, are slow to accept that the situation is serious and quibble over the appropriate action to take. Official notices enacting control measures are posted, but the language used is optimistic and downplays the seriousness of the situation. A "special ward" is opened at the hospital, but its 80 beds are filled within three days. As the death toll begins to rise, more desperate measures are taken. Homes are quarantined; corpses and burials are strictly supervised. A supply of plague serum finally arrives, but there is enough to treat only existing cases, and the country's emergency reserves are depleted. When the daily number of deaths jumps to 30, the town is sealed, and an outbreak of plague is officially declared. The town is sealed off. The town gates are shut, rail travel is prohibited, and all mail service is suspended. The use of telephone lines is restricted only to "urgent" calls, leaving short telegrams as the only means of communicating with friends or family outside the town. The separation affects daily activity and depresses the spirit of the townspeople, who begin to feel isolated and introverted, and the plague begins to affect various characters. One character, Raymond Rambert, devises a plan to escape the city to join his wife in Paris after city officials refused his request to leave. He befriends some underground criminals so that they may smuggle him out of the city. Another character, Father Paneloux, uses the plague as an opportunity to advance his stature in the town by suggesting that the plague was an act of God punishing the citizens' sinful nature. His diatribe falls on the ears of many citizens of the town, who turned to religion in droves, but would not have done so under normal circumstances. Cottard, a criminal remorseful enough to attempt suicide but fearful of being arrested, becomes wealthy as a major smuggler. Meanwhile, Jean Tarrou, a vacationer; Joseph Grand, a civil engineer; and Dr. Rieux, exhaustively treat patients in their homes and in the hospital. Rambert informs Tarrou of his escape plan, but when Tarrou tells him that there are others in the city, including Dr. Rieux, who have loved ones outside the city whom they are not allowed to see, Rambert becomes sympathetic and offers to help Rieux fight the epidemic until he leaves town. In mid-August, the situation continues to worsen. People try to escape the town, but some are shot by armed sentries. Violence and looting break out on a small scale, and the authorities respond by declaring martial law and imposing a curfew. Funerals are conducted with more speed, no ceremony and little concern for the feelings of the families of the deceased. The inhabitants passively endure their increasing feelings of exile and separation. Despondent, they waste away emotionally as well as physically. In September and October, the town remains at the mercy of the plague. Rieux hears from the sanatorium that his wife's condition is worsening. He also hardens his heart regarding the plague victims so that he can continue to do his work. Cottard, on the other hand, seems to flourish during the plague because it gives him a sense of being connected to others, since everybody faces the same danger. Cottard and Tarrou attend a performance of Gluck 's opera Orfeo ed Euridice , but the actor portraying Orpheus collapses with plague symptoms during the performance. After extended negotiations with guards, Rambert finally has a chance to escape, but he decides to stay, saying that he would feel ashamed of himself if he left. Towards the end of October, Castel's new antiplague serum is tried for the first time, but it cannot save the life of Othon's young son, who suffers greatly, as Paneloux, Rieux, and Tarrou tend to his bedside in horror. Paneloux, who has joined the group of volunteers fighting the plague, gives a second sermon. He addresses the problem of an innocent child's suffering and says it is a test of a Christian's faith since it requires him either to deny everything or believe everything. He urges the congregation not to give up the struggle but to do everything possible to fight the plague. A few days after the sermon, Paneloux is taken ill. His symptoms do not conform to those of the plague, but the disease still proves fatal. Tarrou and Rambert visit one of the isolation camps, where they meet Othon. When Othon's period of quarantine ends, he chooses to stay in the camp as a volunteer because this will make him feel less separated from his dead son. Tarrou tells Rieux the story of his life. To take their mind off the epidemic, the two men go swimming together in the sea. Grand catches the plague and instructs Rieux to burn all his papers. However, Grand makes an unexpected recovery, and deaths from the plague start to decline. By late January, the plague is in full retreat, and the townspeople begin to celebrate the imminent opening of the town gates. Othon, however, does not escape death from the disease. Cottard is distressed by the ending of the epidemic from which he has profited by shady dealings. Two government employees approach him, and he flees. Despite the epidemic's ending, Tarrou contracts the plague and dies after a heroic struggle. Rieux is later informed via telegram that his wife has died at the sanatorium. In February, the town gates open and people are reunited with their loved ones from other cities. Rambert is reunited with his wife. Cottard goes mad and shoots at people from his home, and is soon arrested after a brief skirmish with the police. Grand begins working on his novel again. The narrator of the chronicle discloses his identity and states that he tried to present an objective view of the events. He reflects on the epidemic and declares he wrote the chronicle "to write simply about what can be learned in the middle of scourges, that there is more to admire in humans than there is to scorn". In the town of Oran, thousands of rats, initially unnoticed by the populace, begin to die in the streets. Hysteria develops soon afterward, causing the local newspapers to report the incident. Authorities responding to public pressure order the collection and cremation of the rats, unaware that the collection itself was the catalyst for the spread of the bubonic plague . The main character, Dr. Bernard Rieux, lives comfortably in an apartment building when strangely the building's concierge, M. Michel, a confidante, dies from a fever. Dr. Rieux consults his colleague, Dr. Castel, about the illness until they come to the conclusion that a plague is sweeping the town. They both approach fellow doctors and town authorities about their theory but are eventually dismissed on the basis of one death. However, as more deaths quickly ensue, it becomes apparent that there is an epidemic. Meanwhile, Rieux's wife has been sent to a sanatorium in another city, to be treated for an unrelated chronic illness. Authorities, including the Prefect, are slow to accept that the situation is serious and quibble over the appropriate action to take. Official notices enacting control measures are posted, but the language used is optimistic and downplays the seriousness of the situation. A "special ward" is opened at the hospital, but its 80 beds are filled within three days. As the death toll begins to rise, more desperate measures are taken. Homes are quarantined; corpses and burials are strictly supervised. A supply of plague serum finally arrives, but there is enough to treat only existing cases, and the country's emergency reserves are depleted. When the daily number of deaths jumps to 30, the town is sealed, and an outbreak of plague is officially declared.The town is sealed off. The town gates are shut, rail travel is prohibited, and all mail service is suspended. The use of telephone lines is restricted only to "urgent" calls, leaving short telegrams as the only means of communicating with friends or family outside the town. The separation affects daily activity and depresses the spirit of the townspeople, who begin to feel isolated and introverted, and the plague begins to affect various characters. One character, Raymond Rambert, devises a plan to escape the city to join his wife in Paris after city officials refused his request to leave. He befriends some underground criminals so that they may smuggle him out of the city. Another character, Father Paneloux, uses the plague as an opportunity to advance his stature in the town by suggesting that the plague was an act of God punishing the citizens' sinful nature. His diatribe falls on the ears of many citizens of the town, who turned to religion in droves, but would not have done so under normal circumstances. Cottard, a criminal remorseful enough to attempt suicide but fearful of being arrested, becomes wealthy as a major smuggler. Meanwhile, Jean Tarrou, a vacationer; Joseph Grand, a civil engineer; and Dr. Rieux, exhaustively treat patients in their homes and in the hospital. Rambert informs Tarrou of his escape plan, but when Tarrou tells him that there are others in the city, including Dr. Rieux, who have loved ones outside the city whom they are not allowed to see, Rambert becomes sympathetic and offers to help Rieux fight the epidemic until he leaves town.In mid-August, the situation continues to worsen. People try to escape the town, but some are shot by armed sentries. Violence and looting break out on a small scale, and the authorities respond by declaring martial law and imposing a curfew. Funerals are conducted with more speed, no ceremony and little concern for the feelings of the families of the deceased. The inhabitants passively endure their increasing feelings of exile and separation. Despondent, they waste away emotionally as well as physically.In September and October, the town remains at the mercy of the plague. Rieux hears from the sanatorium that his wife's condition is worsening. He also hardens his heart regarding the plague victims so that he can continue to do his work. Cottard, on the other hand, seems to flourish during the plague because it gives him a sense of being connected to others, since everybody faces the same danger. Cottard and Tarrou attend a performance of Gluck 's opera Orfeo ed Euridice , but the actor portraying Orpheus collapses with plague symptoms during the performance. After extended negotiations with guards, Rambert finally has a chance to escape, but he decides to stay, saying that he would feel ashamed of himself if he left. Towards the end of October, Castel's new antiplague serum is tried for the first time, but it cannot save the life of Othon's young son, who suffers greatly, as Paneloux, Rieux, and Tarrou tend to his bedside in horror. Paneloux, who has joined the group of volunteers fighting the plague, gives a second sermon. He addresses the problem of an innocent child's suffering and says it is a test of a Christian's faith since it requires him either to deny everything or believe everything. He urges the congregation not to give up the struggle but to do everything possible to fight the plague. A few days after the sermon, Paneloux is taken ill. His symptoms do not conform to those of the plague, but the disease still proves fatal. Tarrou and Rambert visit one of the isolation camps, where they meet Othon. When Othon's period of quarantine ends, he chooses to stay in the camp as a volunteer because this will make him feel less separated from his dead son. Tarrou tells Rieux the story of his life. To take their mind off the epidemic, the two men go swimming together in the sea. Grand catches the plague and instructs Rieux to burn all his papers. However, Grand makes an unexpected recovery, and deaths from the plague start to decline.By late January, the plague is in full retreat, and the townspeople begin to celebrate the imminent opening of the town gates. Othon, however, does not escape death from the disease. Cottard is distressed by the ending of the epidemic from which he has profited by shady dealings. Two government employees approach him, and he flees. Despite the epidemic's ending, Tarrou contracts the plague and dies after a heroic struggle. Rieux is later informed via telegram that his wife has died at the sanatorium. In February, the town gates open and people are reunited with their loved ones from other cities. Rambert is reunited with his wife. Cottard goes mad and shoots at people from his home, and is soon arrested after a brief skirmish with the police. Grand begins working on his novel again. The narrator of the chronicle discloses his identity and states that he tried to present an objective view of the events. He reflects on the epidemic and declares he wrote the chronicle "to write simply about what can be learned in the middle of scourges, that there is more to admire in humans than there is to scorn". Germaine Brée has characterised the struggle of the characters against the plague as "undramatic and stubborn", and in contrast to the ideology of "glorification of power" in the novels of André Malraux , whereas Camus' characters "are obscurely engaged in saving, not destroying, and this in the name of no ideology". Lulu Haroutunian has discussed Camus' own medical history, including a bout with tuberculosis, and how it informs the novel. Marina Warner notes its larger philosophical themes of "engagement", "paltriness and generosity", "small heroism and large cowardice", and "all kinds of profoundly humanist problems, such as love and goodness, happiness and mutual connection". Thomas L Hanna and John Loose have separately discussed themes related to Christianity in the novel, with particular respect to Father Paneloux and Dr Rieux. Louis R Rossi briefly discusses the role of Tarrou in the novel, and the sense of philosophical guilt behind his character. Elwyn Sterling has analysed the role of Cottard and his final actions at the end of the novel. Father Paneloux has been subject to several literary analyses in the context of faith faced with great suffering. Dr Rieux has been described as a classic example of an idealist doctor. He has also been an inspiration to the life and career of the French doctor Réjean Thomas, and also to the fictional character of Jeanne Dion, starring in the movie trilogy directed by Bernard Émond (beginning with The Novena ). Perri Klass has noted that at the time of the novel, sulfa drugs were available for treatment against plague, and has criticised the novel for this historical-medical omission. The novel has been read as an allegorical treatment of the French resistance to Nazi occupation during World War II. The novel became a bestseller during the worldwide COVID-19 pandemic of 2020 to the point that its British publisher Penguin Classics reported struggling to keep up with demand. The prescience of the fictional cordon sanitaire of Oran with real-life COVID-19 lockdowns worldwide brought revived popular attention. Sales in Italy tripled and it became a top-ten bestseller during its nationwide lockdown . Penguin Classics' editorial director said "it couldn't be more relevant to the current moment" and Camus' daughter Catherine said that the message of the novel had newfound relevance in that "we are not responsible for coronavirus but we can be responsible in the way we respond to it". As early as April 1941, Camus had been working on the novel, as evidenced in his diaries in which he wrote down a few ideas on "the redeeming plague". On 13 March 1942, he informed André Malraux that he was writing "a novel on the plague", adding "Said like that it might sound strange, […] but this subject seems so natural to me."

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Bubonic plague

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San Francisco plague of 1900–1904

The San Francisco plague of 1900–1904 was an epidemic of bubonic plague centered on San Francisco 's Chinatown . It was the first plague epidemic in the continental United States . The epidemic was recognized by medical authorities in March 1900, but its existence was denied for more than two years by California's Governor Henry Gage . His denial was based on business reasons, to protect the reputations of San Francisco and California and to prevent the loss of revenue due to quarantine. The failure to act quickly may have allowed the disease to establish itself among local animal populations. Federal authorities worked to prove that there was a major health problem, and they isolated the affected area; this undermined Gage's credibility, and he lost the governorship in the 1902 elections. The new governor, George Pardee , implemented public-health measures and the epidemic was stopped in 1904. There were 121 cases identified, resulting in 119 deaths. Much of urban San Francisco was destroyed by a fire in the 1906 San Francisco earthquake , including all of the Chinatown district. The process of rebuilding began immediately but took several years. While reconstruction was in full swing, a second plague epidemic hit San Francisco in May and August 1907 but it was not centered in Chinatown. Cases occurred randomly throughout the city, including cases identified across the bay in Oakland . San Francisco's politicians and press reacted very differently this time, wanting the problem to be solved speedily. Health authorities worked quickly to assess and eradicate the disease. Approximately $2 million was spent between 1907 and 1911 to kill as many rats as possible in the city in order to control one of the disease's vectors . In June 1908, 160 more cases had been identified, including 78 deaths, a much lower mortality rate than 1900–1904. All of the infected people were European, and the California ground squirrel was identified as another vector of the disease. The initial denial of the 1900 infection may have allowed the pathogen to gain its first toehold in America, from which it spread sporadically to other states in the form of sylvatic plague (rural plague). However, it is possible that the ground squirrel infection predated 1900. The third pandemic of the plague started in 1855 in China and eventually killed about 15 million people, mainly in India. In 1894, the plague hit Hong Kong , a major trade port between China and the US. US officials were worried that others would get infections from cargo carried by ships that would cross the Pacific Ocean. For these reasons, all ships were rigorously inspected. At that time, however, it was not widely known that rats could carry plague, and that fleas on those rats could transmit the disease to humans. Ships arriving in US ports were declared clean after inspection of the passengers showed no signs of disease. Health officials conducted no tests on rats or fleas. Despite important advances in the 1890s in the fight against bubonic plague, many of the world's doctors did not immediately change their ineffective and outdated methods. In November 1898, the US Marine Hospital Service (MHS) chief surgeon, James M. Gassaway, felt obliged to refute rumors of plague in San Francisco. Supported by the city's health officer, Gassaway said that some Chinese residents had died of pneumonia or lung edema, and it was not bubonic plague. In the newly formed US Territory of Hawaii , the city of Honolulu fell victim to the plague in December 1899. Residents of Honolulu were reporting cases of fever and swollen lymph glands forming buboes , with severe internal organ damage – quickly leading to death. Not knowing precisely how to control the spread of the disease, city health officials decided to burn infected houses. On January 20, 1900, changing winds fanned the flames out of control, and nearly all of Chinatown burned— 38 acres (15 ha) —leaving 6,000 without homes. The extensive maritime operations of the port of San Francisco caused concern among medical men such as Joseph J. Kinyoun , the chief quarantine officer of the MHS in San Francisco, about the infection spreading to California. A Japanese ship, the S.S. Nippon Maru , arriving in San Francisco Bay in June 1899, had two plague deaths at sea, and there were two more cases of stowaways found dead in the bay, with postmortem cultures proving they had the plague. In New York in November 1899, the British ship J.W. Taylor brought three cases of plague from Brazil, but the cases were confined to the ship. The Japanese freighter S.S. Nanyo Maru arrived in Port Townsend, Washington , on January 30, 1900, with 3 deaths out of 17 cases of confirmed plague. All of these ships were quarantined; they are not known to have infected the general population. However, it is possible that plague escaped some unknown ship by way of fleas or rats, later to infect US residents. In this atmosphere of grave danger, January 1900, Kinyoun ordered all ships coming to San Francisco from China, Japan, Australia and Hawaii to fly yellow flags to warn of possible plague on board. Many entrepreneurs and sailing men felt that this was bad for business, and unfair to ships that were free of plague. City promoters were confident that plague could not take hold, and they were unhappy with what they saw as Kinyoun's high-handed abuse of authority. On February 4, 1900, the Sunday magazine supplement of the San Francisco Examiner carried an article titled "Why San Francisco Is Plague-Proof". Certain American experts held the mistaken belief that a rice-based diet left Asians with a lower resistance to plague, and that a diet of meat kept Europeans free from this disease. In January 1900, the four-masted steamship S.S. Australia laid anchor in the Port of San Francisco . The ship sailed between Honolulu and San Francisco regularly, and its passengers and crew were declared clean. Cargo from Honolulu, unloaded at a dock near the outfall of Chinatown's sewers, may have allowed rats carrying the plague to leave the ship and transmit the infection. However, it is difficult to trace the infection to a single vessel. Wherever it came from, the disease was soon established in the cramped Chinese ghetto neighborhood; a sudden increase in dead rats was observed as local rats became infected. Rumors of the plague's presence abounded in the city, quickly gaining the notice of authorities from MHS stationed on Angel Island in San Francisco Bay , including Chief Kinyoun. A Chinese American named Chick Gin, Wing Chung Ging or Wong Chut King became the first official plague victim in California. The 41-year-old man, born in China and a San Francisco resident for 16 years, was a bachelor living in the basement of the Globe Hotel in Chinatown, at the intersection of the streets now called Grant and Jackson. The Globe Hotel was built in 1857, with the appearance of an Italian palazzo. However, by the mid-1870s it was a squalid tenement crowded with Chinese residents. Just outside, Jackson Street was the Chinese red-light district, where unmarried men could visit "hundred-men's-wives". On February 7, 1900, Wong Chut King, the owner of a lumber yard, fell sick with what the Chinese doctors thought was typhus or gonorrhea , the latter a sexually transmitted disease common to Chinatown's residents at that time. After failed medications and no relief for his illness, he died in his bed after suffering for four weeks. In the morning, the body was taken to a Chinese undertaker, where it was examined by San Francisco police surgeon Frank P. Wilson on March 6, 1900. Wilson called for A.P. O'Brien, a city health department officer, after finding suspiciously swollen lymph glands. Wilson and O'Brien then summoned Wilfred H. Kellogg, San Francisco's city bacteriologist, and the three men performed an autopsy as night closed. Looking through his microscope, Kellogg thought he saw plague bacilli. Late at night, Kellogg ran the suspicious samples of lymph fluid to Angel Island to be tested on animals in Kinyoun's better-equipped laboratory – an operation that would take at least four days. Meanwhile, Wilson and O'Brien called upon the city's Board of Health and insisted that Chinatown be quarantined immediately. When dawn came on March 7, 1900, Chinatown was circled by rope and surrounded by policemen preventing egress or access to anyone but Whites. The 12-block area was bordered by four streets: Broadway, Kearney, California and Stockton. Approximately 25,000–35,000 residents were unable to leave. Chinese Consul General Ho Yow felt that the quarantine was likely based on false assumptions and that it was entirely unfair to Chinese people and would seek an injunction to lift the quarantine. San Francisco mayor James D. Phelan was in favor of keeping the Chinese-speaking residents separated from the Anglo-Americans – claiming that Chinese Americans were unclean, filthy, and "a constant menace to the public health." Nevertheless, the Board of Health lifted the quarantine on March 9 after it had been in force for only 2½ days. O'Brien said, by way of explanation, that "the general clamor had become too great to ignore". The animals tested in Kinyoun's lab seemed to be in normal conditions after the first 48 hours of being exposed to the possible plague-causing agents. The lack of early response cast doubt on the theory that plague was the cause of Wong Chut King's death. On March 11, Kinyoun's lab presented its results. Two guinea pigs and one rat died after being exposed to samples from the first victim, proving the plague was indeed in Chinatown. Without restoring the quarantine, the Board of Health inspected every building in Chinatown, and labored to disinfect the neighborhood. Property was taken and burned if it was suspected of harboring filth. Using physical violence, policemen enforced compliance with the Board of Health's directives. Angry and worried Chinese communities reacted by hiding those that were sick. On March 13, another lab animal, a monkey that was exposed to the plague, died. All of the dead animals tested positive for the plague bacteria. U.S. Surgeon General Walter Wyman informed the San Francisco doctors at the end of March 1900 that his laboratory confirmed the fact that fleas can carry the plague and transmit it to a new host. Allied with powerful railroad and city business interests, California governor Henry Gage publicly denied the existence of any pestilent outbreak in San Francisco, fearing that any word of the bubonic plague 's presence would deeply damage the city's and state's economy. Supportive newspapers, such as the Call , the Chronicle and the Bulletin , echoed Gage's denials, beginning what was to become an intense defamation campaign against quarantine officer Kinyoun. In response to the state's denial, Wyman recommended to federal Treasury Secretary Lyman J. Gage that he intervene. Secretary Gage agreed, creating a three-man commission of investigators who were respected medical scholars, experienced with identifying and treating the plague in China or India. The commission examined six San Francisco cases and conclusively determined that bubonic plague was present. As with the findings of Kinyoun, the Treasury commission's findings were again immediately denounced by Governor Gage. Gage believed the federal government's growing presence in the matter was a gross intrusion of what he viewed as a state concern. In his retaliation, Gage denied the federal commission any use of the University of California's laboratories in Berkeley to further study the outbreak, by threatening the university's state funding. The Bulletin also attacked the federal commission, branding it as a "youthful and inexperienced trio." The clash between Gage and federal authorities intensified. Wyman instructed Kinyoun to place Chinatown under a second quarantine, as well as blocking all East Asians from entering state borders. Wyman also instructed Kinyoun to inoculate all persons of Asian heritage in Chinatown, using an experimental vaccine developed by Waldemar Haffkine , one known to have severe side effects. Spokesmen in Chinatown protested strenuously; they did not give their permission for this kind of mass experimentation. The Chinese Consolidated Benevolent Association , also known as the Six Companies, filed suit on behalf of Wong Wai, a merchant who took a stance against what he perceived as a violation of his personal liberty. Not quite a class action suit , the arguments included similar wording such as complaints that all residents of Chinatown were being denied "equal protection under the law" , part of the Fourteenth Amendment to the US constitution. Federal judge William W. Morrow ruled uncharacteristically in favor of the Chinese, largely because the defense by the State of California was unable to prove that Chinese Americans were more susceptible to plague than Anglo Americans. The decision set a precedent for greater limits placed on public health authorities seeking to isolate diseased populations. Between 1901 and 1902, the plague outbreak continued to worsen. In a 1901 address to both houses of the California State Legislature , Gage accused federal authorities, particularly Kinyoun, of injecting plague bacteria into cadavers , falsifying evidence. In response to what he said to be massive scaremongering by the MHS, Gage pushed a censorship bill to gag any media reports of plague infection. The bill failed in the California State Legislature , yet laws to gag reports amongst the medical community succeeded in passage and were signed into law by the governor. In addition, $100,000 was allocated to a public campaign led by Gage to deny the plague's existence. Privately, however, Gage sent a special commission to Washington, D.C. , consisting of Southern Pacific , newspaper and shipping lawyers to negotiate a settlement with the MHS, whereby the federal government would remove Kinyoun from San Francisco with the promise that the state would secretly cooperate with the MHS in stamping out the plague epidemic. Rupert Blue was appointed in Kinyoun's place. Despite the secret agreement allowing for Kinyoun's removal, Gage went back on his promise of assisting federal authorities and continued to obstruct their efforts for study and quarantine. A report issued by the State Board of Health on September 16, 1901, bolstered Gage's claims, denying the plague's outbreak. Widespread racism toward Chinese immigrants was socially accepted during the initial time of the Chinatown plague in the early 1900s. Standard social rights and privileges were often denied to the Chinese people, as shown in the way landlords would refuse to maintain their own property when renting to Chinese immigrants. The living conditions in the Chinatown community reflected the social norms and racial inequalities during that time for Chinese immigrants. Housing for the majority of Chinatown Chinese immigrants was not fit nor adequate for human living, but with scarce housing options and landlords unwilling to provide equal and fair housing, Chinese immigrants were left little option other than to live with such housing disparities. Discrimination against Chinese Americans culminated in two acts, the quarantine of San Francisco's Chinatown, and the permanent extension of the Chinese Exclusion Act of 1882. The extended quarantine of Chinatown was motivated more by racist images of Chinese Americans as carriers of disease than by actual evidence of the presence of Bubonic plague . San Francisco's quarantine measures were explicitly discriminatory and segregatory, allowing European Americans to leave the affected area, but Chinese and Japanese Americans required a health certificate to leave the city. Residents were initially angered as those with jobs outside of San Francisco were prevented from working. Few Chinese agreed to take the inoculation, especially after press reports on May 22, 1900, that people who did agree were experiencing severe pain from the untested vaccine. On May 24, 1900, with the help of Chinese Six Companies , they hired the law firm of Reddy, Campbell, and Metson. Defendants included Joseph J. Kinyoun and all of the members of the San Francisco Board of Health. The Chinese wanted the courts to issue a provisional injunction to enforce what they argued was their constitutional right to travel outside of San Francisco. On July 3, 1900, Judge William W. Morrow ruled that the defendants were violating the plaintiffs' Fourteenth Amendment rights. The ruling required that the same restrictions, if any, be applied to everyone no matter their ethnic group. The defendants did not have enough evidence to prove that the Chinese were transmitting the plague. Morrow agreed with the argument that if they were, the city would not have permitted them to roam the streets of San Francisco. The Board then "attempted to sidestep the decision by instituting a quarantine order that avoided mention of race, but which was precisely drafted so as to encompass all of the Chinatown area of San Francisco while excluding white-owned businesses on the periphery of that area"; this effort was also struck down, with the court noting that the boundaries of the quarantine corresponded with the ethnicity of building occupants rather than the presence of the disease. Upon the death of Wong Chut King, the San Francisco Health Board took immediate action to prevent the spread of plague: Chinatown was quarantined. Health officials, in order to prevent the propagation of the disease, made the decision of placing Chinatown under quarantine, without any notice to the residents – targeting Chinese residents only. White Americans that were walking the streets of Chinatown were allowed to leave; everybody else was forced to stay. Physicians were restricted from crossing into Chinatown to identify and help the sick. The Health Board had to approve whether or not any health official crossed into the quarantined area. Due to lack of evidence that the cause of death of King was plague, the quarantine was removed the day after to avoid controversy. Kinyoun's lab confirmed the disease was bubonic plague and informed the Health Board right away. In an attempt to avoid a second controversial quarantine, the Health Board continued with a house-to-house inspection to look for possible plague infested households – disinfecting those that were thought to be at risk of infection. Participants in the house-to-house examination were mainly volunteer physicians and residents. On the contrary, other residents did not support the inspection and argued that the disinfecting plan was not being done in good faith. Believing a second quarantine would be soon implemented, worried residents began to flee quietly and hide in friends' houses outside of Chinatown . As days passed, more dead bodies were reported and autopsies revealed the presence of plague bacilli, indicating that a plague epidemic had hit San Francisco's Chinatown, but the health board still was trying to deny it. The health board attempted to keep all the information regarding the outbreak secret by implementing strict regulations of what physicians could write official death certificates. Nevertheless, newspapers published the news of the presence of bubonic plague in San Francisco to the entire nation, especially William Randolph Hearst 's New York Journal which published a special plague edition. The official inspection and disinfection of Chinatown finally began, thanks to the monetary contributions of the supervisors of the volunteer physicians, policemen, and inspectors that participated in the actual disinfection campaign. The sanitizing of Chinatown began to show results as the death toll slowly dropped throughout the month of March and the beginning of April. Towards the end of April, the corpse of Law An, a Chinese laborer from a village near the Sacramento River , was found in an alley in Chinatown. The cause of death of Law An was determined to be bubonic plague. After that, a few more Chinese residents that died suddenly were determined to be infested with plague bacilli. The fear that the bubonic plague was spreading intensified. The controversy of the vaccination program organized by Kinyoun with the help of Surgeon General Wyman spiked. The plan was to inoculate the Chinese residents with Haffkine's vaccine , a prophylactic anti-plague vaccine that was intended to provide some protection against the plague for a 6-month period. No one spoke about the side effects and that the vaccine was still not approved for humans. Most Chinese residents refused and demanded the vaccine to be tested in rats first. At first, representatives of the Chinese community had agreed that inoculating the population with such serum could be a reasonable and safe solution, but soon after agreed with the rest of the Chinese population in that it was not ethical to try the vaccine in humans first. The representatives from the Chinese Six companies demanded the vaccination program to be eliminated as an option, and with much pressure and insistence from the Chinese community the vaccination program was halted. Joseph J. Kinyoun was feeling the pressure of the public to clear his reputation. He summoned the help of U.S. Surgeon General Walter Wyman to bring someone from the outside to investigate Kinyoun's procedures. In December 1900 Wyman selected Assistant Surgeon General Joseph H. White to manage the investigation surrounding all of the Pacific Coast stations. White wanted to focus on how food was handled while being imported from China and Japan. Kinyoun tried to hinder these advances because he did not want to publicly admit that there was an outbreak. White made his appearance in January 1901. White and Kinyoun attended the autopsy of Chun Way Lung who was said to have suffered from gonorrhea. Wilfred Kellogg and Henry Ryfkogel conducted the autopsy and achieved respect from White by revealing that Lung had died from the bubonic plague . White concluded that Kinyoun's bacteriological confirmation could no longer be credible. Governor Gage refused to support the diagnoses that were verified by the competent Pasteurians in San Francisco. Kinyoun was starting to express his frustration and suggested that independent outside experts confirm that the plague was present. White agreed and passed this information to the surgeon general. Kinyoun desired that his reputation be restored and that his findings were valid so that he could continue to investigate plague cases. On January 26, Flexner, Novy, and Barker arrived in San Francisco. The three scientists were appointed to an official commission to prove if the plague existed. Gage reacted by sending a telegram to President William McKinley urging that the federal experts work with state health authorities. Gage's request was not granted because the federal government wanted the commission to be allowed to work independently. They would relay all of their findings to the treasury department and then forwarded to Gage. Flexner, Novy, and Barker scheduled an inspection of the sick and dead on February 6. The federal investigators split up the duties. Novy carried out bacteriological tests, while Barker accompanied by a Chinese interpreter visited the sick. By February 12, the team had studied six cases that all identified the characteristics of bubonic plague. This was confirmed by pathological and bacteriological data. Flexner, Novy, and Barker completed their investigation on February 16. They met with Governor Gage the same day and informed him of their conclusion. Gage was upset and accused them of being a threat to public health. Over the next few weeks Gage questioned the diagnoses and blocked the publication of the final report. He blamed the commission of being biased and influenced by Kinyoun. Finally the two senators for California proposed that Gage needed to engage in friendly cooperation with federal authorities. Gage sent representatives to Washington to reach an agreement for federal authorities to suppress their findings concerning the plague in San Francisco. The federal authorities agreed to these demands after Gage's representatives verbally pledged to manage a sanitary campaign in Chinatown. This would be done secretively under the guidance of an expert from the Marine Hospital Service This deal was designed to avoid impairing the state's reputation and economy. Surgeon general Wyman took the majority of the blame. He was accused of violating U.S. laws and breaking international agreements that required him to notify all nations that there was an existence of contagious disease. Wyman and President McKinley destroyed the credibility of the American public health in the eyes of the nation and abroad. Countering the continued denials made by San Francisco-based newspapers, reports from the Sacramento Bee and the Associated Press describing the plague's spread, publicly announced the outbreak throughout the United States. The state governments of Colorado , Texas and Louisiana imposed quarantines of California – arguing that since the state had refused to admit to a health crisis within its borders, states receiving rail or shipping cargo from California ports had the duty to protect themselves. Threats of a national quarantine grew. As the 1902 general elections approached, members of the Southern Pacific board and the "Railroad Republican" faction increasingly saw Gage as an embarrassment to state Republicans . Gage's public denials of the plague outbreak were to protect the state's economy and the business interests of his political allies. However, reports from federal agencies and certain newspapers continued to prove Gage incorrect. Other states were moving to quarantine or boycott California, and the powerful shipping and rail companies sought a new leader. At the state Republican convention that year, the Railroad Republican faction refused Gage's renomination for governorship. In his place, former Mayor of Oakland George Pardee , a German-trained medical physician, received the nomination. Pardee's nomination was largely a compromise between the Railroad Republican factions. In his final speech, to the California State Legislature, in early January 1903, Gage continued to deny the outbreak. He blamed the federal government, in particular, Kinyoun, the MHS, and the San Francisco Board of Health for damaging the state's economy. Upon the death of Wong Chut King, the San Francisco Health Board took immediate action to prevent the spread of plague: Chinatown was quarantined. Health officials, in order to prevent the propagation of the disease, made the decision of placing Chinatown under quarantine, without any notice to the residents – targeting Chinese residents only. White Americans that were walking the streets of Chinatown were allowed to leave; everybody else was forced to stay. Physicians were restricted from crossing into Chinatown to identify and help the sick. The Health Board had to approve whether or not any health official crossed into the quarantined area. Due to lack of evidence that the cause of death of King was plague, the quarantine was removed the day after to avoid controversy. Kinyoun's lab confirmed the disease was bubonic plague and informed the Health Board right away. In an attempt to avoid a second controversial quarantine, the Health Board continued with a house-to-house inspection to look for possible plague infested households – disinfecting those that were thought to be at risk of infection. Participants in the house-to-house examination were mainly volunteer physicians and residents. On the contrary, other residents did not support the inspection and argued that the disinfecting plan was not being done in good faith. Believing a second quarantine would be soon implemented, worried residents began to flee quietly and hide in friends' houses outside of Chinatown . As days passed, more dead bodies were reported and autopsies revealed the presence of plague bacilli, indicating that a plague epidemic had hit San Francisco's Chinatown, but the health board still was trying to deny it. The health board attempted to keep all the information regarding the outbreak secret by implementing strict regulations of what physicians could write official death certificates. Nevertheless, newspapers published the news of the presence of bubonic plague in San Francisco to the entire nation, especially William Randolph Hearst 's New York Journal which published a special plague edition. The official inspection and disinfection of Chinatown finally began, thanks to the monetary contributions of the supervisors of the volunteer physicians, policemen, and inspectors that participated in the actual disinfection campaign. The sanitizing of Chinatown began to show results as the death toll slowly dropped throughout the month of March and the beginning of April. Towards the end of April, the corpse of Law An, a Chinese laborer from a village near the Sacramento River , was found in an alley in Chinatown. The cause of death of Law An was determined to be bubonic plague. After that, a few more Chinese residents that died suddenly were determined to be infested with plague bacilli. The fear that the bubonic plague was spreading intensified. The controversy of the vaccination program organized by Kinyoun with the help of Surgeon General Wyman spiked. The plan was to inoculate the Chinese residents with Haffkine's vaccine , a prophylactic anti-plague vaccine that was intended to provide some protection against the plague for a 6-month period. No one spoke about the side effects and that the vaccine was still not approved for humans. Most Chinese residents refused and demanded the vaccine to be tested in rats first. At first, representatives of the Chinese community had agreed that inoculating the population with such serum could be a reasonable and safe solution, but soon after agreed with the rest of the Chinese population in that it was not ethical to try the vaccine in humans first. The representatives from the Chinese Six companies demanded the vaccination program to be eliminated as an option, and with much pressure and insistence from the Chinese community the vaccination program was halted. Joseph J. Kinyoun was feeling the pressure of the public to clear his reputation. He summoned the help of U.S. Surgeon General Walter Wyman to bring someone from the outside to investigate Kinyoun's procedures. In December 1900 Wyman selected Assistant Surgeon General Joseph H. White to manage the investigation surrounding all of the Pacific Coast stations. White wanted to focus on how food was handled while being imported from China and Japan. Kinyoun tried to hinder these advances because he did not want to publicly admit that there was an outbreak. White made his appearance in January 1901. White and Kinyoun attended the autopsy of Chun Way Lung who was said to have suffered from gonorrhea. Wilfred Kellogg and Henry Ryfkogel conducted the autopsy and achieved respect from White by revealing that Lung had died from the bubonic plague . White concluded that Kinyoun's bacteriological confirmation could no longer be credible. Governor Gage refused to support the diagnoses that were verified by the competent Pasteurians in San Francisco. Kinyoun was starting to express his frustration and suggested that independent outside experts confirm that the plague was present. White agreed and passed this information to the surgeon general. Kinyoun desired that his reputation be restored and that his findings were valid so that he could continue to investigate plague cases. On January 26, Flexner, Novy, and Barker arrived in San Francisco. The three scientists were appointed to an official commission to prove if the plague existed. Gage reacted by sending a telegram to President William McKinley urging that the federal experts work with state health authorities. Gage's request was not granted because the federal government wanted the commission to be allowed to work independently. They would relay all of their findings to the treasury department and then forwarded to Gage. Flexner, Novy, and Barker scheduled an inspection of the sick and dead on February 6. The federal investigators split up the duties. Novy carried out bacteriological tests, while Barker accompanied by a Chinese interpreter visited the sick. By February 12, the team had studied six cases that all identified the characteristics of bubonic plague. This was confirmed by pathological and bacteriological data. Flexner, Novy, and Barker completed their investigation on February 16. They met with Governor Gage the same day and informed him of their conclusion. Gage was upset and accused them of being a threat to public health. Over the next few weeks Gage questioned the diagnoses and blocked the publication of the final report. He blamed the commission of being biased and influenced by Kinyoun. Finally the two senators for California proposed that Gage needed to engage in friendly cooperation with federal authorities. Gage sent representatives to Washington to reach an agreement for federal authorities to suppress their findings concerning the plague in San Francisco. The federal authorities agreed to these demands after Gage's representatives verbally pledged to manage a sanitary campaign in Chinatown. This would be done secretively under the guidance of an expert from the Marine Hospital Service This deal was designed to avoid impairing the state's reputation and economy. Surgeon general Wyman took the majority of the blame. He was accused of violating U.S. laws and breaking international agreements that required him to notify all nations that there was an existence of contagious disease. Wyman and President McKinley destroyed the credibility of the American public health in the eyes of the nation and abroad. Countering the continued denials made by San Francisco-based newspapers, reports from the Sacramento Bee and the Associated Press describing the plague's spread, publicly announced the outbreak throughout the United States. The state governments of Colorado , Texas and Louisiana imposed quarantines of California – arguing that since the state had refused to admit to a health crisis within its borders, states receiving rail or shipping cargo from California ports had the duty to protect themselves. Threats of a national quarantine grew. As the 1902 general elections approached, members of the Southern Pacific board and the "Railroad Republican" faction increasingly saw Gage as an embarrassment to state Republicans . Gage's public denials of the plague outbreak were to protect the state's economy and the business interests of his political allies. However, reports from federal agencies and certain newspapers continued to prove Gage incorrect. Other states were moving to quarantine or boycott California, and the powerful shipping and rail companies sought a new leader. At the state Republican convention that year, the Railroad Republican faction refused Gage's renomination for governorship. In his place, former Mayor of Oakland George Pardee , a German-trained medical physician, received the nomination. Pardee's nomination was largely a compromise between the Railroad Republican factions. In his final speech, to the California State Legislature, in early January 1903, Gage continued to deny the outbreak. He blamed the federal government, in particular, Kinyoun, the MHS, and the San Francisco Board of Health for damaging the state's economy.

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Bubonic plague

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1894 Hong Kong plague

The 1894 Hong Kong plague , part of the third plague pandemic , was a major outbreak of the bubonic plague in Hong Kong . While the plague was harshest in 1894, it returned annually between 1895 and 1929, and killed over 20,000 in total, with a fatality rate of more than 93%. The plague was a major turning point in the history of colonial Hong Kong, as it forced the colonial government to reexamine its policy towards the Chinese community, and invest in the wellbeing of the Chinese.It is thought that the pandemic originated from Yunnan , China, which saw an outbreak as early as 1792, in 1855 and again in 1866–7. An outbreak in neighboring city of Guangzhou from January 1894 onwards killed 80,000. From March 1894, British scientists and doctors in Hong Kong became aware of the outbreak in China. By the end of April, the government in Hong Kong requested Dr. Alexander Rennie, the consular surgeon for Canton, to report on the disease. Rennie identified it as the bubonic plague, but said it would not be not particularly contagious except to those living in filth, poor ventilation, and with a poor water supply. The spread to Hong Kong from Guangdong was accelerated by the unrestricted movement of workers and boats into Hong Kong. The outbreak also coincided with the replacement of junks with steamships, which made travel between infected ports faster and more convenient, and the return of Chinese celebrating Qingming Festival from Guangzhou to Hong Kong. On March 2, 1894, a large Chinese procession was held in Hong Kong, which involved the arrival of 40,000 laborers from Canton. The Chinese-majority Tai Ping Shan district, where the first cases appeared, was characterized by having poor ventilation, drainage and sanitary services, and was overcrowded. In 1880, Colonial Surgeon Dr. Philip Burnard Chenery Ayres reported that, while he was investigating the sanitary conditions of the Chinese, "many and many a time have I come out of the houses to vomit in the street, in spite of using strong scents and essences to prevent it," and he warned that "while this state of things continues we stand in danger of being visited at any moment by some fearful epidemic, and I do not think the most advanced sanitary authority at home would combat this opinion." In 1881, Royal Commissioner Osbert Chadwick was sent to Hong Kong to investigate the sanitation situation of Hong Kong. Chadwick proposed improvements on drainage, water supply and night soil removal system, which he hoped to be implemented "without waiting for the necessity to be demonstrated by the irresistible logic of a severe epidemic." His recommendations were not acted upon on, save for the establishment of the Sanitary Board. The summer of 1894 saw Hong Kong suffering from a dry spell, which did not wash away the usual house refuse accumulating on the streets. This helped the growth of rats and fleas, and was thought to have accelerated the spread of the plague. The Chinese-majority Tai Ping Shan district, where the first cases appeared, was characterized by having poor ventilation, drainage and sanitary services, and was overcrowded. In 1880, Colonial Surgeon Dr. Philip Burnard Chenery Ayres reported that, while he was investigating the sanitary conditions of the Chinese, "many and many a time have I come out of the houses to vomit in the street, in spite of using strong scents and essences to prevent it," and he warned that "while this state of things continues we stand in danger of being visited at any moment by some fearful epidemic, and I do not think the most advanced sanitary authority at home would combat this opinion." In 1881, Royal Commissioner Osbert Chadwick was sent to Hong Kong to investigate the sanitation situation of Hong Kong. Chadwick proposed improvements on drainage, water supply and night soil removal system, which he hoped to be implemented "without waiting for the necessity to be demonstrated by the irresistible logic of a severe epidemic." His recommendations were not acted upon on, save for the establishment of the Sanitary Board. The summer of 1894 saw Hong Kong suffering from a dry spell, which did not wash away the usual house refuse accumulating on the streets. This helped the growth of rats and fleas, and was thought to have accelerated the spread of the plague. The first case was discovered by Scottish doctor James Alfred Lowson, acting superintendent of the Government Civil Hospital , on May 8, 1894. The patient, named "A. Hung", was a ward boy, presumably working in the Government Civil Hospital. "A. Hung" died 5 days later. On May 10, 1894, the city was declared an infected port. On the same day, a Sanitary Board meeting was convened. The Sanitary Board was headed by James Stewart Lockhart . At the meeting, Lowson argued for a strong quarantine policy, including the removal of Chinese from their houses. Some on the Board, including Dr. Kai Ho , expressed concerns that the policy would offend the Chinese, and that the Chinese would refuse to comply to such government policies. The Sanitary Board opted to follow the advice of Lowson. On May 12, a Permanent Committee was formed to enforce quarantine measures. The committee was chaired by J. J. Francis and included Captains-superintendent Francis Henry May and Ayres. Lowson was given de facto charge to contain and combat the plague. On May 11, legislation was passed to make the reporting of cases compulsory, and to allow authorities to enter houses to search for and remove infected persons for isolation. House-to-house inspection and disinfection was performed by the local garrison, the Shropshire Light Infantry . The inspection and disinfection team was known as the "Whitewash Brigade", consisting of around 300 men and 8 officers. During an inspection, the occupants were given new clothes, and sent to temporary lodgings on Chinese boats anchored off Stonecutters Island or to government-hired buildings, including the Alice Memorial and Nethersole Hospitals . Their own clothes and fabrics in the house would be sent to a steam disinfecting station. The house was then sprayed with a solution of perchloride of mercury or fumigated by chlorine gas , the floor and furniture cleaned with Jeyes Fluid and the walls lime-washed ("whitewashing"). Household items suspected of being contaminated were burnt. Members of the Shropshire regiment became the first Europeans to be affected by the plague. At least one officer died to the disease. At the time, Chinese residents of Hong Kong had a deep mistrust for Western medical science, making the containment of the plague difficult. The distrust was exacerbated by ineffective treatment and highly intrusive policies by the colonial government. The Chinese would hide their sick from the authorities, and infected bodies would be thrown out at night to avoid detection. The western practice of using ice to cool down a fever was rejected by the Chinese, who viewed extreme cold as damaging to the body. The quick and hasty burials performed by the government, with the bodies covered in quicklime , were also offensive to the Chinese. In 1903, the government had to reimburse the cost of disinfected clothing to the Chinese, as they had disliked the smell of disinfectant. The house-to-house inspection was especially resisted by the Chinese community. Chinese ladies were reluctant to let strangers, let alone foreigners, enter their boudoirs . Rumors of British soldiers seeking to rape Chinese women arose. In one instance, on May 19, the Whitewash Brigade was pelted with stones, bricks and rubbish. In another instance, around 100 women, relatives of the deceased, organized a meeting at Tung Wah Hospital , where they wailed and cried against the community leaders and hospital administration. The government responded to the meeting by forbidding searchers to enter Chinese households without permission, and by allowing patients to choose Chinese treatment in Chinese hospitals. Members of the Chinese community continued to petition Governor William Robinson to halt the cleansing operations completely, and to allow patients to travel to China to seek treatment. Robinson initially refused, but when compradors of major hongs threatened to have their staff leave their posts, Robinson allowed patients to travel to Guangzhou for treatment, and corpses to be transported there for burials. However, the whitewashing operations was to be continued. As a result, an anti-government poster campaign was launched in Canton and Hong Kong. This inflamed more rumours against the English doctors, who were said to be making medicine with the bodies of plague victims. Robinson responded by moving the gunboat HMS Tweed to Taipingshan and offering a reward for information leading to the arrest of the poster distributors. Viceroy Li Hanzhang of Canton was also requested to make a statement to deny the rumours. However, these efforts proved ineffective in building trust between the Western and Chinese communities. Whitewashing could only continue after a great deal of persuasion and explanation by both the government and some esteemed members of the Chinese community. After a time, the operations were suspended. Established hospitals around the major areas of outbreak would only accept suspected patients for observation. Once the symptoms of plagues appeared, they would be moved to specialized plague hospitals. The plague hospitals included a temporary hospital at the Kennedy Town Police Station (known as the "Kennedy Town Hospital", opened on May 14 ) and the hospital ship Hygeia ( Chinese : 海之家 ), ran by staff of the Nethersole Hospital. When patients were removed according to the policy from Tung Wah Hospital to Hygeia , violent protest erupted in the city. Tung Wah Hospital had been a reputable hospital in the Chinese community. It practiced Chinese medicine and was seen as a symbol of Chinese independence in a colonial city. Thus, the hospital came under fire from the Chinese community when they allowed patients to be transferred away to plague hospitals. At one point, doctors had to carry pistols to protect themselves. The riots led to the establishment of a temporary plague hospital at Kennedy Town glass works, known as the "Glassworks Hospital" on May 21. This hospital would be manned by staff from the Tung Wah Hospital. The patients were offered a choice between the Glassworks Hospital and plague hospitals with European staff. The Chinese-majority patients overwhelmingly chose the Glassworks Hospital. The hospital quickly becoming overcrowded and sanitary conditions worsened. On June 8, another temporary hospital at an unfinished pig depot was also set up, known as the "Slaughterhouse Hospital", again manned by staff from Tung Wah Hospital, in hopes of relieving the situation at the Glassworks Hospital. When the Chinese medicine offered by the Glassworks Hospital proved to be ineffective, and conditions of the hospital continued to worsen, it was closed down on June 16, and its patients were transferred to either Guangzhou or to the Slaughterhouse Hospital. Subsequently, a "New Glassworks Hospital" was set up at the site, this time staffed by European doctors from the Alice Memorial and Nethersole Hospitals. In July, a hospital was established in Lai Chi Kok near a graveyard but it did not receive any patients. This was attributed to the Chinese refusing to be admitted into the hospital as they felt "they were sure to die." Hygeia was later used only to house European, Eurasian and Japanese patients. The plague saw a mass exodus of panic-stricken Chinese workers back to China, causing a significant economic downturn in the city. The North-China Herald noted that "it is not the plague they are flying from, as they are going to the nest at Canton from which [the plague] came to Hong Kong. They seem rather to be flying from the sanitary measures taken in Hong Kong." Some were seeking a proper burial on Chinese grounds. At the height of the plague, around 1,000 persons were leaving Hong Kong daily. In May and June, it was estimated that 80,000 to 90,000 Chinese, out of a population of 200,000, left Hong Kong Island. Owners of hongs left for China, leaving the businesses to caretakers, slowing down the business operations. The colony suffered a severe labour shortage. Inflation followed, with prices of food items rising by 30 to 50 percent. As visitors to Hong Kong had to be quarantined, trade between Hong Kong and China was decimated. In June, Robinson reported to Secretary of State for the Colonies Lord Ripon that "without exaggeration I may assert that so far as trade and commerce are concerned the plague has assumed the importance of an unexampled calamity." On May 31, a bylaw drawn up by the Sanitary Board allowed for the eviction and closure of houses deemed unfit for habitation. Houses on the streets of Kau Yu Fong ( Chinese : 九如坊 ), Sin Hing Lee ( Chinese : å–„æ ¶é‡Œ ), Nga Choi Hong ( Chinese : 芽菜巷 ) and Mei Lun Lee ( Chinese : 美侖里 ) were demolished, and a brick wall was erected surrounding those areas. In September, 1894, the Taipingshan Resumption Ordinance was passed, allowing the resumption of an area of about 10 acres in the Taipingshan district. The area accounted for 50 percent of the cases, and 385 houses in the area were destroyed. Around 7,000 inhabitants were displaced. The area was walled up, and guards were stationed to prevent residents from re-entry. This drastic measure called for, as described by Robinson, "the destruction and rebuilding of one tenth part of Hong Kong." Reconstruction began in the end of 1895 and lasted until 1898. Drainage systems were improved, and balconies were installed for better ventilation. An area was marked out for the construction of a Bacteriological Institute. A public park was also constructed. It was named Blake Garden after then-Governor Henry Arthur Blake . Today, a plaque stands at the park, commemorating the deadly epidemic. At the peak of the 1894 plague, admissions to hospital averaged at 80 a day, and death peaked at over 100 per day. Taipingshan was not the only area affected by the plague. Areas such as Bowrington (now between today's Wan Chai and Causeway Bay ), Sai Ying Pun , Shek Tong Tsui and Kennedy Town saw more deaths than Taipingshan. Internationally, steamships from Hong Kong carried the bacillus to every major seaport in the world, including to India. The plague subsided with the arrival of cold weather, in the winter of 1894. In 1895, only 44 cases were reported, but the plague returned strongly in 1896, affecting mostly Chinese in the Taipingshan district. Once again it subsided in winter, and returned almost annually thereafter. The plague lasted until 1929, when the last cases were recorded. In total, between 1894 and 1929, there were over 24,000 cases with a mortality rate of over 90%. Between 1894 and 1923, there were 21,867 cases and 20,489 deaths, with a fatality rate of 93.7%. In 1894 there was no law to enforce the notification of deaths. Women suffered a higher mortality rate than men, most likely due to their role as the caretakers of the sick. On May 11, legislation was passed to make the reporting of cases compulsory, and to allow authorities to enter houses to search for and remove infected persons for isolation. House-to-house inspection and disinfection was performed by the local garrison, the Shropshire Light Infantry . The inspection and disinfection team was known as the "Whitewash Brigade", consisting of around 300 men and 8 officers. During an inspection, the occupants were given new clothes, and sent to temporary lodgings on Chinese boats anchored off Stonecutters Island or to government-hired buildings, including the Alice Memorial and Nethersole Hospitals . Their own clothes and fabrics in the house would be sent to a steam disinfecting station. The house was then sprayed with a solution of perchloride of mercury or fumigated by chlorine gas , the floor and furniture cleaned with Jeyes Fluid and the walls lime-washed ("whitewashing"). Household items suspected of being contaminated were burnt. Members of the Shropshire regiment became the first Europeans to be affected by the plague. At least one officer died to the disease. At the time, Chinese residents of Hong Kong had a deep mistrust for Western medical science, making the containment of the plague difficult. The distrust was exacerbated by ineffective treatment and highly intrusive policies by the colonial government. The Chinese would hide their sick from the authorities, and infected bodies would be thrown out at night to avoid detection. The western practice of using ice to cool down a fever was rejected by the Chinese, who viewed extreme cold as damaging to the body. The quick and hasty burials performed by the government, with the bodies covered in quicklime , were also offensive to the Chinese. In 1903, the government had to reimburse the cost of disinfected clothing to the Chinese, as they had disliked the smell of disinfectant. The house-to-house inspection was especially resisted by the Chinese community. Chinese ladies were reluctant to let strangers, let alone foreigners, enter their boudoirs . Rumors of British soldiers seeking to rape Chinese women arose. In one instance, on May 19, the Whitewash Brigade was pelted with stones, bricks and rubbish. In another instance, around 100 women, relatives of the deceased, organized a meeting at Tung Wah Hospital , where they wailed and cried against the community leaders and hospital administration. The government responded to the meeting by forbidding searchers to enter Chinese households without permission, and by allowing patients to choose Chinese treatment in Chinese hospitals. Members of the Chinese community continued to petition Governor William Robinson to halt the cleansing operations completely, and to allow patients to travel to China to seek treatment. Robinson initially refused, but when compradors of major hongs threatened to have their staff leave their posts, Robinson allowed patients to travel to Guangzhou for treatment, and corpses to be transported there for burials. However, the whitewashing operations was to be continued. As a result, an anti-government poster campaign was launched in Canton and Hong Kong. This inflamed more rumours against the English doctors, who were said to be making medicine with the bodies of plague victims. Robinson responded by moving the gunboat HMS Tweed to Taipingshan and offering a reward for information leading to the arrest of the poster distributors. Viceroy Li Hanzhang of Canton was also requested to make a statement to deny the rumours. However, these efforts proved ineffective in building trust between the Western and Chinese communities. Whitewashing could only continue after a great deal of persuasion and explanation by both the government and some esteemed members of the Chinese community. After a time, the operations were suspended. Established hospitals around the major areas of outbreak would only accept suspected patients for observation. Once the symptoms of plagues appeared, they would be moved to specialized plague hospitals. The plague hospitals included a temporary hospital at the Kennedy Town Police Station (known as the "Kennedy Town Hospital", opened on May 14 ) and the hospital ship Hygeia ( Chinese : 海之家 ), ran by staff of the Nethersole Hospital. When patients were removed according to the policy from Tung Wah Hospital to Hygeia , violent protest erupted in the city. Tung Wah Hospital had been a reputable hospital in the Chinese community. It practiced Chinese medicine and was seen as a symbol of Chinese independence in a colonial city. Thus, the hospital came under fire from the Chinese community when they allowed patients to be transferred away to plague hospitals. At one point, doctors had to carry pistols to protect themselves. The riots led to the establishment of a temporary plague hospital at Kennedy Town glass works, known as the "Glassworks Hospital" on May 21. This hospital would be manned by staff from the Tung Wah Hospital. The patients were offered a choice between the Glassworks Hospital and plague hospitals with European staff. The Chinese-majority patients overwhelmingly chose the Glassworks Hospital. The hospital quickly becoming overcrowded and sanitary conditions worsened. On June 8, another temporary hospital at an unfinished pig depot was also set up, known as the "Slaughterhouse Hospital", again manned by staff from Tung Wah Hospital, in hopes of relieving the situation at the Glassworks Hospital. When the Chinese medicine offered by the Glassworks Hospital proved to be ineffective, and conditions of the hospital continued to worsen, it was closed down on June 16, and its patients were transferred to either Guangzhou or to the Slaughterhouse Hospital. Subsequently, a "New Glassworks Hospital" was set up at the site, this time staffed by European doctors from the Alice Memorial and Nethersole Hospitals. In July, a hospital was established in Lai Chi Kok near a graveyard but it did not receive any patients. This was attributed to the Chinese refusing to be admitted into the hospital as they felt "they were sure to die." Hygeia was later used only to house European, Eurasian and Japanese patients. The plague saw a mass exodus of panic-stricken Chinese workers back to China, causing a significant economic downturn in the city. The North-China Herald noted that "it is not the plague they are flying from, as they are going to the nest at Canton from which [the plague] came to Hong Kong. They seem rather to be flying from the sanitary measures taken in Hong Kong." Some were seeking a proper burial on Chinese grounds. At the height of the plague, around 1,000 persons were leaving Hong Kong daily. In May and June, it was estimated that 80,000 to 90,000 Chinese, out of a population of 200,000, left Hong Kong Island. Owners of hongs left for China, leaving the businesses to caretakers, slowing down the business operations. The colony suffered a severe labour shortage. Inflation followed, with prices of food items rising by 30 to 50 percent. As visitors to Hong Kong had to be quarantined, trade between Hong Kong and China was decimated. In June, Robinson reported to Secretary of State for the Colonies Lord Ripon that "without exaggeration I may assert that so far as trade and commerce are concerned the plague has assumed the importance of an unexampled calamity." On May 31, a bylaw drawn up by the Sanitary Board allowed for the eviction and closure of houses deemed unfit for habitation. Houses on the streets of Kau Yu Fong ( Chinese : 九如坊 ), Sin Hing Lee ( Chinese : å–„æ ¶é‡Œ ), Nga Choi Hong ( Chinese : 芽菜巷 ) and Mei Lun Lee ( Chinese : 美侖里 ) were demolished, and a brick wall was erected surrounding those areas. In September, 1894, the Taipingshan Resumption Ordinance was passed, allowing the resumption of an area of about 10 acres in the Taipingshan district. The area accounted for 50 percent of the cases, and 385 houses in the area were destroyed. Around 7,000 inhabitants were displaced. The area was walled up, and guards were stationed to prevent residents from re-entry. This drastic measure called for, as described by Robinson, "the destruction and rebuilding of one tenth part of Hong Kong." Reconstruction began in the end of 1895 and lasted until 1898. Drainage systems were improved, and balconies were installed for better ventilation. An area was marked out for the construction of a Bacteriological Institute. A public park was also constructed. It was named Blake Garden after then-Governor Henry Arthur Blake . Today, a plaque stands at the park, commemorating the deadly epidemic. At the peak of the 1894 plague, admissions to hospital averaged at 80 a day, and death peaked at over 100 per day. Taipingshan was not the only area affected by the plague. Areas such as Bowrington (now between today's Wan Chai and Causeway Bay ), Sai Ying Pun , Shek Tong Tsui and Kennedy Town saw more deaths than Taipingshan. Internationally, steamships from Hong Kong carried the bacillus to every major seaport in the world, including to India. The plague subsided with the arrival of cold weather, in the winter of 1894. In 1895, only 44 cases were reported, but the plague returned strongly in 1896, affecting mostly Chinese in the Taipingshan district. Once again it subsided in winter, and returned almost annually thereafter. The plague lasted until 1929, when the last cases were recorded. In total, between 1894 and 1929, there were over 24,000 cases with a mortality rate of over 90%. Between 1894 and 1923, there were 21,867 cases and 20,489 deaths, with a fatality rate of 93.7%. In 1894 there was no law to enforce the notification of deaths. Women suffered a higher mortality rate than men, most likely due to their role as the caretakers of the sick. At the beginning of the outbreak, the plague agent was unknown. Although the germ theory was gaining attention in the 1880s, the medical circle of United Kingdom was still deeply influenced by the miasma theory . For example, the decision by the colonial government to place patients on ships and to demolish houses were, in part, influenced by the miasma theory. Lowson speculated on the origins of the disease as "poison is probably developed from atmospheric conditions underneath houses in certain districts, and that it is caused simply by poverty and dirt. In the ordinary sense the disease is not infectious or contagious." The means of transmission, now known to be the Oriental rat flea , was also not ascertained. For several years, it had been widely accepted that infection was through the gastrointestinal tract via contaminated food. Before 1901, no efforts were made to remove rats and rat corpses as there was no consensus about their role in the transmission of the plague. In 1895, Lowson wrote that "the question of the infection of rats previous to the epidemic being noticed in human beings has been made too much of." In April 1894, the Japanese Home Ministry was made aware of the plague in Hong Kong. In response, the Japanese government sent bacteriologist Kitasato Shibasaburō to investigate the plague. On June 5, Kitasato departed Yokohama on SS City of Rio de Janeiro with a team of 5, arriving at Hong Kong on June 12. On June 14, Kitasato discovered that the bacillus , now known as Yersinia pestis , that was the direct cause of the plague. However, he was doubtful of its significance as the autopsy was done 11 hours after death. His finding was reported by Lowson, who had supported Kitasato's work, to The Lancet . His report was published a week later on August 25. Following Kitasato's discovery, Lowson reversed his position and adopted the germ theory. At almost the same time, on June 15, French-Swiss bacteriologist Alexandre Yersin , a member of the Pasteur Institute working in Saigon , arrived in Hong Kong. He was sent there to investigate the outbreak. Unlike Kitasato, Lowson did not offer Yersin support, as Lowson considered France to be a colonial competitor to Great Britain in East Asia. At the hospital, Yersin would find all the cadavers reserved for Kitasato. He was only able to obtain specimens after bribing English sailors responsible for disposing bodies of plague victims. Yersin discovered the bacillus on June 23. Even though Kitasato made the earlier discovery, Kitasato's description lacked precision and the report was riddled with doubts and confusion. Expert opinion gave credit to Yersin. The fact that Kitasato was in a hurry to publish his work was considered by some to be the reason for the imprecision. Japanese bacteriologist Aoyama Tanemichi and Ishigami Toru ( Japanese : 石神亨 ) also arrived with Kitasato as his assistants. On June 28, two weeks after their arrival, they were infected by the plague and were sent to Hygeia . In 1895, Aoyama wrote a report criticizing Kitasato's misidentification of the bacillus. Even though the means of transmission was still not ascertained, Yersin also found that the bacillus was present in the rodent as well as in the human disease, thus underlining the possible means of transmission. After the role of rats in the spread of the plague was understood, the government offered money for caught rats. This policy ended when it was discovered that rat-catchers had been importing rats from Canton for a higher reward. Later, rat poison, glue traps and rat disposal bins were all employed to help reduce the population of rats. In 1896, Yersin returned to Hong Kong to test his plague serum. However, he found no suitable cases in hospitals, and left for China to carry out his tests in Amoy . The bacillus was later renamed Yersinia pestis in Yersin's honour. In April 1894, the Japanese Home Ministry was made aware of the plague in Hong Kong. In response, the Japanese government sent bacteriologist Kitasato Shibasaburō to investigate the plague. On June 5, Kitasato departed Yokohama on SS City of Rio de Janeiro with a team of 5, arriving at Hong Kong on June 12. On June 14, Kitasato discovered that the bacillus , now known as Yersinia pestis , that was the direct cause of the plague. However, he was doubtful of its significance as the autopsy was done 11 hours after death. His finding was reported by Lowson, who had supported Kitasato's work, to The Lancet . His report was published a week later on August 25. Following Kitasato's discovery, Lowson reversed his position and adopted the germ theory. At almost the same time, on June 15, French-Swiss bacteriologist Alexandre Yersin , a member of the Pasteur Institute working in Saigon , arrived in Hong Kong. He was sent there to investigate the outbreak. Unlike Kitasato, Lowson did not offer Yersin support, as Lowson considered France to be a colonial competitor to Great Britain in East Asia. At the hospital, Yersin would find all the cadavers reserved for Kitasato. He was only able to obtain specimens after bribing English sailors responsible for disposing bodies of plague victims. Yersin discovered the bacillus on June 23. Even though Kitasato made the earlier discovery, Kitasato's description lacked precision and the report was riddled with doubts and confusion. Expert opinion gave credit to Yersin. The fact that Kitasato was in a hurry to publish his work was considered by some to be the reason for the imprecision. Japanese bacteriologist Aoyama Tanemichi and Ishigami Toru ( Japanese : 石神亨 ) also arrived with Kitasato as his assistants. On June 28, two weeks after their arrival, they were infected by the plague and were sent to Hygeia . In 1895, Aoyama wrote a report criticizing Kitasato's misidentification of the bacillus. Even though the means of transmission was still not ascertained, Yersin also found that the bacillus was present in the rodent as well as in the human disease, thus underlining the possible means of transmission. After the role of rats in the spread of the plague was understood, the government offered money for caught rats. This policy ended when it was discovered that rat-catchers had been importing rats from Canton for a higher reward. Later, rat poison, glue traps and rat disposal bins were all employed to help reduce the population of rats. In 1896, Yersin returned to Hong Kong to test his plague serum. However, he found no suitable cases in hospitals, and left for China to carry out his tests in Amoy . The bacillus was later renamed Yersinia pestis in Yersin's honour. Some historians consider the plague as the starting point of the colonial government's direct involvement and interference of the Chinese community of Hong Kong. The epidemic gave the government an opportunity to displace Chinese medicine with western medicine. Prejudices over western medicine were overcome. Tung Wah Hospital, where Chinese medicine was originally practiced, was at first considered to be a menace to public safety by the colonial government. The plague allowed the government to reform the hospital. In 1896, it was decided that the hospital would continue its operations but with greater government oversight. In 1897, the government mandated that the hospital should provide western treatment. In the same year, over 85 percent of the patients opted for Chinese treatment. The percentage decreased to 68 percent by 1900. A silver medal was struck "in honor of those who assisted in the cleaning up of Tai Ping Shan." On the obverse, a scene of the epidemic was engraved. On the reverse were the inscriptions "For services rendered during the Plague of 1894" and "Presented by the Hong Kong community." In 1903, the Public Health and Buildings Ordinance was passed to improve the lodging standards of the Chinese. The ordinance, regulating the designs and sanitary conditions of tenement blocks, was drawn up according to recommendations by Scottish physician William John Simpson , who observed the plague in 1902. On March 15, 1906, the Bacteriological Institute was opened near the Taipingshan area. Headed by Scottish bacteriologist William Hunter, the institute was used for post-mortem and bacteriological examinations, along with the development of vaccines . It is now the Hong Kong Museum of Medical Sciences . Annual cleaning-up events, known as "Cleaning up of the Environment" ( Chinese : 洗太平地 ), was held until the early 1950s.

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Plague vaccine

none Plague vaccine is a vaccine used against Yersinia pestis to prevent the plague . Inactivated bacterial vaccines have been used since 1890 but are less effective against the pneumonic plague , so live, attenuated vaccines and recombinant protein vaccines have been developed to prevent the disease. The first plague vaccine was developed by bacteriologist Waldemar Haffkine in 1897. He tested the vaccine on himself to prove that the vaccine was safe. Later, Haffkine conducted a massive inoculation program in British India , and it is estimated that 26 million doses of Haffkine's anti-plague vaccine were sent out from Bombay between 1897 and 1925, reducing the plague mortality by 50%-85%. A plague vaccine is used for an induction of active specific immunity in an organism susceptible to plague by means of administrating an antigenic material (a vaccine ) via a variety of routes to people at risk of contracting any clinical form of plague. This method is known as plague immunization . There is strong evidence for the efficacy of administration of some plague vaccines in preventing or ameliorating the effects of a variety of clinical forms of infection by Yersinia pestis . Plague immunization also encompasses incurring a state of passive specific immunity to plague in a susceptible organism after administration of a plague serum or plague immunological in people with an immediate risk of developing the disease. A systematic review by the Cochrane Collaboration found no studies of sufficient quality to be included in the review, and were thus unable to make any statement on the efficacy of modern vaccines.

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History of plague

Globally about 600 cases of plague are reported a year. In 2017 and November 2019 the countries with the most cases include the Democratic Republic of the Congo , Madagascar , and Peru . Local outbreaks of the plague are grouped into three plague pandemics , whereby the respective start and end dates and the assignment of some outbreaks to either pandemic are still subject to discussion. The pandemics were: However, the late medieval Black Death (roughly 1331 to 1353) is sometimes seen not as the start of the second, but as the end of the first pandemic – in that case, the first pandemic ended in around 1353, and the second pandemic's start would be about 1361. Also various end dates of the second pandemic are given in the literature, ranging from about 1840 to 1890. The word plague is believed to come from the Latin word plāga ("blow, wound") and plangere ("to strike, or to strike down"), via the German Plage ("infestation"). [ citation needed ] Some authors have suggested that the plague was responsible for the Neolithic decline . That is supported by the discovery of a tomb in modern-day Sweden containing 79 corpses buried within a short time, in which the authors discovered fragments of a unique strain of the plague pathogen Yersinia pestis . Plasmids of Y. pestis have been detected in archaeological samples of the teeth of seven Bronze Age individuals from 5000 years ago (3000 BC), in the Afanasievo culture in Siberia, the Corded Ware culture in Estonia, the Sintashta culture in Russia, the Unetice culture in Poland and the Andronovo culture in Siberia. Y. pestis existed over Eurasia during the Bronze Age. Estimates of the age of the most recent common ancestor of all Y. pestis is estimated at 5,783 years Before Present . The Yersinia murine toxin ( ymt ) allows the bacteria to infect fleas, which can then transmit bubonic plague. Early ancestral versions of Y. pestis did not have the ymt gene, which was only detected in a 951 calibrated BC sample. The Amarna letters and the Plague Prayers of Mursili II describe an outbreak of a disease among the Hittites . The First Book of Samuel describes a possible plague outbreak in Philistia , and the Septuagint version says it was caused by a "ravaging of mice". In the second year of the Peloponnesian War (430 BC), Thucydides described an epidemic disease which was said to have begun in Ethiopia , passed through Egypt and Libya , then come to the Greek world. In the Plague of Athens , the city lost possibly one third of its population, including Pericles . Modern historians disagree on whether the plague was a critical factor in the loss of the war. Although this epidemic has long been considered an outbreak of plague, many modern scholars believe that typhus , smallpox , or measles may better fit the surviving descriptions. A recent study of DNA found in the dental pulp of plague victims suggests that typhoid was actually responsible. In the first century AD, Rufus of Ephesus , a Greek anatomist, refers to an outbreak of plague in Libya , Egypt , and Syria . He records that Alexandrian doctors named Dioscorides and Posidonius described symptoms including acute fever, pain, agitation, and delirium. Buboes—large, hard, and non-suppurating—developed behind the knees, around the elbows, and "in the usual places." The death toll of those infected was very high. Rufus also wrote that similar buboes were reported by a Dionysius Curtus, who may have practiced medicine in Alexandria in the third century BC. If this is correct, the eastern Mediterranean world may have been familiar with bubonic plague at that early date. In the second century, the Antonine Plague , named after Marcus Aurelius ' family name of Antoninus and also known as the Plague of Galen, who had first hand knowledge of the disease, may in fact have been smallpox . Galen was in Rome when it struck in 166 AD, and was also present in the winter of 168–69 during an outbreak among troops stationed at Aquileia ; he had experience with the epidemic, referring to it as very long lasting, and describes its symptoms and his treatment of it, though his references are scattered and brief. According to Barthold Georg Niebuhr "this pestilence must have raged with incredible fury; it carried off innumerable victims. The ancient world never recovered from the blow inflected upon it by the plague which visited it in the reign of M. Aurelius." The mortality rate of the plague was 7–10 percent; the outbreak in 165/6–168 would have caused approximately 3.5 to 5 million deaths. [ citation needed ] Otto Seek believes that over half the population of the empire perished. [ citation needed ] J. F. Gilliam believes that the Antonine plague probably caused more deaths than any other epidemic during the empire before the mid-3rd century. [ citation needed ]The Plague of Justinian in AD 541–542 is the first known attack on record, and marks the first firmly recorded pattern of bubonic plague. This disease is thought to have originated in China. It then spread to Africa from where the huge city of Constantinople imported massive amounts of grain, mostly from Egypt, to feed its citizens. The grain ships were the source of contagion for the city, with massive public granaries nurturing the rat and flea population. At its peak, Procopius said the plague was killing 10,000 people in Constantinople every day. The real number was more likely close to 5,000 a day. The plague ultimately killed perhaps 40% of the city's inhabitants, and then continued to kill up to a quarter of the human population of the eastern Mediterranean. [ citation needed ] In AD 588 a second major wave of plague spread through the Mediterranean into what is now France. It is estimated that the Plague of Justinian killed as many as 100 million people across the world. It caused Europe's population to drop by around 50% between 541 and 700. It also may have contributed to the success of the Arab conquests . An outbreak of it in the AD 560s was described in AD 790 as causing "swellings in the glands ... in the manner of a nut or date" in the groin "and in other rather delicate places followed by an unbearable fever". While the swellings in this description have been identified by some as buboes, there is some contention as to whether the pandemic should be attributed to the bubonic plague, Yersinia pestis , known in modern times. From 1331 to 1351, the Black Death , a massive and deadly pandemic originating in China, spread along the Silk Road and swept through Asia, Europe and Africa. It may have reduced the world's population from 450 million to between 350 and 375 million . China lost around half of its population, from around 123 million to around 65 million ; Europe around one third of its population, from about 75 million to about 50 million ; and Africa approximately 1 ⁄ 8 of its population, from around 80 million to 70 million (mortality rates tended to be correlated with population density so Africa, being less dense overall, had the lowest death rate). This makes the Black Death the largest death toll from any known non-viral epidemic. Although accurate statistical data does not exist, it is thought that 1.4 million died in England ( 1 ⁄ 3 of England's 4.2 million people), while an even higher percentage of Italy's population was likely wiped out. On the other hand, north-eastern Germany, Bohemia, Poland and Hungary are believed to have suffered less, and there are no estimates available for Russia or the Balkans. It is conceivable that Russia may not have been as affected due to its very cold climate and large size, hence often less close contact with the contagion. The plague repeatedly returned to haunt Europe and the Mediterranean throughout the 14th to 17th centuries. According to Biraben, plague was present somewhere in Europe in every year between 1346 and 1671. The Second Pandemic was particularly widespread in the following years: 1360–1363; 1374; 1400; 1438–1439; 1456–1457; 1464–1466; 1481–1485; 1500–1503; 1518–1531; 1544–1548; 1563–1566; 1573–1588; 1596–1599; 1602–1611; 1623–1640; 1644–1654; and 1664–1667; subsequent outbreaks, though severe, marked the retreat from most of Europe (18th century) and northern Africa (19th century). According to Geoffrey Parker, " France alone lost almost a million people to plague in the epidemic of 1628–31." In England, in the absence of census figures, historians propose a range of pre-incident population figures from as high as 7 million to as low as 4 million in 1300, and a postincident population figure as low as 2 million. By the end of 1350, the Black Death subsided, but it never really died out in England. Over the next few hundred years, further outbreaks occurred in 1361–62, 1369, 1379–83, 1389–93, and throughout the first half of the 15th century. An outbreak in 1471 took as much as 10–15% of the population, while the death rate of the plague of 1479–80 could have been as high as 20%. The most general outbreaks in Tudor and Stuart England seem to have begun in 1498, 1535, 1543, 1563, 1589, 1603, 1625, and 1636, and ended with the Great Plague of London in 1665. In 1466, perhaps 40,000 people died of plague in Paris. During the 16th and 17th centuries, plague visited Paris for almost one year out of three. The Black Death ravaged Europe for three years before it continued on into Russia, where the disease hit somewhere once every five or six years from 1350 to 1490. Plague epidemics ravaged London in 1563, 1593, 1603, 1625, 1636, and 1665, reducing its population by 10 to 30% during those years. Over 10% of Amsterdam 's population died in 1623–1625, and again in 1635–1636, 1655, and 1664. There were 22 outbreaks of plague in Venice between 1361 and 1528. The plague of 1576–1577 killed 50,000 in Venice, almost a third of the population. Late outbreaks in central Europe included the Italian Plague of 1629–1631 , which is associated with troop movements during the Thirty Years' War , and the Great Plague of Vienna in 1679. Over 60% of Norway's population died from 1348 to 1350. The last plague outbreak ravaged Oslo in 1654. In the first half of the 17th century, the Great Plague of Milan claimed some 1.7 million victims in Italy, or about 14% of the population. In 1656, the plague killed about half of Naples ' 300,000 inhabitants. More than 1.25 million deaths resulted from the extreme incidence of plague in 17th-century Spain . The plague of 1649 probably reduced the population of Seville by half. In 1709–1713, a plague epidemic that followed the Great Northern War (1700–1721, Sweden v. Russia and allies) killed about 100,000 in Sweden, and 300,000 in Prussia. The plague killed two-thirds of the inhabitants of Helsinki , and claimed a third of Stockholm 's population. Western Europe's last major epidemic occurred in 1720 in Marseilles , in Central Europe the last major outbreaks happened during the plague during the Great Northern War , and in Eastern Europe during the Russian plague of 1770–72 . The Black Death ravaged much of the Islamic world . Plague was present in at least one location in the Islamic world virtually every year between 1500 and 1850. Plague repeatedly struck the cities of North Africa. Algiers lost 30,000–50,000 to it in 1620–1621, and again in 1654–1657, 1665, 1691, and 1740–1742. Plague remained a major event in Ottoman society until the second quarter of the 19th century. Between 1701 and 1750, 37 larger and smaller epidemics were recorded in Constantinople , and 31 between 1751 and 1800. Baghdad has suffered severely from visitations of the plague, and sometimes two-thirds of its population has been wiped out. The Third Pandemic began in China's Yunnan province in 1855, spreading plague to all inhabited continents and ultimately killing more than 12 million people in India and China alone. Casualty patterns indicate that waves of this pandemic may have come from two different sources. The first was primarily bubonic and was carried around the world through ocean-going trade, transporting infected persons, rats, and cargoes harboring fleas. The second, more virulent, strain was primarily pneumonic in character, with a strong person-to-person contagion. This strain was largely confined to Manchuria and Mongolia . Researchers during the "Third Pandemic" identified plague vectors and the plague bacterium (see above), leading in time to modern treatment methods. [ citation needed ] Plague occurred in Russia in 1877–1889 in rural areas near the Ural Mountains and the Caspian Sea . Efforts in hygiene and patient isolation reduced the spread of the disease, with approximately 420 deaths in the region. Significantly, the region of Vetlianka in this area is near a population of the bobak marmot , a small rodent considered a very dangerous plague reservoir. The last significant Russian outbreak of Plague was in Siberia in 1910 after sudden demand for marmot skins (a substitute for sable ) increased the price by 400 percent. The traditional hunters would not hunt a sick Marmot and it was taboo to eat the fat from under the arm (the axillary lymphatic gland that often harboured the plague) so outbreaks tended to be confined to single individuals. The price increase, however, attracted thousands of Chinese hunters from Manchuria who not only caught the sick animals but also ate the fat, which was considered a delicacy. The plague spread from the hunting grounds to the terminus of the Chinese Eastern Railway and then followed the track for 2,700 km. The plague lasted 7 months and killed 60,000 people. [ citation needed ] The bubonic plague continued to circulate through different ports globally for the next fifty years; however, it was primarily found in Southeast Asia. The 1894 Hong Kong plague had particularly high death rates, 90%. As late as 1897, medical authorities in the European powers organized a conference in Venice , seeking ways to keep the plague out of Europe. Mumbai plague epidemic struck the city of Bombay (Mumbai) in 1896. The disease reached the Territory of Hawaii in December 1899, and the Board of Health's decision to initiate controlled burns of select buildings in Honolulu 's Chinatown turned into an uncontrolled fire which led to the inadvertent burning of most of Chinatown on January 20, 1900. Shortly thereafter, plague reached the continental US, initiating the San Francisco plague of 1900–1904 . Plague persisted in Hawaii on the outer islands of Maui and Hawaii (The Big Island) until it was finally eradicated in 1960. Research done by a team of biologists from the Institute of Pasteur in Paris and Johannes Gutenberg University Mainz in Germany by analyzing the DNA and proteins from plague pits, published in October 2010, reported beyond doubt that all 'the three major plagues' were due to at least two previously unknown strains of Yersinia pestis and originated from China. A team of medical geneticists led by Mark Achtman of University College Cork in Ireland reconstructed a family tree of the bacterium and concluded in an online issue of Nature Genetics published on 31 October 2010 that all three of the great waves of plague originated from China. Plague cases were massively reduced during the second half of the 20th century, but outbreaks still occurred, especially in developing countries. Between 1954 and 1997, human plague was reported in 38 countries, making the disease a re-emerging threat to human health. Between 1987 and 2001, 36,876 confirmed cases of plague with 2,847 deaths are reported to the World Health Organization . In the 21st century, fewer than 200 people die of the plague worldwide each year, mainly due to lack of treatment. Plague is considered to be endemic in 26 countries around the world, with most cases found in remote areas of Africa . The three most endemic countries are Madagascar , the Democratic Republic of the Congo and Peru . Outbreaks with dozens of deaths occurred in Madagascar in 2014 and 2017 , in India in 1994 , and Congo in 2006. During 1995, plague was confirmed in the United States from nine western states. Currently, five to 15 people in the United States are estimated to catch the disease each year — typically in western states. The reservoir is thought to be mice. In the U.S., about half of all fatal cases of plague since 1970 have occurred in New Mexico . There were two plague deaths in the state in 2006, the first fatalities in 12 years. In New Mexico, four people were diagnosed with the plague in 2015; one died. In 2016, four were diagnosed and all were treated with success. Three others were diagnosed by late June in 2017. Vegetation such as pinyon and juniper trees are thought to support rodents such as the prairie dog and rock squirrel, with their fleas, according to Paul Ettestad of the New Mexico public health department. As well, pets can bring back fleas from dead rodents, he said. The CDC indicates that over the past century, plague in the U.S. has been most common in the areas of northern New Mexico, northwestern Arizona and southern Colorado. There was an outbreak of the bubonic plague in the Nyimba district of Eastern Zambia in 2015. Epidemiologists estimated a basic reproduction number of 1.75 with a 95 percent confidence interval ranging from 1.51 to 1.98. This is almost certainly substantially lower than how the plague propagated during the Black Death pandemic of the fourteenth century with the with living conditions and existing genetic diversity in the human population at that time.

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Plague doctor costume

The clothing worn by plague doctors was intended to protect them from airborne diseases during outbreaks of bubonic plague in Europe. It is often seen as a symbol of death and disease. However, the costume was mostly worn by late Renaissance and early modern physicians studying and treating plague patients. The costume consists of a leather hat, mask with glass eyes and a beak, stick to remove clothes of a plague victim, gloves, waxed linen robe, and boots. The typical mask had glass openings for the eyes and a curved beak shaped like a bird's beak with straps that held the beak in front of the doctor's nose. The mask had two small nose holes and was a type of respirator which contained aromatic items. The beak could hold dried flowers (commonly roses and carnations ), herbs (commonly lavender and peppermint ), camphor , or a vinegar sponge, as well as juniper berry , ambergris , cloves , labdanum , myrrh , and storax . The purpose of the mask was to keep away bad smells, such as the smell of decaying bodies. The smell taken with the most caution was known as miasma , a noxious form of "bad air". This was thought to be the principal cause of the disease. Doctors believed the herbs would counter the "evil" smells of the plague and prevent them from becoming infected. Though these particular theories about the plague's nature were incorrect, it is likely that the costume actually did afford the wearer some protection. The garments covered the body, shielding against splattered blood, lymph, and cough droplets, and the waxed robe prevented fleas (the true carriers of the plague) from touching the body or clinging to the linen. The wide-brimmed leather hat indicated their profession. Doctors used wooden canes in order to point out areas needing attention and to examine patients without touching them. The canes were also used to keep people away and to remove clothing from plague victims without having to touch them. The exact origins of the costume are unclear, as most depictions come from satirical writings and political cartoons. An early reference to plague doctors wearing masks is in 1373 when Johannes Jacobi recommends their use but he offers no physical description of them. The beaked plague doctor inspired costumes in Italian theatre as a symbol of general horror and death, though some historians insist that the plague doctor was originally fictional and inspired the real plague doctors later. Depictions of the beaked plague doctor rose in response to superstition and fear about the unknown source of the plague. Often, these plague doctors were the last thing a patient would see before death; therefore, the doctors were seen as a foreboding of death. The garments were first mentioned by a physician to King Louis XIII of France , Charles de Lorme , who wrote in a 1619 plague outbreak in Paris that he developed an outfit made of Moroccan goat leather , including boots, breeches, a long coat, hat, and gloves modeled after a soldier's canvas gown which went from the neck to the ankle. The garment was impregnated with similar fragrant items as the mask. De Lorme wrote that the mask had a "nose half a foot long, shaped like a beak, filled with perfume with only two holes, one on each side near the nostrils, but that can suffice to breathe and to carry along with the air one breathes the impression of the drugs enclosed further along in the beak." However, recent research has revealed that strong caveats must be applied with regard to De Lorme's assertions. The Genevan physician, Jean-Jacques Manget , in his 1721 work Treatise on the Plague written just after the Great Plague of Marseille , describes the costume worn by plague doctors at Nijmegen in 1636–1637. The costume forms the frontispiece of Manget's 1721 work. Their robes, leggings, hats, and gloves were also made of Morocco leather. This costume was also worn by plague doctors during the Naples Plague of 1656 , which killed 145,000 people in Rome and 300,000 in Naples . The costume is also associated with a commedia dell'arte character called Il Medico della Peste (lit.: The Plague Doctor ), who wears a distinctive plague doctor's mask . The Venetian mask was normally white, consisting of a hollow beak and round eye-holes covered with clear glass, and is one of the distinctive masks worn during the Carnival of Venice . During the COVID-19 pandemic beginning in 2020, the plague doctor costume grew in popularity due to its relevance to the pandemic, with news reports of plague doctor-costumed individuals in public places and photos of people wearing plague doctor costumes appearing in social media.

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Chapekar brothers

The Chapekar Brothers , Damodar Hari Chapekar (25 June 1869 – 18 April 1898), Balkrishna Hari Chapekar (1873 – 12 May 1899, also called Bapurao) and Vasudeo Hari Chapekar (1880 – 8 May 1899), also spelt Wasudeva or Wasudev, were Indian revolutionaries involved in assassinating W. C. Rand, the British Plague Commissioner of Pune , after the public of Pune was frustrated with the vandalism from the officers and soldiers appointed by him, in late 19th century. Mahadev Vinayak Ranade was also an accomplice in the assassination. The brothers initially belonged to Chapa, a small hamlet named Chinchwad in the city of Pune , India. When the bubonic plague hit India in 1896–97, the government had set up a Special Plague Committee for managing the pandemic, whose commissioner was Walter Charles Rand , an Indian Civil Services officer. Troops were brought in to deal with the emergency. Despite orders from the government to pay heed to religious sentiments, Rand appointed over 800 officers and soldiers - the measures employed included entry into private houses, stripping and examination of occupants (including women) by British officers in public, evacuation to hospitals and segregation camps and preventing movement from the city. Some of these officers also vandalized properties and religious symbols. These measures were considered oppressive by the populace of Pune and complaints were ignored by Rand. Thus, to put an end to the injustice borne by the people of Pune, the Chapekar brothers shot Rand, and his military escort Lieutenant Ayerst, on 22 June 1897. On 22 June 1897, the Diamond Jubilee of the coronation of Queen Victoria , Rand and his military escort Lt. Ayerst were shot while returning from the celebrations at Government House . Both died, Ayerst on the spot and Rand of his wounds on 3 July. The Chapekar brothers and two accomplices ( Mahadev Ranade and Shathe [First-name not known]) were charged with the murders in various roles, as well as the shooting of two informants and an attempt to shoot a police officer. All three brothers were found guilty and hanged , an accomplice was dealt with similarly, and another, then a schoolboy, was sentenced to ten years' rigorous imprisonment. Damodar, Balkrishna and Vasudeo Chapekar hailed from Chinchwad , then a village near the former Peshwa capital Pune , in the present day Indian state of Maharashtra . Damodar the eldest, was born in 1869 [nb 1] The brothers' grandfather, Vinayak Chapekar, was the head of an extended family which consisted of the brothers parents, Dwarka and Hari, and about twenty members including six uncles, two aunts, and two grandmothers. The family was wealthy at the time of Damodar's birth, earlier having had a turnover of lakhs of rupees. [ citation needed ] With passage of time, mainly on account of Vinayak Chapekar's independent spirit and ways which made him incapable of submitting himself to government service, and his many unsuccessful business ventures, the family gradually sank into poverty. At one time when Damodar Hari was a young boy, the family, consisting of a party of twenty five travellers, went on a pilgrimage to Kashi , with two servants and three carts. Damodar remembers the death of his elder sister at Gwalior . [ citation needed ] Damodar recalls that their family rose to richness which was a result of this pilgrimage; he refutes it, and is thankful to his grandfather for the opportunity he had of drinking the waters of the Ganga – Ganges , bathing in it , giving alms and touching the feet of Kashivishveshwara . The brothers' father, Hari, was sent to Poona High School up to 6th standard, after which a Shastri was deputed to teach him Sanskrit at home so as to prepare him in the profession of a kirtankar . Hari Chapekar's brothers were taught to play musical instruments so that they could accompany him during his performance. The taking up of the profession of a kirtankar by Hari was regarded with disapproval by his caste men and friends of the family, considering the status and antiquity of the family. Vinayak Hari's brothers too looked down on the profession and left it, leaving the house, going their own ways. Even Vinayak Chapekar left the house for the then Maratha capitals of Indore and Dhar , he worked there as a writer, he had an excellent Balbodh and Modi hand. He subsequently stopped speaking any language but Sanskrit, became careless in dress, stopped interaction with others as far as possible, and started to beg on the streets. Other members of the family faced poverty too, and were forced to feed themselves at charity kitchens. [ citation needed ] Hari Chapekar died and was cremated on the banks of Kshipra , sixteen miles from Indore. Hari Vinayak and his family were at Nagpur then but could not attend the funeral, as they were too poor to pay for the journey. Hari Chapekar's wife too was alone when she died, Hari's poverty prevented him from being with his parents when they died. Hari Vinayak's brothers too went their own ways, only one brother staying back in their ancestral home. Hari Vinayak was left to fend for his family on his own, he did not have the means to hire professional musicians to accompany him during his kirtan , so he trained his children to do so. The father and children became proficient in their art and were admired for their work. The Chapekar brothers received little formal education, but the "company of good people, hearing of kirtans, travelling, witnessing darbars of great princes and seeing assemblies of eminent scholars" was a source of knowledge far more enriching than a few examinations passed in school", writes Damodar Hari in his autobiography. Hari Vinayak, father of the Chapekar brothers is credited to have authored Satyanarayanakatha , of the Skandapurana , a Sanskrit text with translations. Hari Vinayak was left to fend for his family on his own, he did not have the means to hire professional musicians to accompany him during his kirtan , so he trained his children to do so. The father and children became proficient in their art and were admired for their work. The Chapekar brothers received little formal education, but the "company of good people, hearing of kirtans, travelling, witnessing darbars of great princes and seeing assemblies of eminent scholars" was a source of knowledge far more enriching than a few examinations passed in school", writes Damodar Hari in his autobiography. Hari Vinayak, father of the Chapekar brothers is credited to have authored Satyanarayanakatha , of the Skandapurana , a Sanskrit text with translations. Pune, was a very important military base with a large cantonment during the British colonial rule. The cantonment had a significant European population of soldiers, officers, and their families. A number of public health initiatives were undertaken during this period ostensibly to protect the Indian population, but mainly to keep Europeans safe from the periodic epidemics of diseases like Cholera , bubonic plague , small pox , etc. The action took form in vaccinating the population and better sanitary arrangements. Given the vast cultural differences, and at times the arrogance of colonial officers, these health measures often led to public anger. However, the heavy handedness particularly bad in 1897, during the bubonic plague epidemic in the city. By the end of February 1897, the epidemic was raging with a mortality rate twice the norm (657 deaths or 0.6% of the city population), and half the city's population had fled. A Special Plague Committee was formed under the chairmanship of W.C. Rand, an Indian Civil Services officer. He brought European troops to deal with the emergency. The heavy handed measures he employed included forcibly entering peoples' homes, at times in the middle of the night and removing infected people and digging up floors, where it was believed in those days, the plague bacillus bacteria resided. It was also required of the principal occupant of a house or a building to report all deaths and all illnesses suspected to be plague. Funerals were declared unlawful until the deaths were registered. The committee had the right to mark special grounds for giving funeral to corpses suspected to have succumbed from plague, and prohibit use of any other place for the purpose. Disobedience of the orders would subject the offender to criminal prosecution. The work of the committee began on 13 March and ended on 19 May. The total estimated plague mortality was 2091. These measures were deeply unpopular. Nationalist leader Bal Gangadhar Tilak fulminated against the measures in his newspapers, Kesari and Maratha. The resentment culminated in Rand and his military escort being shot dead by the Chapekar brothers on 22 June 1897.The assassination led to a re-evaluation of public health policies. This led even Tilak to support the vaccination efforts later in 1906. In his report on the administration of the Puna plague, Rand wrote, "It is a matter of great satisfaction to the members of the Plague Committee that no credible complaint that the modesty of a woman had been intentionally insulted was made either to themselves or to the officers under whom the troops worked". He also writes that closest watch was kept on the troops employed on plague duty and utmost consideration was shown for the customs and traditions of the people. A missionary, Rev. Robert P. Wilder, quoted in a contemporary New York Times article, asserted that the cause of plague was native practices such as going bare-foot, the distrust of the natives about the government segregation camps; further, that houses have been shut up with corpses inside, and search parties have been going around to unearth them. The same article included reported rumours that the plague has been caused by grain hoarded for twenty years by the banias or grocers being sold in the market, while others felt it was Queen Victoria 's curse for the daubing of her statue with tar. In contrast to the above accounts, accounts based on local sources quote, among others, Narasimha Chintaman Kelkar as stating that the appointment of military officers introduced an element of severity and coercion in the house searches, the highhandedness of the government provoked the people of Puna, and some soldiers were beaten in the Rasta Peth locality. Kelkar alleged that the soldiers involved in the house searches "either, through ignorance or impudence, would mock, indulge in monkey tricks, talk foolishly, intimidate, touch innocent people, shove them, enter any place without justification, pocket valuable items, etc". His close associate, Bal Gangadhar Tilak , wrote: "Her Majesty the Queen, the Secretary of State and his Council, should not have issued the orders for practising tyranny upon the people of India without any special advantage to be gained... the government should not have entrusted the execution of this order to a suspicious, sullen and tyrannical officer like Rand." Gopal Krishna Gokhale alleged in an interview with the Manchester Guardian , while on a visit to Britain, that soldiers "ignorant of the language and contemptuous of the customs, the sentiments and the religious susceptibilities of the [Indian] people" had been "let loose" upon the city of Poona , and had "wantonly destroyed property, appropriated jewellery, burnt furniture, entered kitchens and places of worship, contaminated food, spat upon idols or broke them by throwing them on the ground, and dragged women into the streets for inspection before removal to hospitals" during house searches. Gokhale further alleged during the interview that his associated reported to him that two women were sexually assaulted by soldiers, one of whom subsequently committed suicide. Gokhale subsequently came under a storm of criticism for his claims, and eventually offered an "unqualified apology" for them, for which he came under further criticism from Indian nationalists. In Independent India, a Maharashtra government agency published school textbook describes the Pune plague as follows, In 1897, there was an epidemic of plague in Poona. To control the epidemic, an officer named Mr. Rand was appointed. He used tyrannical methods and harassed the people. In his report on the administration of the Puna plague, Rand wrote, "It is a matter of great satisfaction to the members of the Plague Committee that no credible complaint that the modesty of a woman had been intentionally insulted was made either to themselves or to the officers under whom the troops worked". He also writes that closest watch was kept on the troops employed on plague duty and utmost consideration was shown for the customs and traditions of the people. A missionary, Rev. Robert P. Wilder, quoted in a contemporary New York Times article, asserted that the cause of plague was native practices such as going bare-foot, the distrust of the natives about the government segregation camps; further, that houses have been shut up with corpses inside, and search parties have been going around to unearth them. The same article included reported rumours that the plague has been caused by grain hoarded for twenty years by the banias or grocers being sold in the market, while others felt it was Queen Victoria 's curse for the daubing of her statue with tar. In contrast to the above accounts, accounts based on local sources quote, among others, Narasimha Chintaman Kelkar as stating that the appointment of military officers introduced an element of severity and coercion in the house searches, the highhandedness of the government provoked the people of Puna, and some soldiers were beaten in the Rasta Peth locality. Kelkar alleged that the soldiers involved in the house searches "either, through ignorance or impudence, would mock, indulge in monkey tricks, talk foolishly, intimidate, touch innocent people, shove them, enter any place without justification, pocket valuable items, etc". His close associate, Bal Gangadhar Tilak , wrote: "Her Majesty the Queen, the Secretary of State and his Council, should not have issued the orders for practising tyranny upon the people of India without any special advantage to be gained... the government should not have entrusted the execution of this order to a suspicious, sullen and tyrannical officer like Rand." Gopal Krishna Gokhale alleged in an interview with the Manchester Guardian , while on a visit to Britain, that soldiers "ignorant of the language and contemptuous of the customs, the sentiments and the religious susceptibilities of the [Indian] people" had been "let loose" upon the city of Poona , and had "wantonly destroyed property, appropriated jewellery, burnt furniture, entered kitchens and places of worship, contaminated food, spat upon idols or broke them by throwing them on the ground, and dragged women into the streets for inspection before removal to hospitals" during house searches. Gokhale further alleged during the interview that his associated reported to him that two women were sexually assaulted by soldiers, one of whom subsequently committed suicide. Gokhale subsequently came under a storm of criticism for his claims, and eventually offered an "unqualified apology" for them, for which he came under further criticism from Indian nationalists. In Independent India, a Maharashtra government agency published school textbook describes the Pune plague as follows, In 1897, there was an epidemic of plague in Poona. To control the epidemic, an officer named Mr. Rand was appointed. He used tyrannical methods and harassed the people. On 22 June 1897, the Diamond Jubilee of the coronation of Queen Victoria was celebrated in Pune. In his autobiography Damodar Hari writes that he believed the jubilee celebrations would cause Europeans of all ranks to go to the Government House, and give them the opportunity to kill Rand. The brothers Damodar Hari and Balkrishna Hari selected a spot of Ganeshkhind road, by side of a yellow bungalow to shoot at Rand. Each armed with a sword and a pistol. Balkrishna in addition carried a hatchet. They reached Ganeshkhind, they saw what looked like Rand's carriage pass by, but they let it go, not being sure, deciding to attack him on his way back. They reached Government House at 7.00 – 7.30 in the evening, the sun had set and darkness began to set in. A large number of people had gathered to witness the spectacle at the Government House. There were bonfires on the hills. The swords and the hatchets they carried made movement without raising suspicion difficult, so they cached them under a stone culvert near the bungalow. As planned, Damodar Hari waited at the gate of the Government House, and as Rand's carriage emerged, ran 10 – 15 paces behind it. As the carriage reached the yellow bungalow, Damodar made up the distance, and called out "Gondya ala re"("Gondya has come," or "here is Gondya"), a predetermined signal for Balkrishna to take action. Damodar Hari undid the flap of the carriage, raised it and fired from a distance of about a span. It was originally planned that both would shoot at Rand, so as to ensure that Rand would not live, however Balkrishna Hari lagged behind and Rand's carriage rolled on, Balkrishna Hari meanwhile on the suspicion that the occupants of the following carriage were whispering to each other, fired at the head of one of them from behind. Lieutenant Ayerst, Rand's military escort who was riding in the following carriage died on the spot, Rand was taken to Sassoon Hospital where he succumbed to his injuries 3 July 1897. Damodar Hari was arrested in connection with the above, on the basis of information given by the Dravid brothers. In his statement, recorded on 8 October 1897, Damodar Hari, said that atrocities like the pollution of sacred places and the breaking of idols were committed by European soldiers at the time of house searches in Pune, during the plague. Chapekar tells that they wanted to take revenge of this. His statement was treated as a confession and he was charged under section 302 of the Indian Penal Code , tried and hanged, on 18 April 1898. Balkrishna Hari absconded, and could be found only in January 1899, betrayed by a friend. Police informants: the Dravid brothers, were eliminated by Vasudeo Hari, Mahadev Vinayak Ranade and Khando Vishnu Sathe, who were arrested in their attempt to shoot police chief constable Rama Pandu later the same evening, of 9 February 1899. All were subsequently apprehended and tried. There the Chapekar brothers Balkrishna Hari, Vasudeo Hari, and Ranade were sentenced to death and executed by the gallows, Vasudev Hari: 8 May 1899, Mahadeva Vinayak Ranade: 10 May 1899, Balkrishna Hari :12 May 1899. Sathe, though a juvenile, was sentenced to 10 years' Rigorous Imprisonment. An article, published in The New York Times , dated 4 October 1897, reports the arrest of Damodar Chapekar Deccani, and 28 others, Ayerst's and Rand's slayers. This article states that Deccani is Damodar's last name and refers to him as such. It also terms him an advocate. Another dated 4 November 1897, reports the incident and the subsequent trial, it calls Damodar Chapekar a Brahmin lawyer. The former article says that Damodar became embittered with Europeans as he was refused enlistment in the army, by the authorities in Shimla. Both articles also mention Damodar's admission of an earlier incident of tarring of Queen Victoria's statue. On 2 February 1898, The New York Times reported the death sentence passed on Damodar. The Sydney Morning Herald , dated 13 February 1899, reports that a brother of Damodar Hari, who was sentenced to death for the shooting to death of Poona Plague Commissioner and Lt. Ayerst, fired upon a native police officer. A connection between the shooting of the Dravid brothers on the streets of Poona is also mentioned with the shooting. It further states that Chapekar boasted of murder the Dravids and also named an accomplice, Ranade. It also reports the arrest of Chapekar and Ranade. The 1979 Indian Marathi -language film, 22 June 1897 , covers events prior to the assassination, the act and its aftermath. The Hindi film Chapekar Brothers (film) was released in 2016 covering the same historical events. An Indian web television series about the brothers in Marathi , Gondya Ala Re , was released in 2019 on Zee5 . In 2023 the story of Chapekar brothers Shown in DD National 's TV series Swaraj in episode 43.

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Plague pit

A plague pit is the informal term used to refer to mass graves in which victims of the Black Death were buried. The term is most often used to describe pits located in Great Britain , but can be applied to any place where bubonic plague victims were buried. [ citation needed ]The plague which swept across China , Middle East , and Europe in the 14th century is estimated to have killed between one-third and two-thirds of Europe's population . Disposal of the bodies of those who died presented huge problems for the authorities, and eventually the normal patterns of burial and funerary observance broke down. [ citation needed ]Plague pits were used especially often during major plague outbreaks, such as the London epidemic of 1665 . Graveyards rapidly filled and parishes became strained; for example the number of deaths in the parish of St Bride's Church , Fleet Street, in 1665 was almost six times normal.

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Bubonic plague

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Great Plague of Marseille

The Great Plague of Marseille , also known as the Plague of Provence, was the last major outbreak of bubonic plague in Western Europe . Arriving in Marseille , France , in 1720, the disease killed over 100,000 people: 50,000 in the city during the next two years and another 50,000 to the north in surrounding provinces and towns. While economic activity took only a few years to recover, as trade expanded to the West Indies and Latin America , it was not until 1765 that the population returned to its pre-1720 level.At the end of the plague of 1580, the people at Marseille took some measures to attempt to control the future spread of disease. The city council of Marseille established a sanitation board, whose members were to be drawn from the city council as well as the doctors of the city. The exact founding date of the board is unknown, but its existence is first mentioned in a 1622 text of the Parliament of Aix . The newly established sanitation board made a series of recommendations to maintain the health of the city. They established a bureaucracy to maintain the health of Marseille. In addition to protecting the city from exterior vulnerabilities, the sanitation board sought to build a public infrastructure. The first public hospital of Marseille was also built during this time period and was given a full-sized staff of doctors and nurses. Additionally, the sanitation board was responsible for the accreditation of local doctors. Citing the vast amount of misinformation that propagates during a plague, the sanitation board sought to, at a minimum, provide citizens with a list of doctors who were believed to be credible. The sanitation board was one of the first executive bodies formed by the city of Marseille. It was staffed to support the board's increasing responsibilities. [ citation needed ] The Sanitation Board established a three-tiered control and quarantine system. Members of the board inspected all incoming ships and gave them one of three "bills of health". The "bill of health" then determined the level of access to the city by the ship and its cargo. [ citation needed ] A delegation of members of the sanitation board was to greet every incoming ship. They reviewed the captain's log, which recorded every city where the ship had landed, and checked it against the sanitation board's master list of cities throughout the Mediterranean that had rumors of recent plague incidents. The delegation also inspected all the cargo, crew and passengers, looking for signs of possible disease. If the team saw signs of disease, the ship was not allowed to land at a Marseille dock. [ citation needed ] If the ship passed that first test and there were no signs of disease, but the ship's itinerary included a city with documented plague activity, the ship was sent to the second tier of quarantine, at islands outside of Marseille harbour. The criteria for the lazarets were ventilation (to drive off what was thought to be the miasma of disease), be near the sea to facilitate communication and pumping of water to clean, and to be isolated yet easily accessible. Even a clean bill of health for a ship required a minimum of 18 days' quarantine at the off-island location. During such time, the crew would be held in one of the lazarettos/lazarets that were constructed around the city. The lazarettos were also classified in relation to bills of health given to the ship and individuals. With a clean bill, a crewman went to the largest quarantine site, which was equipped with stores and was large enough to accommodate many ships and crews at a time. If crew members were believed subject to a possibility of plague, they were sent to the more isolated quarantine site, which was built on an island off the coast of the Marseille harbour. The crew and passengers were required to wait there for 50 to 60 days to see if they developed any sign of plague. Once crews served their time, they were allowed into the city in order to sell their goods and enjoy themselves prior to departure. [ citation needed ]At the end of the plague of 1580, the people at Marseille took some measures to attempt to control the future spread of disease. The city council of Marseille established a sanitation board, whose members were to be drawn from the city council as well as the doctors of the city. The exact founding date of the board is unknown, but its existence is first mentioned in a 1622 text of the Parliament of Aix . The newly established sanitation board made a series of recommendations to maintain the health of the city. They established a bureaucracy to maintain the health of Marseille. In addition to protecting the city from exterior vulnerabilities, the sanitation board sought to build a public infrastructure. The first public hospital of Marseille was also built during this time period and was given a full-sized staff of doctors and nurses. Additionally, the sanitation board was responsible for the accreditation of local doctors. Citing the vast amount of misinformation that propagates during a plague, the sanitation board sought to, at a minimum, provide citizens with a list of doctors who were believed to be credible. The sanitation board was one of the first executive bodies formed by the city of Marseille. It was staffed to support the board's increasing responsibilities. [ citation needed ]The Sanitation Board established a three-tiered control and quarantine system. Members of the board inspected all incoming ships and gave them one of three "bills of health". The "bill of health" then determined the level of access to the city by the ship and its cargo. [ citation needed ] A delegation of members of the sanitation board was to greet every incoming ship. They reviewed the captain's log, which recorded every city where the ship had landed, and checked it against the sanitation board's master list of cities throughout the Mediterranean that had rumors of recent plague incidents. The delegation also inspected all the cargo, crew and passengers, looking for signs of possible disease. If the team saw signs of disease, the ship was not allowed to land at a Marseille dock. [ citation needed ] If the ship passed that first test and there were no signs of disease, but the ship's itinerary included a city with documented plague activity, the ship was sent to the second tier of quarantine, at islands outside of Marseille harbour. The criteria for the lazarets were ventilation (to drive off what was thought to be the miasma of disease), be near the sea to facilitate communication and pumping of water to clean, and to be isolated yet easily accessible. Even a clean bill of health for a ship required a minimum of 18 days' quarantine at the off-island location. During such time, the crew would be held in one of the lazarettos/lazarets that were constructed around the city. The lazarettos were also classified in relation to bills of health given to the ship and individuals. With a clean bill, a crewman went to the largest quarantine site, which was equipped with stores and was large enough to accommodate many ships and crews at a time. If crew members were believed subject to a possibility of plague, they were sent to the more isolated quarantine site, which was built on an island off the coast of the Marseille harbour. The crew and passengers were required to wait there for 50 to 60 days to see if they developed any sign of plague. Once crews served their time, they were allowed into the city in order to sell their goods and enjoy themselves prior to departure. [ citation needed ]This great outburst of plague was the last recurrence of a pandemic of bubonic plague , following the devastating episodes which began in the early fourteenth century; the first known instance of bubonic plague in Marseille was the arrival of the Black Death in the autumn of 1347. According to contemporary reports, in May 1720, Yersinia pestis arrived at the port of Marseille from the Levant upon the merchant ship Grand-Saint-Antoine. The vessel had departed from Sidon in Lebanon , having previously called at Smyrna , Tripoli [ clarification needed ] , and plague-ridden Cyprus . A Turkish passenger was the first to be infected and soon died, followed by several crew members and the ship's surgeon. The ship was refused entry to the port of Livorno . [ citation needed ] When it arrived at Marseille, it was promptly placed under quarantine in the lazaret by the port authorities. Due largely to Marseille's monopoly on French trade with the Levant, this important port had a large stock of imported goods in warehouses. It was also expanding its trade with other areas of the Middle East and emerging markets in the New World. Powerful city merchants wanted the silk and cotton cargo of the ship for the great medieval fair at Beaucaire and pressured authorities to lift the quarantine. [ citation needed ] A few days later, the disease broke out in the city. Hospitals were quickly overwhelmed, and residents panicked, driving the sick from their homes and out of the city. Mass graves were dug but were quickly filled. Eventually, the number of dead overcame city public health efforts, until thousands of corpses lay scattered and in piles around the city. [ citation needed ] Attempts to stop the spread of plague included an Act of the Parlement of Aix that levied the death penalty for any communication between Marseille and the rest of Provence. To enforce this separation, a plague wall, or mur de la peste , was erected across the countryside. The wall was built of dry stone, 2 m (6 ft 7 in) high and 70 cm (28 in) thick, with guard posts set back from the wall. Remains of the wall can still be seen in different parts of the Plateau de Vaucluse. [ citation needed ] At the onset of the plague, Nicolas Roze , who had been vice-consul at a factory on the Peloponnese coast and dealt against epidemics there, proposed his services to the local authorities, the échevins. On the strength of his experience dealing with the Greek outbreaks, he was made General Commissioner for the Rive-Neuve neighbourhood. He established a quarantine by setting up checkpoints , and went as far as building gallows as a deterrence against looters. He also had five large mass graves dug out, converted La Corderie into a field hospital, and organised distribution of humanitarian supply to the population. He furthermore organised supply for the city itself. On 16 September 1720, Roze personally headed a 150-strong group of volunteers and prisoners to remove 1,200 corpses in the poor neighbourhood of the Esplanade de la Tourette. Some of the corpses were three weeks old and contemporary sources describe them as "hardly human in shape and set in movement by maggots". In half an hour, the corpses were thrown into open pits that were then filled with lime and covered with soil. Out of 1,200 volunteers and prisoners deployed to fight the plague, only three survived. Roze himself caught the disease, but survived, although chances of survival without modern medicine are between 20 and 40%. During a two-year period, 50,000 of Marseille's total population of 90,000 died. An additional 50,000 people in other areas succumbed as the plague spread north, eventually reaching Aix-en-Provence , Arles , Apt and Toulon . Estimates indicate an overall death rate of between 25 and 50% for the population in the larger area, with the city of Marseille at 40%, the area of Toulon at above 50%, and the area of Aix and Arles at 25%. [ citation needed ] After the plague subsided, the royal government strengthened the plague defenses of the port, building the waterside Lazaret d'Arenc . A double line of fifteen-foot walls ringed the whitewashed compound, pierced on the waterside to permit the offloading of cargo from lighters. Merchantmen were required to pass inspection at an island further out in the harbour, where crews and cargoes were examined. In 1998, an excavation of a mass grave of victims of the bubonic plague outbreak was conducted by scholars from the Université de la Méditerranée . The excavation provided an opportunity to study more than 200 skeletons from an area in the second arrondissement in Marseille, known as the Monastery of the Observance. In addition to modern laboratory testing, archival records were studied to determine the conditions and dates surrounding the use of this mass grave. This multidisciplinary approach revealed previously unknown facts and insights concerning the epidemic of 1722. The reconstruction of the skull of one body, a 15-year-old boy, revealed the first historical evidence of an autopsy dated to the spring of 1722. The anatomic techniques used appear to be identical to those described in a surgical book dating from 1708. [ citation needed ]

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Bubonic plague

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1629–1631 Italian plague

The Italian plague of 1629–1631 , also referred to as the Great Plague of Milan , was part of the second plague pandemic that began with the Black Death in 1348 and ended in the 18th century. One of two major outbreaks in Italy during the 17th century, it affected northern and central Italy and resulted in at least 280,000 deaths, with some estimating fatalities as high as one million, or about 35% of the population. The plague may have contributed to the decline of Italy's economy relative to those of other Western European countries. Thought to have originated in Northern France in 1623, the plague was carried throughout Europe as a result of troop movements associated with the Thirty Years' War and was allegedly brought to Lombardy in 1629 by soldiers involved in the War of the Mantuan Succession . The disease first spread to Venetian troops and in October 1629 reached Milan , Lombardy's major commercial centre. Although the city instituted a quarantine and limited access to external visitors and trade goods, it failed to eliminate the disease. A major outbreak in March 1630 resulted from relaxed health measures during the carnival season, followed by a second wave in the spring and summer of 1631. Overall, Milan suffered approximately 60,000 fatalities out of a total population of 130,000. East of Lombardy, the Republic of Venice was infected in 1630–31. The city of Venice was severely hit, with recorded casualties of 46,000 out of a population of 140,000. Some historians believe that the drastic loss of life, and its impact on commerce, ultimately resulted in the downfall of Venice as a major commercial and political power. The papal city of Bologna lost an estimated 15,000 citizens to the plague, with neighboring smaller cities of Modena and Parma also being heavily affected. This outbreak of plague also spread north into Tyrol , an alpine region of western Austria and northern Italy. [ citation needed ] Later outbreaks of bubonic plague in Italy occurred in the city of Florence in 1630–1633 and the areas surrounding Naples , Rome and Genoa in 1656–57. [ citation needed ] Population before the plague and death toll, selected cities: A 2019 study argues the plague of 1629–1631 led to lower growth in several cities affected by the plague and "caused long-lasting damage to the size of Italian urban populations and to urbanization rates. These findings support the hypothesis that seventeenth-century plagues played a fundamental role in triggering the process of relative decline of the Italian economies." The 1630 Milan plague is the backdrop for several chapters of Alessandro Manzoni 's 1840 novel The Betrothed ( Italian : I promessi sposi ). Although a work of fiction, Manzoni's description of the conditions and events in plague-ravaged Milan are completely historical and extensively documented from primary sources researched by the author. [ citation needed ] An expunged section of the book, describing the historical trial and execution of three alleged "plague-spreaders", was later published in a pamphlet entitled Storia della colonna infame (History of the pillar of infamy). [ citation needed ]

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Bubonic plague

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Unit 731

Biological weapons Chemical weapons Explosives 400,000 or higher from biological warfare Over 3,000 from inside experiments from each unit (not including branches, 1940–1945 only) : 20 At least 10,000 prisoners died No documented survivors Unit 731 ( Japanese : 731部隊 , Hepburn : Nana-san-ichi Butai ) , [note 1] short for Manchu Detachment 731 and also known as the Kamo Detachment : 198 and the Ishii Unit , was a covert biological and chemical warfare research and development unit of the Imperial Japanese Army that engaged in lethal human experimentation and biological weapons manufacturing during the Second Sino-Japanese War (1937–1945) and World War II . It killed an estimated 200,000 to 300,000 people. It was based in the Pingfang district of Harbin , the largest city in the Japanese puppet state of Manchukuo (now Northeast China ) and had active branch offices throughout China and Southeast Asia . Unit 731 was responsible for some of the most notorious war crimes committed by the Japanese armed forces . It routinely conducted tests on people who were dehumanized and internally referred to as "logs". Experiments included disease injections, controlled dehydration, biological weapons testing, hypobaric pressure chamber testing, vivisection , organ harvesting , amputation , and standard weapons testing. Victims included not only kidnapped men, women (including pregnant women) and children but also babies born from the systemic rape perpetrated by the staff inside the compound. The victims also came from different nationalities, with the majority being Chinese and a significant minority being Russian . Additionally, Unit 731 produced biological weapons that were used in areas of China not occupied by Japanese forces, which included Chinese cities and towns, water sources, and fields. Estimates of those killed by Unit 731 and its related programs range up to half a million people, and none of the inmates survived. In the final moments of the Second World War, all prisoners were killed to conceal evidence. Originally set up by the military police of the Empire of Japan , Unit 731 was taken over and commanded until the end of the war by General Shirō Ishii , a combat medic officer. The facility itself was built in 1935 as a replacement for the Zhongma Fortress , a prison and experimentation camp. Ishii and his team used it to expand their capabilities. The program received generous support from the Japanese government until the end of the war in 1945. While Unit 731 researchers arrested by Soviet forces were tried at the December 1949 Khabarovsk war crimes trials , those captured by the United States were secretly given immunity in exchange for the data gathered during their human experiments. The United States helped cover up the human experimentations and handed stipends to the perpetrators. The Americans co-opted the researchers' bioweapons information and experience for use in their own biological warfare program , much like what had been done with Nazi German researchers in Operation Paperclip . On 28 August 2002, Tokyo District Court ruled that Japan had committed biological warfare in China and consequently had slaughtered many residents. Japan initiated its biological weapons program during the 1930s, in part due to the prohibition of biological weapons in interstate conflicts by the Geneva Protocol of 1925. They reasoned that the ban verified its effectiveness as a weapon. Japan's occupation of Manchuria began in 1931 after the Japanese invasion of Manchuria . Japan decided to build Unit 731 in Manchuria because the occupation not only gave the Japanese an advantage of separating the research station from their island, but also gave them access to as many Chinese individuals as they wanted for use as test subjects. They viewed the Chinese as no-cost assets, and hoped this would give them a competitive advantage in biological warfare. Most of the victims were Chinese, but many victims were also from different nationalities. In 1932, Surgeon General Shirō Ishii , chief medical officer of the Imperial Japanese Army and protégé of Army Minister Sadao Araki , was placed in command of the Army Epidemic Prevention Research Laboratory ( AEPRL ). Ishii organized a secret research group, the "Tōgō Unit," for chemical and biological experimentation in Manchuria. Ishii had proposed the creation of a Japanese biological and chemical research unit in 1930, after a two-year study trip abroad, on the grounds that Western powers were developing their own programs. One of Ishii's main supporters inside the army was Colonel Chikahiko Koizumi , who later served as Japan's Health Minister from 1941 to 1945. Koizumi had joined a secret poison gas research committee in 1915, during World War I , when he and other Imperial Japanese Army officers were impressed by the successful German use of chlorine gas at the Second Battle of Ypres , in which the Allies suffered 6,000 deaths and 15,000 wounded as a result of the chemical attack. Unit Tōgō was set into motion in the Zhongma Fortress , a prison and experimentation camp in Beiyinhe, a village 100 kilometers (62 mi) south of Harbin on the South Manchuria Railway . The prisoners brought to Zhongma included common criminals , captured bandits, anti-Japanese partisans, as well as political prisoners and people rounded up on trumped up charges by the Kempeitai . Prisoners were generally well fed on a diet of rice or wheat , meat , fish , and occasionally even alcohol in order to be in normal health at the beginning of experiments. Then, over several days, prisoners were eventually drained of blood and deprived of nutrients and water. Their deteriorating health was recorded. Some were also vivisected . Others were deliberately infected with plague bacteria and other microbes . A prison break in the autumn of 1934, which jeopardized the facility's secrecy, and an explosion in 1935 (believed to be sabotage) led Ishii to shut down Zhongma Fortress. He then received authorization to move to Pingfang, approximately 24 kilometers (15 mi) south of Harbin, to set up a new, much larger facility. In 1936, Emperor Hirohito issued a decree authorizing the expansion of the unit and its integration into the Kwantung Army as the Epidemic Prevention Department. It was divided at that time into the "Ishii Unit" and "Wakamatsu Unit", with a base in Xinjing . From August 1940 on, the units were known collectively as the "Epidemic Prevention and Water Purification Department of the Kwantung Army" or "Unit 731" short. His younger brother, Prince Mikasa , toured the Unit 731 headquarters in China, and wrote in his memoir that he watched films showing how Chinese prisoners were "made to march on the plains of Manchuria for poison gas experiments on humans." Hideki Tojo , who later became Prime Minister in 1941, was also shown films of the experiments, which he described as "unpleasant." In addition to the establishment of Unit 731, the decree also called for the creation of an additional biological warfare development unit, called the Kwantung Army Military Horse Epidemic Prevention Workshop (later referred to as Manchuria Unit 100 ), and a chemical warfare development unit called the Kwantung Army Technical Testing Department (later referred to as Manchuria Unit 516 ). After the Japanese invasion of China in 1937, sister chemical and biological warfare units were founded in major Chinese cities and were referred to as Epidemic Prevention and Water Supply Units. Detachments included Unit 1855 in Beijing , Unit Ei 1644 in Nanjing , Unit 8604 in Guangzhou , and later Unit 9420 in Singapore . All of these units comprised Ishii's network, which, at its height in 1939, oversaw over 10,000 personnel. Medical doctors and professors from Japan were attracted to join Unit 731 both by the rare opportunity to conduct human experimentation and the Army's strong financial backing. Unit Tōgō was set into motion in the Zhongma Fortress , a prison and experimentation camp in Beiyinhe, a village 100 kilometers (62 mi) south of Harbin on the South Manchuria Railway . The prisoners brought to Zhongma included common criminals , captured bandits, anti-Japanese partisans, as well as political prisoners and people rounded up on trumped up charges by the Kempeitai . Prisoners were generally well fed on a diet of rice or wheat , meat , fish , and occasionally even alcohol in order to be in normal health at the beginning of experiments. Then, over several days, prisoners were eventually drained of blood and deprived of nutrients and water. Their deteriorating health was recorded. Some were also vivisected . Others were deliberately infected with plague bacteria and other microbes . A prison break in the autumn of 1934, which jeopardized the facility's secrecy, and an explosion in 1935 (believed to be sabotage) led Ishii to shut down Zhongma Fortress. He then received authorization to move to Pingfang, approximately 24 kilometers (15 mi) south of Harbin, to set up a new, much larger facility. In 1936, Emperor Hirohito issued a decree authorizing the expansion of the unit and its integration into the Kwantung Army as the Epidemic Prevention Department. It was divided at that time into the "Ishii Unit" and "Wakamatsu Unit", with a base in Xinjing . From August 1940 on, the units were known collectively as the "Epidemic Prevention and Water Purification Department of the Kwantung Army" or "Unit 731" short. His younger brother, Prince Mikasa , toured the Unit 731 headquarters in China, and wrote in his memoir that he watched films showing how Chinese prisoners were "made to march on the plains of Manchuria for poison gas experiments on humans." Hideki Tojo , who later became Prime Minister in 1941, was also shown films of the experiments, which he described as "unpleasant." In addition to the establishment of Unit 731, the decree also called for the creation of an additional biological warfare development unit, called the Kwantung Army Military Horse Epidemic Prevention Workshop (later referred to as Manchuria Unit 100 ), and a chemical warfare development unit called the Kwantung Army Technical Testing Department (later referred to as Manchuria Unit 516 ). After the Japanese invasion of China in 1937, sister chemical and biological warfare units were founded in major Chinese cities and were referred to as Epidemic Prevention and Water Supply Units. Detachments included Unit 1855 in Beijing , Unit Ei 1644 in Nanjing , Unit 8604 in Guangzhou , and later Unit 9420 in Singapore . All of these units comprised Ishii's network, which, at its height in 1939, oversaw over 10,000 personnel. Medical doctors and professors from Japan were attracted to join Unit 731 both by the rare opportunity to conduct human experimentation and the Army's strong financial backing. A special project, codenamed Maruta , used human beings for experiments. Test subjects were gathered from the surrounding population and sometimes euphemistically referred to as "logs" ( 丸太 , maruta ) , used in such contexts as "How many logs fell?" This term originated as a joke on the part of the staff because the official cover story for the facility given to local authorities was that it was a lumber mill . According to a junior uniformed civilian employee of the Imperial Japanese Army working in Unit 731, the project was internally called "Holzklotz", German for log. In a further parallel, the corpses of "sacrificed" subjects were disposed of by incineration . Researchers in Unit 731 also published some of their results in peer-reviewed journals , writing as though the research had been conducted on nonhuman primates called "Manchurian monkeys" or "long-tailed monkeys." According to American historian Sheldon H. Harris : The Togo Unit employed gruesome tactics to secure specimens of select body organs. If Ishii or one of his co-workers wished to do research on the human brain, then they would order the guards to find them a useful sample. A prisoner would be taken from his cell. Guards would hold him while another guard would smash the victim's head open with an ax. His brain would be extracted off to the pathologist, and then to the crematorium for the usual disposal. Nakagawa Yonezo [ ja ] , professor emeritus at Osaka University , studied at Kyoto University during the war. While he was there, he watched footage of human experiments and executions from Unit 731. He later testified about the playfulness of the experimenters: Some of the experiments had nothing to do with advancing the capability of germ warfare , or of medicine. There is such a thing as professional curiosity: 'What would happen if we did such and such?' What medical purpose was served by performing and studying beheadings? None at all. That was just playing around. Professional people, too, like to play." Prisoners were injected with diseases, disguised as vaccinations , to study their effects. To study the effects of untreated venereal diseases , male and female prisoners were deliberately infected with syphilis and gonorrhea , then studied. Prisoners were also repeatedly subjected to rape by guards. Thousands of men, women, children, and infants interned at prisoner of war camps were subjected to vivisection , often performed without anesthesia and usually lethal. In a video interview, former Unit 731 member Okawa Fukumatsu admitted to having vivisected a pregnant woman. Vivisections were performed on prisoners after infecting them with various diseases. Researchers performed invasive surgery on prisoners, removing organs to study the effects of disease on the human body. Prisoners had limbs amputated in order to study blood loss . Limbs removed were sometimes reattached to the opposite side of victims' bodies. Some prisoners had their stomachs surgically removed and their esophagus reattached to the intestines . Parts of organs, such as the brain, lungs, and liver, were removed from others. Imperial Japanese Army surgeon Ken Yuasa suggests that practising vivisection on human subjects was widespread even outside Unit 731, estimating that at least 1,000 Japanese personnel were involved in the practice in mainland China. Yuasa said that when he performed vivisections on captives, they were "all for practice rather than for research," and that such practises were "routine" among Japanese doctors stationed in China during the war. The New York Times interviewed a former member of Unit 731. Insisting on anonymity, the former Japanese medical assistant recounted his first experience in vivisecting a live human being, who had been deliberately infected with the plague , for the purpose of developing "plague bombs" for war. "The fellow knew that it was over for him, and so he didn't struggle when they led him into the room and tied him down, but when I picked up the scalpel, that's when he began screaming. I cut him open from the chest to the stomach, and he screamed terribly, and his face was all twisted in agony. He made this unimaginable sound, he was screaming so horribly. But then finally he stopped. This was all in a day's work for the surgeons, but it really left an impression on me because it was my first time." Other sources suggest that it was the usual practice in the Unit for surgeons to stuff a rag (or medical gauze) into the mouth of prisoners before commencing vivisection in order to stifle any screaming. Unit 731 and its affiliated units ( Unit 1644 and Unit 100 , among others) were involved in research, development and experimental deployment of epidemic-creating biological weapons in assaults against the Chinese populace (both military and civilian) throughout World War II. Plague -infected fleas , bred in the laboratories of Unit 731 and Unit 1644, were spread by low-flying airplanes over Chinese cities, including coastal Ningbo and Changde , Hunan Province , in 1940 and 1941. These operations killed tens of thousands with bubonic plague epidemics. An expedition to Nanjing involved spreading typhoid and paratyphoid germs into the wells , marshes , and houses of the city, as well as infusing them in snacks distributed to locals. Epidemics broke out shortly after, to the elation of many researchers, who concluded that paratyphoid fever was "the most effective" of the pathogens. : xii, 173 At least 12 large-scale bioweapon field trials were carried out, and at least 11 Chinese cities attacked with biological agents. An attack on Changde in 1941 reportedly led to approximately 10,000 biological casualties and 1,700 deaths among ill-prepared Japanese troops, in most cases due to cholera . Japanese researchers performed tests on prisoners with bubonic plague , cholera , smallpox , botulism , and other diseases. This research led to the development of the defoliation bacilli bomb and the flea bomb used to spread bubonic plague. Some of these bombs were designed with porcelain shells, an idea proposed by Ishii in 1938. These bombs enabled Japanese soldiers to launch biological attacks, infecting agriculture, reservoirs , wells, as well as other areas, with anthrax - and plague -carrier fleas, typhoid , cholera , or other deadly pathogens. During biological bomb experiments, researchers dressed in protective suits would examine the dying victims. Infected food supplies and clothing were dropped by airplane into areas of China not occupied by Japanese forces. In addition, poisoned food and candy were given to unsuspecting victims. Plague fleas, infected clothing, and infected supplies encased in bombs were dropped on various targets. The resulting cholera , anthrax , and plague were estimated to have killed at least 400,000 Chinese civilians. Tularemia was also tested on Chinese civilians. Due to pressure from numerous accounts of the biowarfare attacks, Chiang Kai-shek sent a delegation of army and foreign medical personnel in November 1941 to document evidence and treat the afflicted. A report on the Japanese use of plague-infected fleas on Changde was made widely available the following year but was not addressed by the Allied Powers until Franklin D. Roosevelt issued a public warning in 1943 condemning the attacks. In December 1944, the Japanese Navy explored the possibility of attacking cities in California with biological weapons, known as Operation PX or Operation Cherry Blossoms at Night. The plan for the attack involved Seiran aircraft launched by submarine aircraft carriers upon the West Coast of the United States—specifically, the cities of San Diego, Los Angeles, and San Francisco. The planes would spread weaponized bubonic plague , cholera , typhus , dengue fever , and other pathogens in a biological terror attack upon the population. The submarine crews would infect themselves and run ashore in a suicide mission. Planning for Operation PX was finalized on March 26, 1945, but shelved shortly thereafter due to the strong opposition of Chief of General Staff Yoshijirō Umezu . Umezu later explained his decision as such: "If bacteriological warfare is conducted, it will grow from the dimension of war between Japan and America to an endless battle of humanity against bacteria. Japan will earn the derision of the world." Human targets were used to test grenades positioned at various distances and in various positions. Flamethrowers were tested on people. Victims were also tied to stakes and used as targets to test pathogen-releasing bombs , chemical weapons , shrapnel bombs with varying amounts of fragments, and explosive bombs as well as bayonets and knives. To determine the best course of treatment for varying degrees of shrapnel wounds sustained on the field by Japanese Soldiers, Chinese prisoners were exposed to direct bomb blasts. They were strapped, unprotected, to wooden planks that were staked into the ground at increasing distances around a bomb that was then detonated. It was surgery for most, autopsies for the rest. In other tests, subjects were deprived of food and water to determine the amount of time until death; placed into low-pressure chambers until their eyes popped from the sockets ; experimented upon to determine the relationship between temperature, burns, and human survival; hung upside down until death; crushed with heavy objects ; electrocuted ; dehydrated with hot fans; placed into centrifuges and spun until death; injected with animal blood, notably with horse blood; exposed to lethal doses of X-rays ; subjected to various chemical weapons inside gas chambers; injected with seawater; and burned or buried alive . In addition to chemical agents, the properties of many different toxins were also investigated by the Unit. To name a few, prisoners were exposed to tetrodotoxin ( pufferfish or fugu poison), heroin , Korean bindweed , bactal , and castor-oil seeds ( ricin ). Massive amounts of blood were drained from some prisoners in order to study the effects of blood loss according to former Unit 731 vivisectionist Okawa Fukumatsu. In one case, at least half a liter of blood was drawn at two-to-three-day intervals. As stated above, dehydration experiments were performed on the victims. The purpose of these tests was to determine the amount of water in an individual's body and to see how long one could survive with a very low to no water intake. It is known that victims were also starved before these tests began. The deteriorating physical states of these victims were documented by staff at a periodic interval. "It was said that a small number of these poor men, women, and children who became marutas were also mummified alive in total dehydration experiments. They sweated themselves to death under the heat of several hot dry fans. At death, the corpses would only weigh ≈1/5 normal bodyweight." Unit 731 also performed transfusion experiments with different blood types . Unit member Naeo Ikeda wrote: In my experience, when A type blood 100 cc was transfused to an O type subject, whose pulse was 87 per minute and temperature was 35.4 degrees C, 30 minutes later the temperature rose to 38.6 degrees with slight trepidation. Sixty minutes later the pulse was 106 per minute and the temperature was 39.4 degrees. Two hours later the temperature was 37.7 degrees, and three hours later the subject recovered. When AB type blood 120 cc was transfused to an O type subject, an hour later the subject described malaise and psychroesthesia in both legs. When AB type blood 100 cc was transfused to a B type subject, there seemed to be no side effect. Unit 731 tested many different chemical agents on prisoners and had a building dedicated to gas experiments. Some of the agents tested were mustard gas , lewisite , cyanic acid gas , white phosphorus , adamsite , and phosgene gas . A former army major and technician gave the following testimony anonymously (at the time of the interview, this man was a professor emeritus at a national university): In 1943, I attended a poison gas test held at the Unit 731 test facilities. A glass-walled chamber about three meters square [97 sq ft] and two meters [6.6 ft] high was used. Inside of it, a Chinese man was blindfolded, with his hands tied around a post behind him. The gas was adamsite (sneezing gas), and as the gas filled the chamber the man went into violent coughing convulsions and began to suffer excruciating pain. More than ten doctors and technicians were present. After I had watched for about ten minutes, I could not stand it any more, and left the area. I understand that other types of gasses were also tested there. Takeo Wano, a former medical worker in Unit 731, said that he saw a Western man, who was vertically cut into two pieces, pickled in a jar of formaldehyde . Wano guessed that the man was Russian because there were many Russians living in the area at that time. Unit 100 also experimented with toxic gas. Phone booth-like tanks were used as portable gas chambers for the prisoners. Some were forced to wear various types of gas masks ; others wore military uniforms, and some wore no clothes at all. Some of the tests have been described as "psychopathically sadistic, with no conceivable military application". For example, one experiment documented the time it took for three-day-old babies to freeze to death. Unit 731 also tested chemical weapons on prisoners in field conditions. A report authored by unknown researcher in the Kamo Unit (Unit 731) describes a large human experiment of yperite gas ( mustard gas ) on 7–10 September 1940. Twenty subjects were divided into three groups and placed in combat emplacements, trenches , gazebos, and observatories. One group was clothed with Chinese underwear, no hat, and no mask and was subjected to as much as 1,800 field gun rounds of yperite gas over 25 minutes. Another group was clothed in summer military uniform and shoes; three had masks and another three had no mask. They also were exposed to as much as 1,800 rounds of yperite gas. A third group was clothed in summer military uniform, three with masks and two without masks, and were exposed to as much as 4,800 rounds. Then their general symptoms and damage to skin, eye, respiratory organs , and digestive organs were observed at 4 hours, 24 hours, and 2, 3, and 5 days after the shots. Injecting the blister fluid from one subject into another subject and analyses of blood and soil were also performed. Five subjects were forced to drink a solution of yperite and lewisite gas in water, with or without decontamination . The report describes conditions of every subject precisely without mentioning what happened to them in the long run. The following is an excerpt of one of these reports: Number 376, dugout of the first area: September 7, 1940, 6 pm: Tired and exhausted. Looks with hollow eyes. Weeping redness of the skin of the upper part of the body. Eyelids edematous, swollen. Epiphora. Hyperemic conjunctivae. September 8, 6 am: Neck, breast, upper abdomen and scrotum weeping, reddened, swollen. Covered with millet-seed-size to bean-size blisters. Eyelids and conjunctivae hyperemic and edematous. Had difficulties opening the eyes. September 8, 6 pm: Tired and exhausted. Feels sick. Body temperature 37 degrees Celsius. Mucous and bloody erosions across the shoulder girdle. Abundant mucous nose secretions. Abdominal pain. Mucous and bloody diarrhea. Proteinuria. September 9, 7 am: Tired and exhausted. Weakness of all four extremities. Low morale. Body temperature 37 degrees Celsius. Skin of the face still weeping. Army Engineer Hisato Yoshimura conducted experiments by taking captives outside, dipping various appendages into water of varying temperatures, and allowing the limb to freeze . Once frozen, Yoshimura would strike their affected limbs with a short stick, "emitting a sound resembling that which a board gives when it is struck." Ice was then chipped away, with the affected area being subjected to various treatments, such as being doused in water, exposed to the heat of fire, etc. Members of the Unit referred to Yoshimura as a "scientific devil" and a "cold-blooded animal" because he would conduct his work with strictness. Naoji Uezono, a member of Unit 731, described in a 1980s interview a grisly scene where Yoshimura had "two naked men put in an area 40–50 degrees below zero and researchers filmed the whole process until [the subjects] died. [The subjects] suffered such agony they were digging their nails into each other's flesh." Yoshimura's lack of remorse was evident in an article he wrote for the Japanese Journal of Physiology in 1950 in which he admitted to using 20 children and a three-day-old infant in experiments which exposed them to zero-degree-Celsius ice and salt water. Although this article drew criticism, Yoshimura denied any guilt when contacted by a reporter from the Mainichi Shimbun . [ user-generated source? ] Yoshimura developed a "resistance index of frostbite" based on the mean temperature 5 to 30 minutes after immersion in freezing water, the temperature of the first rise after immersion, and the time until the temperature first rises after immersion. In a number of separate experiments it was then determined how these parameters depend on the time of day a victim's body part was immersed in freezing water, the surrounding temperature and humidity during immersion, how the victim had been treated before the immersion ("after keeping awake for a night", "after hunger for 24 hours", "after hunger for 48 hours", "immediately after heavy meal", "immediately after hot meal", "immediately after muscular exercise", "immediately after cold bath", "immediately after hot bath"), what type of food the victim had been fed over the five days preceding the immersions with regard to dietary nutrient intake ("high protein (of animal nature)", "high protein (of vegetable nature)", "low protein intake", and "standard diet"), and salt intake (45 g NaCl per day, 15 g NaCl per day, no salt). This original data is seen in the attached figure. Unit members orchestrated forced sex acts between infected and non-infected prisoners to transmit the disease, as the testimony of a prison guard on the subject of devising a method for transmission of syphilis between patients shows: Infection of venereal disease by injection was abandoned, and the researchers started forcing the prisoners into sexual acts with each other. Four or five unit members, dressed in white laboratory clothing completely covering the body with only eyes and mouth visible, rest covered, handled the tests. A male and female, one infected with syphilis, would be brought together in a cell and forced into sex with each other. It was made clear that anyone resisting would be shot. After victims were infected, they were vivisected at different stages of infection, so that internal and external organs could be observed as the disease progressed. Testimony from multiple guards blames the female victims as being hosts of the diseases, even as they were forcibly infected. Genitals of female prisoners that were infected with syphilis were called "jam-filled buns" by guards. Some children grew up inside the walls of Unit 731, infected with syphilis. A Youth Corps member deployed to train at Unit 731 recalled viewing a batch of subjects that would undergo syphilis testing: "one was a Chinese woman holding an infant, one was a White Russian woman with a daughter of four or five years of age, and the last was a White Russian woman with a boy of about six or seven." The children of these women were tested in ways similar to their parents, with specific emphasis on determining how longer infection periods affected the effectiveness of treatments. Female prisoners were forced to become pregnant for use in experiments. The hypothetical possibility of vertical transmission (from mother to child) of diseases, particularly syphilis, was the stated reason for the torture. Fetal survival and damage to mother's reproductive organs were objects of interest. Though "a large number of babies were born in captivity," there have been no accounts of any survivors of Unit 731, children included. It is suspected that the children of female prisoners were killed after birth or aborted . While male prisoners were often used in single studies, so that the results of the experimentation on them would not be clouded by other variables, women were sometimes used in bacteriological or physiological experiments, sex experiments, and as the victims of sex crimes . The testimony of a unit member that served as a guard graphically demonstrated this reality: One of the former researchers I located told me that one day he had a human experiment scheduled, but there was still time to kill. So he and another unit member took the keys to the cells and opened one that housed a Chinese woman. One of the unit members raped her; the other member took the keys and opened another cell. There was a Chinese woman in there who had been used in a frostbite experiment. She had several fingers missing and her bones were black, with gangrene set in. He was about to rape her anyway, then he saw that her sex organ was festering, with pus oozing to the surface. He gave up the idea, left and locked the door, then later went on to his experimental work. Thousands of men, women, children, and infants interned at prisoner of war camps were subjected to vivisection , often performed without anesthesia and usually lethal. In a video interview, former Unit 731 member Okawa Fukumatsu admitted to having vivisected a pregnant woman. Vivisections were performed on prisoners after infecting them with various diseases. Researchers performed invasive surgery on prisoners, removing organs to study the effects of disease on the human body. Prisoners had limbs amputated in order to study blood loss . Limbs removed were sometimes reattached to the opposite side of victims' bodies. Some prisoners had their stomachs surgically removed and their esophagus reattached to the intestines . Parts of organs, such as the brain, lungs, and liver, were removed from others. Imperial Japanese Army surgeon Ken Yuasa suggests that practising vivisection on human subjects was widespread even outside Unit 731, estimating that at least 1,000 Japanese personnel were involved in the practice in mainland China. Yuasa said that when he performed vivisections on captives, they were "all for practice rather than for research," and that such practises were "routine" among Japanese doctors stationed in China during the war. The New York Times interviewed a former member of Unit 731. Insisting on anonymity, the former Japanese medical assistant recounted his first experience in vivisecting a live human being, who had been deliberately infected with the plague , for the purpose of developing "plague bombs" for war. "The fellow knew that it was over for him, and so he didn't struggle when they led him into the room and tied him down, but when I picked up the scalpel, that's when he began screaming. I cut him open from the chest to the stomach, and he screamed terribly, and his face was all twisted in agony. He made this unimaginable sound, he was screaming so horribly. But then finally he stopped. This was all in a day's work for the surgeons, but it really left an impression on me because it was my first time." Other sources suggest that it was the usual practice in the Unit for surgeons to stuff a rag (or medical gauze) into the mouth of prisoners before commencing vivisection in order to stifle any screaming. Unit 731 and its affiliated units ( Unit 1644 and Unit 100 , among others) were involved in research, development and experimental deployment of epidemic-creating biological weapons in assaults against the Chinese populace (both military and civilian) throughout World War II. Plague -infected fleas , bred in the laboratories of Unit 731 and Unit 1644, were spread by low-flying airplanes over Chinese cities, including coastal Ningbo and Changde , Hunan Province , in 1940 and 1941. These operations killed tens of thousands with bubonic plague epidemics. An expedition to Nanjing involved spreading typhoid and paratyphoid germs into the wells , marshes , and houses of the city, as well as infusing them in snacks distributed to locals. Epidemics broke out shortly after, to the elation of many researchers, who concluded that paratyphoid fever was "the most effective" of the pathogens. : xii, 173 At least 12 large-scale bioweapon field trials were carried out, and at least 11 Chinese cities attacked with biological agents. An attack on Changde in 1941 reportedly led to approximately 10,000 biological casualties and 1,700 deaths among ill-prepared Japanese troops, in most cases due to cholera . Japanese researchers performed tests on prisoners with bubonic plague , cholera , smallpox , botulism , and other diseases. This research led to the development of the defoliation bacilli bomb and the flea bomb used to spread bubonic plague. Some of these bombs were designed with porcelain shells, an idea proposed by Ishii in 1938. These bombs enabled Japanese soldiers to launch biological attacks, infecting agriculture, reservoirs , wells, as well as other areas, with anthrax - and plague -carrier fleas, typhoid , cholera , or other deadly pathogens. During biological bomb experiments, researchers dressed in protective suits would examine the dying victims. Infected food supplies and clothing were dropped by airplane into areas of China not occupied by Japanese forces. In addition, poisoned food and candy were given to unsuspecting victims. Plague fleas, infected clothing, and infected supplies encased in bombs were dropped on various targets. The resulting cholera , anthrax , and plague were estimated to have killed at least 400,000 Chinese civilians. Tularemia was also tested on Chinese civilians. Due to pressure from numerous accounts of the biowarfare attacks, Chiang Kai-shek sent a delegation of army and foreign medical personnel in November 1941 to document evidence and treat the afflicted. A report on the Japanese use of plague-infected fleas on Changde was made widely available the following year but was not addressed by the Allied Powers until Franklin D. Roosevelt issued a public warning in 1943 condemning the attacks. In December 1944, the Japanese Navy explored the possibility of attacking cities in California with biological weapons, known as Operation PX or Operation Cherry Blossoms at Night. The plan for the attack involved Seiran aircraft launched by submarine aircraft carriers upon the West Coast of the United States—specifically, the cities of San Diego, Los Angeles, and San Francisco. The planes would spread weaponized bubonic plague , cholera , typhus , dengue fever , and other pathogens in a biological terror attack upon the population. The submarine crews would infect themselves and run ashore in a suicide mission. Planning for Operation PX was finalized on March 26, 1945, but shelved shortly thereafter due to the strong opposition of Chief of General Staff Yoshijirō Umezu . Umezu later explained his decision as such: "If bacteriological warfare is conducted, it will grow from the dimension of war between Japan and America to an endless battle of humanity against bacteria. Japan will earn the derision of the world." Human targets were used to test grenades positioned at various distances and in various positions. Flamethrowers were tested on people. Victims were also tied to stakes and used as targets to test pathogen-releasing bombs , chemical weapons , shrapnel bombs with varying amounts of fragments, and explosive bombs as well as bayonets and knives. To determine the best course of treatment for varying degrees of shrapnel wounds sustained on the field by Japanese Soldiers, Chinese prisoners were exposed to direct bomb blasts. They were strapped, unprotected, to wooden planks that were staked into the ground at increasing distances around a bomb that was then detonated. It was surgery for most, autopsies for the rest.In other tests, subjects were deprived of food and water to determine the amount of time until death; placed into low-pressure chambers until their eyes popped from the sockets ; experimented upon to determine the relationship between temperature, burns, and human survival; hung upside down until death; crushed with heavy objects ; electrocuted ; dehydrated with hot fans; placed into centrifuges and spun until death; injected with animal blood, notably with horse blood; exposed to lethal doses of X-rays ; subjected to various chemical weapons inside gas chambers; injected with seawater; and burned or buried alive . In addition to chemical agents, the properties of many different toxins were also investigated by the Unit. To name a few, prisoners were exposed to tetrodotoxin ( pufferfish or fugu poison), heroin , Korean bindweed , bactal , and castor-oil seeds ( ricin ). Massive amounts of blood were drained from some prisoners in order to study the effects of blood loss according to former Unit 731 vivisectionist Okawa Fukumatsu. In one case, at least half a liter of blood was drawn at two-to-three-day intervals. As stated above, dehydration experiments were performed on the victims. The purpose of these tests was to determine the amount of water in an individual's body and to see how long one could survive with a very low to no water intake. It is known that victims were also starved before these tests began. The deteriorating physical states of these victims were documented by staff at a periodic interval. "It was said that a small number of these poor men, women, and children who became marutas were also mummified alive in total dehydration experiments. They sweated themselves to death under the heat of several hot dry fans. At death, the corpses would only weigh ≈1/5 normal bodyweight." Unit 731 also performed transfusion experiments with different blood types . Unit member Naeo Ikeda wrote: In my experience, when A type blood 100 cc was transfused to an O type subject, whose pulse was 87 per minute and temperature was 35.4 degrees C, 30 minutes later the temperature rose to 38.6 degrees with slight trepidation. Sixty minutes later the pulse was 106 per minute and the temperature was 39.4 degrees. Two hours later the temperature was 37.7 degrees, and three hours later the subject recovered. When AB type blood 120 cc was transfused to an O type subject, an hour later the subject described malaise and psychroesthesia in both legs. When AB type blood 100 cc was transfused to a B type subject, there seemed to be no side effect. Unit 731 tested many different chemical agents on prisoners and had a building dedicated to gas experiments. Some of the agents tested were mustard gas , lewisite , cyanic acid gas , white phosphorus , adamsite , and phosgene gas . A former army major and technician gave the following testimony anonymously (at the time of the interview, this man was a professor emeritus at a national university): In 1943, I attended a poison gas test held at the Unit 731 test facilities. A glass-walled chamber about three meters square [97 sq ft] and two meters [6.6 ft] high was used. Inside of it, a Chinese man was blindfolded, with his hands tied around a post behind him. The gas was adamsite (sneezing gas), and as the gas filled the chamber the man went into violent coughing convulsions and began to suffer excruciating pain. More than ten doctors and technicians were present. After I had watched for about ten minutes, I could not stand it any more, and left the area. I understand that other types of gasses were also tested there. Takeo Wano, a former medical worker in Unit 731, said that he saw a Western man, who was vertically cut into two pieces, pickled in a jar of formaldehyde . Wano guessed that the man was Russian because there were many Russians living in the area at that time. Unit 100 also experimented with toxic gas. Phone booth-like tanks were used as portable gas chambers for the prisoners. Some were forced to wear various types of gas masks ; others wore military uniforms, and some wore no clothes at all. Some of the tests have been described as "psychopathically sadistic, with no conceivable military application". For example, one experiment documented the time it took for three-day-old babies to freeze to death. Unit 731 also tested chemical weapons on prisoners in field conditions. A report authored by unknown researcher in the Kamo Unit (Unit 731) describes a large human experiment of yperite gas ( mustard gas ) on 7–10 September 1940. Twenty subjects were divided into three groups and placed in combat emplacements, trenches , gazebos, and observatories. One group was clothed with Chinese underwear, no hat, and no mask and was subjected to as much as 1,800 field gun rounds of yperite gas over 25 minutes. Another group was clothed in summer military uniform and shoes; three had masks and another three had no mask. They also were exposed to as much as 1,800 rounds of yperite gas. A third group was clothed in summer military uniform, three with masks and two without masks, and were exposed to as much as 4,800 rounds. Then their general symptoms and damage to skin, eye, respiratory organs , and digestive organs were observed at 4 hours, 24 hours, and 2, 3, and 5 days after the shots. Injecting the blister fluid from one subject into another subject and analyses of blood and soil were also performed. Five subjects were forced to drink a solution of yperite and lewisite gas in water, with or without decontamination . The report describes conditions of every subject precisely without mentioning what happened to them in the long run. The following is an excerpt of one of these reports: Number 376, dugout of the first area: September 7, 1940, 6 pm: Tired and exhausted. Looks with hollow eyes. Weeping redness of the skin of the upper part of the body. Eyelids edematous, swollen. Epiphora. Hyperemic conjunctivae. September 8, 6 am: Neck, breast, upper abdomen and scrotum weeping, reddened, swollen. Covered with millet-seed-size to bean-size blisters. Eyelids and conjunctivae hyperemic and edematous. Had difficulties opening the eyes. September 8, 6 pm: Tired and exhausted. Feels sick. Body temperature 37 degrees Celsius. Mucous and bloody erosions across the shoulder girdle. Abundant mucous nose secretions. Abdominal pain. Mucous and bloody diarrhea. Proteinuria. September 9, 7 am: Tired and exhausted. Weakness of all four extremities. Low morale. Body temperature 37 degrees Celsius. Skin of the face still weeping. Army Engineer Hisato Yoshimura conducted experiments by taking captives outside, dipping various appendages into water of varying temperatures, and allowing the limb to freeze . Once frozen, Yoshimura would strike their affected limbs with a short stick, "emitting a sound resembling that which a board gives when it is struck." Ice was then chipped away, with the affected area being subjected to various treatments, such as being doused in water, exposed to the heat of fire, etc. Members of the Unit referred to Yoshimura as a "scientific devil" and a "cold-blooded animal" because he would conduct his work with strictness. Naoji Uezono, a member of Unit 731, described in a 1980s interview a grisly scene where Yoshimura had "two naked men put in an area 40–50 degrees below zero and researchers filmed the whole process until [the subjects] died. [The subjects] suffered such agony they were digging their nails into each other's flesh." Yoshimura's lack of remorse was evident in an article he wrote for the Japanese Journal of Physiology in 1950 in which he admitted to using 20 children and a three-day-old infant in experiments which exposed them to zero-degree-Celsius ice and salt water. Although this article drew criticism, Yoshimura denied any guilt when contacted by a reporter from the Mainichi Shimbun . [ user-generated source? ] Yoshimura developed a "resistance index of frostbite" based on the mean temperature 5 to 30 minutes after immersion in freezing water, the temperature of the first rise after immersion, and the time until the temperature first rises after immersion. In a number of separate experiments it was then determined how these parameters depend on the time of day a victim's body part was immersed in freezing water, the surrounding temperature and humidity during immersion, how the victim had been treated before the immersion ("after keeping awake for a night", "after hunger for 24 hours", "after hunger for 48 hours", "immediately after heavy meal", "immediately after hot meal", "immediately after muscular exercise", "immediately after cold bath", "immediately after hot bath"), what type of food the victim had been fed over the five days preceding the immersions with regard to dietary nutrient intake ("high protein (of animal nature)", "high protein (of vegetable nature)", "low protein intake", and "standard diet"), and salt intake (45 g NaCl per day, 15 g NaCl per day, no salt). This original data is seen in the attached figure. Unit members orchestrated forced sex acts between infected and non-infected prisoners to transmit the disease, as the testimony of a prison guard on the subject of devising a method for transmission of syphilis between patients shows: Infection of venereal disease by injection was abandoned, and the researchers started forcing the prisoners into sexual acts with each other. Four or five unit members, dressed in white laboratory clothing completely covering the body with only eyes and mouth visible, rest covered, handled the tests. A male and female, one infected with syphilis, would be brought together in a cell and forced into sex with each other. It was made clear that anyone resisting would be shot. After victims were infected, they were vivisected at different stages of infection, so that internal and external organs could be observed as the disease progressed. Testimony from multiple guards blames the female victims as being hosts of the diseases, even as they were forcibly infected. Genitals of female prisoners that were infected with syphilis were called "jam-filled buns" by guards. Some children grew up inside the walls of Unit 731, infected with syphilis. A Youth Corps member deployed to train at Unit 731 recalled viewing a batch of subjects that would undergo syphilis testing: "one was a Chinese woman holding an infant, one was a White Russian woman with a daughter of four or five years of age, and the last was a White Russian woman with a boy of about six or seven." The children of these women were tested in ways similar to their parents, with specific emphasis on determining how longer infection periods affected the effectiveness of treatments. Female prisoners were forced to become pregnant for use in experiments. The hypothetical possibility of vertical transmission (from mother to child) of diseases, particularly syphilis, was the stated reason for the torture. Fetal survival and damage to mother's reproductive organs were objects of interest. Though "a large number of babies were born in captivity," there have been no accounts of any survivors of Unit 731, children included. It is suspected that the children of female prisoners were killed after birth or aborted . While male prisoners were often used in single studies, so that the results of the experimentation on them would not be clouded by other variables, women were sometimes used in bacteriological or physiological experiments, sex experiments, and as the victims of sex crimes . The testimony of a unit member that served as a guard graphically demonstrated this reality: One of the former researchers I located told me that one day he had a human experiment scheduled, but there was still time to kill. So he and another unit member took the keys to the cells and opened one that housed a Chinese woman. One of the unit members raped her; the other member took the keys and opened another cell. There was a Chinese woman in there who had been used in a frostbite experiment. She had several fingers missing and her bones were black, with gangrene set in. He was about to rape her anyway, then he saw that her sex organ was festering, with pus oozing to the surface. He gave up the idea, left and locked the door, then later went on to his experimental work. Army Engineer Hisato Yoshimura conducted experiments by taking captives outside, dipping various appendages into water of varying temperatures, and allowing the limb to freeze . Once frozen, Yoshimura would strike their affected limbs with a short stick, "emitting a sound resembling that which a board gives when it is struck." Ice was then chipped away, with the affected area being subjected to various treatments, such as being doused in water, exposed to the heat of fire, etc. Members of the Unit referred to Yoshimura as a "scientific devil" and a "cold-blooded animal" because he would conduct his work with strictness. Naoji Uezono, a member of Unit 731, described in a 1980s interview a grisly scene where Yoshimura had "two naked men put in an area 40–50 degrees below zero and researchers filmed the whole process until [the subjects] died. [The subjects] suffered such agony they were digging their nails into each other's flesh." Yoshimura's lack of remorse was evident in an article he wrote for the Japanese Journal of Physiology in 1950 in which he admitted to using 20 children and a three-day-old infant in experiments which exposed them to zero-degree-Celsius ice and salt water. Although this article drew criticism, Yoshimura denied any guilt when contacted by a reporter from the Mainichi Shimbun . [ user-generated source? ] Yoshimura developed a "resistance index of frostbite" based on the mean temperature 5 to 30 minutes after immersion in freezing water, the temperature of the first rise after immersion, and the time until the temperature first rises after immersion. In a number of separate experiments it was then determined how these parameters depend on the time of day a victim's body part was immersed in freezing water, the surrounding temperature and humidity during immersion, how the victim had been treated before the immersion ("after keeping awake for a night", "after hunger for 24 hours", "after hunger for 48 hours", "immediately after heavy meal", "immediately after hot meal", "immediately after muscular exercise", "immediately after cold bath", "immediately after hot bath"), what type of food the victim had been fed over the five days preceding the immersions with regard to dietary nutrient intake ("high protein (of animal nature)", "high protein (of vegetable nature)", "low protein intake", and "standard diet"), and salt intake (45 g NaCl per day, 15 g NaCl per day, no salt). This original data is seen in the attached figure.Unit members orchestrated forced sex acts between infected and non-infected prisoners to transmit the disease, as the testimony of a prison guard on the subject of devising a method for transmission of syphilis between patients shows: Infection of venereal disease by injection was abandoned, and the researchers started forcing the prisoners into sexual acts with each other. Four or five unit members, dressed in white laboratory clothing completely covering the body with only eyes and mouth visible, rest covered, handled the tests. A male and female, one infected with syphilis, would be brought together in a cell and forced into sex with each other. It was made clear that anyone resisting would be shot. After victims were infected, they were vivisected at different stages of infection, so that internal and external organs could be observed as the disease progressed. Testimony from multiple guards blames the female victims as being hosts of the diseases, even as they were forcibly infected. Genitals of female prisoners that were infected with syphilis were called "jam-filled buns" by guards. Some children grew up inside the walls of Unit 731, infected with syphilis. A Youth Corps member deployed to train at Unit 731 recalled viewing a batch of subjects that would undergo syphilis testing: "one was a Chinese woman holding an infant, one was a White Russian woman with a daughter of four or five years of age, and the last was a White Russian woman with a boy of about six or seven." The children of these women were tested in ways similar to their parents, with specific emphasis on determining how longer infection periods affected the effectiveness of treatments.Female prisoners were forced to become pregnant for use in experiments. The hypothetical possibility of vertical transmission (from mother to child) of diseases, particularly syphilis, was the stated reason for the torture. Fetal survival and damage to mother's reproductive organs were objects of interest. Though "a large number of babies were born in captivity," there have been no accounts of any survivors of Unit 731, children included. It is suspected that the children of female prisoners were killed after birth or aborted . While male prisoners were often used in single studies, so that the results of the experimentation on them would not be clouded by other variables, women were sometimes used in bacteriological or physiological experiments, sex experiments, and as the victims of sex crimes . The testimony of a unit member that served as a guard graphically demonstrated this reality: One of the former researchers I located told me that one day he had a human experiment scheduled, but there was still time to kill. So he and another unit member took the keys to the cells and opened one that housed a Chinese woman. One of the unit members raped her; the other member took the keys and opened another cell. There was a Chinese woman in there who had been used in a frostbite experiment. She had several fingers missing and her bones were black, with gangrene set in. He was about to rape her anyway, then he saw that her sex organ was festering, with pus oozing to the surface. He gave up the idea, left and locked the door, then later went on to his experimental work. In 2002, Changde , China, site of the plague flea bombing, held an "International Symposium on the Crimes of Bacteriological Warfare," which estimated that the number of people slaughtered by the Imperial Japanese Army germ warfare and other human experiments was around 580,000. : xii, 173 The American historian Sheldon H. Harris states that over 200,000 died. In addition to Chinese casualties, 1,700 Japanese troops in Zhejiang during Zhejiang-Jiangxi campaign were killed by their own biological weapons while attempting to unleash the biological agent, indicating serious issues with distribution. Harris also said plague-infected animals were released near the end of the war, and caused plague outbreaks that killed at least 30,000 people in the Harbin area from 1946 to 1948. Some test subjects were selected to gather a wide cross-section of the population and included common criminals, captured bandits, anti-Japanese partisans , political prisoners , homeless and mentally disabled people, which included infants, men, the elderly and pregnant women, as well as those rounded up by the Kenpeitai military police for alleged "suspicious activities." Unit 731 staff included approximately 300 researchers, including doctors and bacteriologists . At least 3,000 men, women, and children : 117 —of which at least 600 every year were provided by the Kenpeitai —were subjected to Unit 731 experimentation conducted at the Pingfang camp alone, not including victims from other medical experimentation sites such as Unit 100 . Although 3,000 internal victims is the widely accepted figure in the literature, former Unit member Okawa Fukumatsu claims that there were at least 10,000 victims of internal experiments at the Unit, he himself vivisecting thousands. According to A. S. Wells, the majority of victims were Chinese , with a lesser percentage being Russian , Mongolian , and Korean . They may also have included a small number of European, American, Indian, Australian, and New Zealander prisoners of war . A member of the Yokusan Sonendan paramilitary political youth branch, who worked for Unit 731, stated that not only were Chinese, Russians, and Koreans present, but also Americans, British, and French people. Sheldon H. Harris documented that the victims were generally political dissidents , communist sympathizers, ordinary criminals, impoverished civilians, and the mentally disabled. Author Seiichi Morimura estimates that almost 70 percent of the victims who died in the Pingfang camp were Chinese (both military and civilian), while close to 30 percent of the victims were Russian. No one who entered Unit 731 came out alive. Prisoners were usually received into Unit 731 at night in motor vehicles painted black with a ventilation hole but no windows. The vehicle would pull up at the main gates and one of the drivers would go to the guardroom and report to the guard. That guard would then telephone to the "Special Team" in the inner-prison ( Shiro Ishii's brother was head of this Special Team). Then, the prisoners would be transported through a secret tunnel dug under the facade of the central building to the inner-prisons. One of the prisons housed women and children (Building 8), while the other prison housed men (Building 7). Once at the inner-prison, technicians would take samples of the prisoners' blood and stool, test their kidney function , and collect other physical data. Once deemed healthy and fit for experimentation, prisoners lost their names and were given a three-digit number, which they retained until their death. Whenever prisoners died after the experiments they had been subjected to, a clerk of the 1st Division struck their numbers off an index card and took the deceased prisoner's manacles to be put on new arrivals to the prison. There is at least one recorded instance of "friendly" social interaction between prisoners and Unit 731 staff. Technician Naokata Ishibashi interacted with two female prisoners, a 21-year-old Chinese woman and a 19-year-old Ukrainian woman. The two prisoners told Ishibashi that they had not seen their faces in a mirror since being captured and begged him to get one. Ishibashi snuck a mirror to them through a hole in the cell door. The prison cells had wooden floors and a squat toilet in each. There was space between the outer walls of the cells and the outer walls of the prison, enabling the guards to walk behind the cells. Each cell door had a small window in it. Chief of the Personnel Division of the Kwantung Army Headquarters Tamura Tadashi testified that, when he was shown the inner-prison, he looked into the cells and saw living people in chains, some moved around, others were lying on the bare floor and were in a very sick and helpless condition. Former Unit 731 Youth Corps member Yoshio Shinozuka testified that the windows in these prison doors were so small that it was difficult to see in. The inner-prison was a highly secured building complete with cast iron doors. No one could enter without special permits and an ID pass with a photograph, and the entry/exit times were recorded. The "special team" worked in these two inner-prison buildings. This team wore white overall suits, army hats, rubber boots, and pistols strapped to their sides. Despite the prison's status as a highly secure building, at least one unsuccessful escape attempt did occur. Corporal Kikuchi Norimitsu testified that he was told by another unit member that a prisoner "had shown violence and had struck the experimenter with a door handle" and then "jumped out of the cell and ran down the corridor, seized the keys and opened the iron doors and some of the cells. Some of the prisoners managed to jump out but these were only the bold ones. These bold ones were shot." Seiichi Morimura in his book The Devil's Feast went into some greater detail regarding this escape attempt. Two Russian male prisoners were in a cell with handcuffs on, one of them lay flat on the floor pretending to be sick. This got the attention of a staff member who saw it as an unusual condition. That staff member decided to enter the cell. The Russian lying on the floor suddenly sprang up and knocked the guard down. The two Russians opened their handcuffs, took the keys, and opened some other cells while yelling. Some prisoners, including Russian and Chinese, were frantically roaming the corridors and kept yelling and shouting. One Russian shouted to the members of Unit 731, demanding to be shot rather than used as an experimental object. This Russian was shot to death. One staff member, who was an eyewitness at this escape attempt, recalled: "spiritually we were all lost in front of the 'marutas' who had no freedom and no weapons. At that time we understood in our hearts that justice was not on our side." Unfortunately for the prisoners of Unit 731, escape was an impossibility. Even if they had managed to escape the quadrangle (itself a heavily fortified building full of staff), they would have had to get over a three-meter-high (9.8 ft) brick wall surrounding the complex, and then across a dry moat filled with electrified wire running around the perimeter of the complex. Members of Unit 731 were not immune from being subjects of experiments. Yoshio Tamura, an assistant in the Special Team, recalled that Yoshio Sudō, an employee of the first division at Unit 731, became infected with bubonic plague as a result of the production of plague bacteria. The Special Team was then ordered to vivisect Sudō. Tamura recalled: Sudō had, a few days previously, been interested in talking about women, but now he was thin as a rake, with many purple spots over his body. A large area of scratches on his chest were bleeding. He painfully cried and breathed with difficulty. I sanitised his whole body with disinfectant. Whenever he moved, a rope around his neck tightened. After Sudō's body was carefully checked [by the surgeon], I handed a scalpel to [the surgeon] who, reversely gripping the scalpel, touched Sudō's stomach skin and sliced downward. Sudō shouted "brute!" and died with this last word. Additionally, Unit 731 Youth Corps member Yoshio Shinozuka testified that his friend junior assistant Mitsuo Hirakawa was vivisected as a result of being accidentally infected with plague. Despite the prison's status as a highly secure building, at least one unsuccessful escape attempt did occur. Corporal Kikuchi Norimitsu testified that he was told by another unit member that a prisoner "had shown violence and had struck the experimenter with a door handle" and then "jumped out of the cell and ran down the corridor, seized the keys and opened the iron doors and some of the cells. Some of the prisoners managed to jump out but these were only the bold ones. These bold ones were shot." Seiichi Morimura in his book The Devil's Feast went into some greater detail regarding this escape attempt. Two Russian male prisoners were in a cell with handcuffs on, one of them lay flat on the floor pretending to be sick. This got the attention of a staff member who saw it as an unusual condition. That staff member decided to enter the cell. The Russian lying on the floor suddenly sprang up and knocked the guard down. The two Russians opened their handcuffs, took the keys, and opened some other cells while yelling. Some prisoners, including Russian and Chinese, were frantically roaming the corridors and kept yelling and shouting. One Russian shouted to the members of Unit 731, demanding to be shot rather than used as an experimental object. This Russian was shot to death. One staff member, who was an eyewitness at this escape attempt, recalled: "spiritually we were all lost in front of the 'marutas' who had no freedom and no weapons. At that time we understood in our hearts that justice was not on our side." Unfortunately for the prisoners of Unit 731, escape was an impossibility. Even if they had managed to escape the quadrangle (itself a heavily fortified building full of staff), they would have had to get over a three-meter-high (9.8 ft) brick wall surrounding the complex, and then across a dry moat filled with electrified wire running around the perimeter of the complex. Members of Unit 731 were not immune from being subjects of experiments. Yoshio Tamura, an assistant in the Special Team, recalled that Yoshio Sudō, an employee of the first division at Unit 731, became infected with bubonic plague as a result of the production of plague bacteria. The Special Team was then ordered to vivisect Sudō. Tamura recalled: Sudō had, a few days previously, been interested in talking about women, but now he was thin as a rake, with many purple spots over his body. A large area of scratches on his chest were bleeding. He painfully cried and breathed with difficulty. I sanitised his whole body with disinfectant. Whenever he moved, a rope around his neck tightened. After Sudō's body was carefully checked [by the surgeon], I handed a scalpel to [the surgeon] who, reversely gripping the scalpel, touched Sudō's stomach skin and sliced downward. Sudō shouted "brute!" and died with this last word. Additionally, Unit 731 Youth Corps member Yoshio Shinozuka testified that his friend junior assistant Mitsuo Hirakawa was vivisected as a result of being accidentally infected with plague. There are unit members who were known to be interned at the Fushun War Criminals Management Centre and Taiyuan War Criminals Management Centre after the war, who then went on to be repatriated to Japan and founded the Association of Returnees from China and testified about Unit 731 and the crimes perpetrated there. Some members included: In April 2018, the National Archives of Japan disclosed a nearly complete list of 3,607 members of Unit 731 to Katsuo Nishiyama , a professor at Shiga University of Medical Science . Nishiyama reportedly intended to publish the list online to encourage further study into the unit. Previously disclosed members included: Twelve members were formally tried and sentenced in the Khabarovsk war crimes trials :Unit 731 was divided into eight divisions:Unit 731 had other units underneath it in the chain of command ; there were several other units under the auspice of Japan's biological weapons programs . Most or all Units had branch offices, which were also often referred to as "Units." The term Unit 731 can refer to the Harbin complex, or it can refer to the organization and its branches, sub-Units and their branches. The Unit 731 complex covered six square kilometers (2.3 sq mi) and consisted of more than 150 buildings. The design of the facilities made them hard to destroy by bombing. The complex contained various factories. It had around 4,500 containers to be used to raise fleas , six cauldrons to produce various chemicals, and around 1,800 containers to produce biological agents. Approximately 30 kilograms (66 lb) of bubonic plague bacteria could be produced in a few days. Some of Unit 731's satellite (branch) facilities are still in use by various Chinese industrial companies. A portion has been preserved and is open to visitors as a museum . Unit 731 had branches in Linkou (Branch 162), Mudanjiang , Hailin (Branch 643), Sunwu (Branch 673), Toan , and Hailar (Branch 543). : 60, 84, 124, 310 A medical school and research facility belonging to Unit 731 operated in the Shinjuku District of Tokyo during World War II. In 2006, Toyo Ishii—a nurse who worked at the school during the war—revealed that she had helped bury bodies and pieces of bodies on the school's grounds shortly after Japan's surrender in 1945. In response, in February 2011 the Ministry of Health began to excavate the site. While Tokyo courts acknowledged in 2002 that Unit 731 has been involved in biological warfare research, as of 2011 [ update ] the Japanese government had made no official acknowledgment of the atrocities committed against test subjects and rejected the Chinese government's requests for DNA samples to identify human remains (including skulls and bones) found near an army medical school. At Tokyo's Kyushu Imperial University in 1945, US POWs from a shot down B-29 were subjected to fatal medical experimentation . Unit 731 had branches in Linkou (Branch 162), Mudanjiang , Hailin (Branch 643), Sunwu (Branch 673), Toan , and Hailar (Branch 543). : 60, 84, 124, 310A medical school and research facility belonging to Unit 731 operated in the Shinjuku District of Tokyo during World War II. In 2006, Toyo Ishii—a nurse who worked at the school during the war—revealed that she had helped bury bodies and pieces of bodies on the school's grounds shortly after Japan's surrender in 1945. In response, in February 2011 the Ministry of Health began to excavate the site. While Tokyo courts acknowledged in 2002 that Unit 731 has been involved in biological warfare research, as of 2011 [ update ] the Japanese government had made no official acknowledgment of the atrocities committed against test subjects and rejected the Chinese government's requests for DNA samples to identify human remains (including skulls and bones) found near an army medical school. At Tokyo's Kyushu Imperial University in 1945, US POWs from a shot down B-29 were subjected to fatal medical experimentation . Operations and experiments continued until the end of the war. Ishii had wanted to use biological weapons in the Pacific War since May 1944, but his attempts were repeatedly snubbed. As the Second World War started to come to an end, all prisoners within the compound were killed to conceal evidence, and there were no documented survivors. With the coming of the Red Army in August 1945, the unit had to abandon their work in haste. Ministries in Tokyo ordered the destruction of all incriminating materials, including those in Pingfang . Potential witnesses, such as the 300 remaining prisoners, were either gassed or fed poison while the 600 Chinese and Manchurian laborers were shot. Ishii ordered every member of the group to disappear and "take the secret to the grave." Potassium cyanide vials were issued for use in case the remaining personnel were captured. Skeleton crews of Ishii's Japanese troops blew up the compound in the final days of the war to destroy evidence of their activities, but many were sturdy enough to remain somewhat intact. Among the individuals in Japan after its 1945 surrender was Lieutenant Colonel Murray Sanders , who arrived in Yokohama via the American ship Sturgess in September 1945. Sanders was a highly regarded microbiologist and a member of America's military center for biological weapons. Sanders' duty was to investigate Japanese biological warfare activity. At the time of his arrival in Japan, he had no knowledge of what Unit 731 was. Until Sanders finally threatened the Japanese with bringing the Soviets into the picture, little information about biological warfare was being shared with the Americans. The Japanese wanted to avoid prosecution under the Soviet legal system , so, the morning after he made his threat, Sanders received a manuscript describing Japan's involvement in biological warfare. Sanders took this information to General Douglas MacArthur , who was the Supreme Commander of the Allied Powers and responsible for rebuilding Japan during the Allied occupations. MacArthur struck a deal with Japanese informants : he secretly granted immunity to the physicians of Unit 731, including their leader, in exchange for providing exclusive American access to their research on biological warfare and data from human experimentation. American occupation authorities monitored the activities of former unit members, including reading and censoring their mail. The Americans believed that the research data was valuable and did not want other nations, particularly the Soviet Union, to acquire data on biological weapons. The Tokyo War Crimes Tribunal heard only one reference to Japanese experiments with "poisonous serums" on Chinese civilians. This took place in August 1946 and was instigated by David Sutton, assistant to the Chinese prosecutor. The Japanese defense counsel argued that the claim was vague and uncorroborated and it was dismissed by the tribunal president, Sir William Webb , for lack of evidence. The subject was not pursued further by Sutton, who was probably unaware of Unit 731's activities. His reference to it at the trial is believed to have been accidental. Later in 1981, one of the last surviving members of the Tokyo Tribunal, Judge Röling, had expressed bitterness in not being made aware of the suppression of evidence of Unit 731 and wrote, "It is a bitter experience for me to be informed now that centrally ordered Japanese war criminality of the most disgusting kind was kept secret from the court by the U.S. government." While German physicians were brought to trial and had their crimes publicized, the U.S. concealed information about Japanese biological warfare experiments and secured immunity for the perpetrators. Critics argue that racism led to the double standard in the American postwar responses to the experiments conducted on different nationalities. Whereas the perpetrators of Unit 731 were exempt from prosecution, the U.S. held a tribunal in Yokohama in 1948 that indicted nine Japanese physician professors and medical students for conducting vivisection upon captured American pilots; two professors were sentenced to death and others to 15–20 years' imprisonment. Although publicly silent on the issue at the Tokyo Trials, the Soviet Union pursued the case and prosecuted 12 top military leaders and scientists from Unit 731 and its affiliated biological-war prisons Unit 1644 in Nanjing and Unit 100 in Changchun in the Khabarovsk war crimes trials . Among those accused of war crimes , including germ warfare, was General Otozō Yamada , commander-in-chief of the million-man Kwantung Army occupying Manchuria. The trial of the Japanese perpetrators was held in Khabarovsk in December 1949; a lengthy partial transcript of trial proceedings was published in different languages the following year by the Moscow foreign languages press, including an English-language edition. The lead prosecuting attorney at the Khabarovsk trial was Lev Smirnov , who had been one of the top Soviet prosecutors at the Nuremberg Trials . The Japanese doctors and army commanders who had perpetrated the Unit 731 experiments received sentences from the Khabarovsk court ranging from 2 to 25 years in a Siberian labor camp . The United States refused to acknowledge the trials, branding them communist propaganda. The sentences doled out to the Japanese perpetrators were unusually lenient by Soviet standards, and all but two of the defendants returned to Japan by the 1950s (with one prisoner dying in prison and the other committing suicide inside his cell). In addition to the accusations of propaganda, the US also asserted that the trials were to only serve as a distraction from the Soviet treatment of several hundred thousand Japanese prisoners of war; meanwhile, the USSR asserted that the US had given the Japanese diplomatic leniency in exchange for information about their human experimentation. However, former Unit 731 members had also passed information about their biological experimentation to the Soviet government in exchange for judicial leniency. This was evidenced by the Soviet Union building a biological weapons facility in Sverdlovsk using documentation captured from Unit 731 in Manchuria. As above, during the United States occupation of Japan, the members of Unit 731 and the members of other experimental units were allowed to go free. On 6 May 1947, Douglas MacArthur , the Supreme Commander of the Allied Forces , wrote to Washington in order to inform it that "additional data, possibly some statements from Ishii, can probably be obtained by informing Japanese involved that information will be retained in intelligence channels and will not be employed as 'war crimes' evidence". According to an investigation by The Guardian , after the end of the war, under the pretense of vaccine development, former members of Unit 731 conducted human experiments on Japanese prisoners, babies and mental patients, with secret funding from the U.S. Government. One graduate of Unit 1644 , Masami Kitaoka, continued to perform experiments on unwilling Japanese subjects from 1947 to 1956. He performed his experiments while he was working for Japan's National Institute of Health Sciences. He infected prisoners with rickettsia and infected mentally-ill patients with typhus . As the chief of the unit, Shiro Ishii was granted immunity from prosecution for war crimes by the American occupation authorities, because he had provided human experimentation research materials to them. From 1948 to 1958, less than five percent of the documents were transferred onto microfilm and stored in the US National Archives before they were shipped back to Japan. Japanese discussions of Unit 731's activity began in the 1950s, after the end of the American occupation of Japan . In 1952, an infant girl at Nagoya City Pediatric Hospital died after being infected with E coli bacteria; the incident was publicly tied to former Unit 731 scientists. Later in that decade, journalists suspected that the murders attributed by the government to Sadamichi Hirasawa were actually carried out by members of Unit 731. In 1958, Japanese author Shūsaku Endō published the book The Sea and Poison about human experimentation in Fukuoka , which is thought to have been based on a real incident. In 1950, former members of Unit 731 including Masaji Kitano founded the blood bank and pharmaceutical company Green Cross , for which Murray Sanders also served as a consultant. The company became the target of a scandal in the 1980s after up to 3,000 Japanese contracted HIV through the distribution and use of its blood products, which were deemed unsafe. The author Seiichi Morimura published The Devil's Gluttony [ ja ] (悪魔の飽食) in 1981, followed by The Devil's Gluttony: A Sequel in 1983. These books purported to reveal the "true" operations of Unit 731, but falsely attributed unrelated photos to the Unit, which raised questions about their accuracy. Also in 1981, the first direct testimony of human vivisection in China was given by Ken Yuasa . Since then, much more in depth testimony has been given in Japan. The 2001 documentary Japanese Devils largely consists of interviews with fourteen Unit 731 staff members taken prisoner by China and later released. Japanese biological warfare operations were by far the largest during WWII, and "possibly with more people and resources than the BW producing nations of France , Hungary , Italy , Poland , and the Soviet Union combined, between the world wars. Despite the apparent success, Unit 731 lacked adequate scientific and engineering foundations to further maximize its effectiveness. Harris speculated that US scientists generally wanted to acquire it due to the concept of forbidden fruit , believing that lawful and ethical prohibitions could affect the outcomes of their research. During the COVID-19 pandemic , some scientists called for experimental data from Unit 731 to be publicly released to the international medical community because the data available on human-pathogen interactions could have helped epidemiologists with pandemic control. The information has been withheld by both the US and Japanese government. In 1983, the Japanese Ministry of Education asked Japanese historian Saburō Ienaga to remove a reference from one of his textbooks that stated Unit 731 conducted experiments on thousands of Chinese. The ministry alleged that no academic research supported the claim. In 1984, Japanese historian Tsuneishi Keiichi translated and published over 4,000 pages of U.S. documents on Japanese biological warfare. The ministry backed down after new studies were published in Japan and important evidence surfaced in the United States. Japanese history textbooks usually contain references to Unit 731, but do not go into detail about allegations, in accordance with this principle. Saburō Ienaga's New History of Japan included a detailed description, based on officers' testimony. The Ministry for Education attempted to remove this passage from his textbook before it was taught in public schools, on the basis that the testimony was insufficient. The Supreme Court of Japan ruled in 1997 that the testimony was indeed sufficient and that requiring it to be removed was an illegal violation of freedom of speech . In 1997, international lawyer Kōnen Tsuchiya filed a class action suit against the Japanese government, demanding reparations for the actions of Unit 731, using evidence filed by Professor Makoto Ueda of Rikkyo University . All levels of the Japanese court system found the suit baseless. No findings of fact were made about the existence of human experimentation, but the courts' ruling was that reparations are determined by international treaties , not national courts. [ citation needed ] In August 2002, the Tokyo district court ruled for the first time that Japan had engaged in biological warfare. Presiding judge Koji Iwata ruled that Unit 731, on the orders of the Imperial Japanese Army headquarters, used bacteriological weapons on Chinese civilians between 1940 and 1942, spreading diseases, including plague and typhoid , in the cities of Quzhou , Ningbo , and Changde . He rejected victims' compensation claims on the grounds that they had already been settled by international peace treaties. In October 2003, a member of Japan's House of Representatives filed an inquiry. Prime Minister Junichiro Koizumi responded that the Japanese government did not then possess any records related to Unit 731, but recognized the gravity of the matter and would publicize any records located in the future. In April 2018, the National Archives of Japan released the names of 3,607 members of Unit 731, in response to a request by Professor Katsuo Nishiyama of the Shiga University of Medical Science . After World War II, the Office of Special Investigations created a watchlist of suspected Axis collaborators and persecutors who are banned from entering the United States. While they have added over 60,000 names to the watchlist, they have only been able to identify under 100 Japanese participants. In a 1998 correspondence letter between the DOJ and Rabbi Abraham Cooper, Eli Rosenbaum, director of OSI, stated that this was due to two factors:As the Second World War started to come to an end, all prisoners within the compound were killed to conceal evidence, and there were no documented survivors. With the coming of the Red Army in August 1945, the unit had to abandon their work in haste. Ministries in Tokyo ordered the destruction of all incriminating materials, including those in Pingfang . Potential witnesses, such as the 300 remaining prisoners, were either gassed or fed poison while the 600 Chinese and Manchurian laborers were shot. Ishii ordered every member of the group to disappear and "take the secret to the grave." Potassium cyanide vials were issued for use in case the remaining personnel were captured. Skeleton crews of Ishii's Japanese troops blew up the compound in the final days of the war to destroy evidence of their activities, but many were sturdy enough to remain somewhat intact.Among the individuals in Japan after its 1945 surrender was Lieutenant Colonel Murray Sanders , who arrived in Yokohama via the American ship Sturgess in September 1945. Sanders was a highly regarded microbiologist and a member of America's military center for biological weapons. Sanders' duty was to investigate Japanese biological warfare activity. At the time of his arrival in Japan, he had no knowledge of what Unit 731 was. Until Sanders finally threatened the Japanese with bringing the Soviets into the picture, little information about biological warfare was being shared with the Americans. The Japanese wanted to avoid prosecution under the Soviet legal system , so, the morning after he made his threat, Sanders received a manuscript describing Japan's involvement in biological warfare. Sanders took this information to General Douglas MacArthur , who was the Supreme Commander of the Allied Powers and responsible for rebuilding Japan during the Allied occupations. MacArthur struck a deal with Japanese informants : he secretly granted immunity to the physicians of Unit 731, including their leader, in exchange for providing exclusive American access to their research on biological warfare and data from human experimentation. American occupation authorities monitored the activities of former unit members, including reading and censoring their mail. The Americans believed that the research data was valuable and did not want other nations, particularly the Soviet Union, to acquire data on biological weapons. The Tokyo War Crimes Tribunal heard only one reference to Japanese experiments with "poisonous serums" on Chinese civilians. This took place in August 1946 and was instigated by David Sutton, assistant to the Chinese prosecutor. The Japanese defense counsel argued that the claim was vague and uncorroborated and it was dismissed by the tribunal president, Sir William Webb , for lack of evidence. The subject was not pursued further by Sutton, who was probably unaware of Unit 731's activities. His reference to it at the trial is believed to have been accidental. Later in 1981, one of the last surviving members of the Tokyo Tribunal, Judge Röling, had expressed bitterness in not being made aware of the suppression of evidence of Unit 731 and wrote, "It is a bitter experience for me to be informed now that centrally ordered Japanese war criminality of the most disgusting kind was kept secret from the court by the U.S. government." While German physicians were brought to trial and had their crimes publicized, the U.S. concealed information about Japanese biological warfare experiments and secured immunity for the perpetrators. Critics argue that racism led to the double standard in the American postwar responses to the experiments conducted on different nationalities. Whereas the perpetrators of Unit 731 were exempt from prosecution, the U.S. held a tribunal in Yokohama in 1948 that indicted nine Japanese physician professors and medical students for conducting vivisection upon captured American pilots; two professors were sentenced to death and others to 15–20 years' imprisonment. Although publicly silent on the issue at the Tokyo Trials, the Soviet Union pursued the case and prosecuted 12 top military leaders and scientists from Unit 731 and its affiliated biological-war prisons Unit 1644 in Nanjing and Unit 100 in Changchun in the Khabarovsk war crimes trials . Among those accused of war crimes , including germ warfare, was General Otozō Yamada , commander-in-chief of the million-man Kwantung Army occupying Manchuria. The trial of the Japanese perpetrators was held in Khabarovsk in December 1949; a lengthy partial transcript of trial proceedings was published in different languages the following year by the Moscow foreign languages press, including an English-language edition. The lead prosecuting attorney at the Khabarovsk trial was Lev Smirnov , who had been one of the top Soviet prosecutors at the Nuremberg Trials . The Japanese doctors and army commanders who had perpetrated the Unit 731 experiments received sentences from the Khabarovsk court ranging from 2 to 25 years in a Siberian labor camp . The United States refused to acknowledge the trials, branding them communist propaganda. The sentences doled out to the Japanese perpetrators were unusually lenient by Soviet standards, and all but two of the defendants returned to Japan by the 1950s (with one prisoner dying in prison and the other committing suicide inside his cell). In addition to the accusations of propaganda, the US also asserted that the trials were to only serve as a distraction from the Soviet treatment of several hundred thousand Japanese prisoners of war; meanwhile, the USSR asserted that the US had given the Japanese diplomatic leniency in exchange for information about their human experimentation. However, former Unit 731 members had also passed information about their biological experimentation to the Soviet government in exchange for judicial leniency. This was evidenced by the Soviet Union building a biological weapons facility in Sverdlovsk using documentation captured from Unit 731 in Manchuria. As above, during the United States occupation of Japan, the members of Unit 731 and the members of other experimental units were allowed to go free. On 6 May 1947, Douglas MacArthur , the Supreme Commander of the Allied Forces , wrote to Washington in order to inform it that "additional data, possibly some statements from Ishii, can probably be obtained by informing Japanese involved that information will be retained in intelligence channels and will not be employed as 'war crimes' evidence". According to an investigation by The Guardian , after the end of the war, under the pretense of vaccine development, former members of Unit 731 conducted human experiments on Japanese prisoners, babies and mental patients, with secret funding from the U.S. Government. One graduate of Unit 1644 , Masami Kitaoka, continued to perform experiments on unwilling Japanese subjects from 1947 to 1956. He performed his experiments while he was working for Japan's National Institute of Health Sciences. He infected prisoners with rickettsia and infected mentally-ill patients with typhus . As the chief of the unit, Shiro Ishii was granted immunity from prosecution for war crimes by the American occupation authorities, because he had provided human experimentation research materials to them. From 1948 to 1958, less than five percent of the documents were transferred onto microfilm and stored in the US National Archives before they were shipped back to Japan. Japanese discussions of Unit 731's activity began in the 1950s, after the end of the American occupation of Japan . In 1952, an infant girl at Nagoya City Pediatric Hospital died after being infected with E coli bacteria; the incident was publicly tied to former Unit 731 scientists. Later in that decade, journalists suspected that the murders attributed by the government to Sadamichi Hirasawa were actually carried out by members of Unit 731. In 1958, Japanese author Shūsaku Endō published the book The Sea and Poison about human experimentation in Fukuoka , which is thought to have been based on a real incident. In 1950, former members of Unit 731 including Masaji Kitano founded the blood bank and pharmaceutical company Green Cross , for which Murray Sanders also served as a consultant. The company became the target of a scandal in the 1980s after up to 3,000 Japanese contracted HIV through the distribution and use of its blood products, which were deemed unsafe. The author Seiichi Morimura published The Devil's Gluttony [ ja ] (悪魔の飽食) in 1981, followed by The Devil's Gluttony: A Sequel in 1983. These books purported to reveal the "true" operations of Unit 731, but falsely attributed unrelated photos to the Unit, which raised questions about their accuracy. Also in 1981, the first direct testimony of human vivisection in China was given by Ken Yuasa . Since then, much more in depth testimony has been given in Japan. The 2001 documentary Japanese Devils largely consists of interviews with fourteen Unit 731 staff members taken prisoner by China and later released. Japanese biological warfare operations were by far the largest during WWII, and "possibly with more people and resources than the BW producing nations of France , Hungary , Italy , Poland , and the Soviet Union combined, between the world wars. Despite the apparent success, Unit 731 lacked adequate scientific and engineering foundations to further maximize its effectiveness. Harris speculated that US scientists generally wanted to acquire it due to the concept of forbidden fruit , believing that lawful and ethical prohibitions could affect the outcomes of their research. During the COVID-19 pandemic , some scientists called for experimental data from Unit 731 to be publicly released to the international medical community because the data available on human-pathogen interactions could have helped epidemiologists with pandemic control. The information has been withheld by both the US and Japanese government.In 1983, the Japanese Ministry of Education asked Japanese historian Saburō Ienaga to remove a reference from one of his textbooks that stated Unit 731 conducted experiments on thousands of Chinese. The ministry alleged that no academic research supported the claim. In 1984, Japanese historian Tsuneishi Keiichi translated and published over 4,000 pages of U.S. documents on Japanese biological warfare. The ministry backed down after new studies were published in Japan and important evidence surfaced in the United States. Japanese history textbooks usually contain references to Unit 731, but do not go into detail about allegations, in accordance with this principle. Saburō Ienaga's New History of Japan included a detailed description, based on officers' testimony. The Ministry for Education attempted to remove this passage from his textbook before it was taught in public schools, on the basis that the testimony was insufficient. The Supreme Court of Japan ruled in 1997 that the testimony was indeed sufficient and that requiring it to be removed was an illegal violation of freedom of speech . In 1997, international lawyer Kōnen Tsuchiya filed a class action suit against the Japanese government, demanding reparations for the actions of Unit 731, using evidence filed by Professor Makoto Ueda of Rikkyo University . All levels of the Japanese court system found the suit baseless. No findings of fact were made about the existence of human experimentation, but the courts' ruling was that reparations are determined by international treaties , not national courts. [ citation needed ] In August 2002, the Tokyo district court ruled for the first time that Japan had engaged in biological warfare. Presiding judge Koji Iwata ruled that Unit 731, on the orders of the Imperial Japanese Army headquarters, used bacteriological weapons on Chinese civilians between 1940 and 1942, spreading diseases, including plague and typhoid , in the cities of Quzhou , Ningbo , and Changde . He rejected victims' compensation claims on the grounds that they had already been settled by international peace treaties. In October 2003, a member of Japan's House of Representatives filed an inquiry. Prime Minister Junichiro Koizumi responded that the Japanese government did not then possess any records related to Unit 731, but recognized the gravity of the matter and would publicize any records located in the future. In April 2018, the National Archives of Japan released the names of 3,607 members of Unit 731, in response to a request by Professor Katsuo Nishiyama of the Shiga University of Medical Science . After World War II, the Office of Special Investigations created a watchlist of suspected Axis collaborators and persecutors who are banned from entering the United States. While they have added over 60,000 names to the watchlist, they have only been able to identify under 100 Japanese participants. In a 1998 correspondence letter between the DOJ and Rabbi Abraham Cooper, Eli Rosenbaum, director of OSI, stated that this was due to two factors:There have been several films about the atrocities of Unit 731. In Call of Duty: Black Ops III , the Zombies map included in the second DLC pack, "Zetsubou no Shima", is loosely inspired by Unit 731's divisions, with the story playing on the idea of a ninth hidden one aptly named 'Division 9'. In the indie horror game Spooky's Jumpscare Mansion , the Unit 731 experiments are explicitly referenced multiple times in terms of Specimen 9 (specifically stated to be a survivor of the Unit 731 experiments), as well as the labeling of human bodies as "logs": "I'm taking all those 'logs' they keep throwing out, and I'm nailing them together."There have been several films about the atrocities of Unit 731.In Call of Duty: Black Ops III , the Zombies map included in the second DLC pack, "Zetsubou no Shima", is loosely inspired by Unit 731's divisions, with the story playing on the idea of a ninth hidden one aptly named 'Division 9'. In the indie horror game Spooky's Jumpscare Mansion , the Unit 731 experiments are explicitly referenced multiple times in terms of Specimen 9 (specifically stated to be a survivor of the Unit 731 experiments), as well as the labeling of human bodies as "logs": "I'm taking all those 'logs' they keep throwing out, and I'm nailing them together."

Wiki

Bubonic plague

https://api.wikimedia.org/core/v1/wikipedia/en/page/Chinatown,_Honolulu/html

Chinatown, Honolulu

The Chinatown Historic District is a neighborhood of Honolulu , Hawaii , known for its Chinese American community. It is one of the oldest Chinatowns in the United States.There is conflicting information about the boundaries that make up Chinatown. One source identifies the natural boundary to the west as Honolulu Harbor , and to the north, Nu ʻ uanu stream. Beretania Street is usually considered the eastern boundary, and the southern boundary is Nu ʻ uanu Avenue, although the Chinatown Special District is considered to extend approximately a block and a half south of Nu ʻ uanu along Merchant Street. In total, the land area is 522 acres (211 ha) . A few blocks to the east is the Hawaii Capital Historic District , and adjacent to the south is the Merchant Street Historic District . Alternatively, the Hawaiian language newspaper Nupepa Kuokoa described Taona Pake (Chinatown) in 1900 as "that whole area from West side of Kukui Street until the river mouth called Makaaho, then travel straight until reaching Hotel street; and travel on [Hotel] this street on the West side until reaching Konia Street, and travel until you reach King St. Points of interest Parks and open spaces Since 2002, there are two small paifang on the sidewalks flanking North King Street, just north of where King crosses Nu ʻ uanu Stream, and just south of where Hotel splits from King. There is also a small brick entrance arch to Maunakea Marketplace off Maunakea Street, decorated with an awning featuring a green-tile roof. Two guardian lions mark the southern entrance to Chinatown on Hotel, between Bethel and Nu ʻ uanu near the Dr. Sun Yat-sen Memorial Park (formerly Chinatown Gateway Park); they were gifted to Honolulu by a sister city, Kaohsiung , in 1989. Dr. Sun was born in another of Honolulu's sister cities, Zhongshan . The Wo Fat Restaurant was Honolulu's oldest. The business first opened in 1882, but the building was destroyed in the 1886 fire. A new building was built at 115 North Hotel Street ( 21°18′44.4″N 157°51′47″W / 21.312333°N 157.86306°W / 21.312333; -157.86306 ) after the 1900 fire, and the current three-story building at the same location opened in 1938, designed by Y.T. Char. The Wo Fat Restaurant closed in 2005, and the building housed a nightclub in the early 2000s. In 1904, the Oahu Market was opened by Tuck Young at the corner of King and Kekaulike streets, coordinates 21°18′45″N 157°51′51″W / 21.31250°N 157.86417°W / 21.31250; -157.86417 ( Oahu Market ) . The simply designed functional construction, consisting of a large, open-air, covered space divided into stalls, remains in use today for selling fresh fish and produce. Points of interest Parks and open spaces Since 2002, there are two small paifang on the sidewalks flanking North King Street, just north of where King crosses Nu ʻ uanu Stream, and just south of where Hotel splits from King. There is also a small brick entrance arch to Maunakea Marketplace off Maunakea Street, decorated with an awning featuring a green-tile roof. Two guardian lions mark the southern entrance to Chinatown on Hotel, between Bethel and Nu ʻ uanu near the Dr. Sun Yat-sen Memorial Park (formerly Chinatown Gateway Park); they were gifted to Honolulu by a sister city, Kaohsiung , in 1989. Dr. Sun was born in another of Honolulu's sister cities, Zhongshan . The Wo Fat Restaurant was Honolulu's oldest. The business first opened in 1882, but the building was destroyed in the 1886 fire. A new building was built at 115 North Hotel Street ( 21°18′44.4″N 157°51′47″W / 21.312333°N 157.86306°W / 21.312333; -157.86306 ) after the 1900 fire, and the current three-story building at the same location opened in 1938, designed by Y.T. Char. The Wo Fat Restaurant closed in 2005, and the building housed a nightclub in the early 2000s. In 1904, the Oahu Market was opened by Tuck Young at the corner of King and Kekaulike streets, coordinates 21°18′45″N 157°51′51″W / 21.31250°N 157.86417°W / 21.31250; -157.86417 ( Oahu Market ) . The simply designed functional construction, consisting of a large, open-air, covered space divided into stalls, remains in use today for selling fresh fish and produce. The area was probably used by fishermen in ancient Hawaii but little evidence of this remains. Keali ʻ imaika ʻ i , the brother of Kamehameha I lived in the area at the end of the 18th century. One of the first early settlers from outside was Isaac Davis , who lived there until 1810. Spaniard Don Francisco de Paula Marín lived in the southern end of the area in the early 19th century, and planted a vineyard in the northern end, for which Vineyard Boulevard is named. During the 19th century laborers were imported from China to work on sugar plantations in Hawaii . Many became merchants after their contracts expired and moved to this area. The ethnic makeup has always been diverse, peaking at about 56% Chinese people in the 1900 census, and then declining. Honolulu is traditionally known in Chinese as 檀香山 ( Tánxiāngshān ), meaning Sandalwood Mountain . Two major fires destroyed many buildings in 1886 and 1900. The 1886 fire started at 4 p.m. on April 18; according to contemporary news reports, the Chinese fire company was blamed for being unable to halt the progress and the fire consumed 60 acres (24 ha) , destroying almost all of Chinatown, save two or three buildings. 8,000 residents were displaced. Sailors and marines from HMS Heroine were credited with keeping the fire contained to Chinatown by blowing up buildings. The 1900 fire started during the destruction of a building infected with bubonic plague ; the plague was confirmed in Honolulu on December 12, 1899. Schools were closed and 7000 residents of the area were put under quarantine . After 13 people died, the Board of Health ordered structures suspected of being infected to be burned. Residents were evacuated, and a few buildings were successfully destroyed while the Honolulu Fire Department stood by. However, on January 20, 1900, the fire went out of control after winds shifted, and destroyed most of the neighborhood instead. The neighborhood was rebuilt and many of the current buildings date from 1901. Very few are over four stories tall. King Kamehameha III created the Board of Health on December 13, 1850. This became the first Board of Health in the United States. It was established to supervise the public health of the people of Hawaii, and to protect them against epidemic diseases. The Board of Health, which at that time was under the control of three physicians, Nathaniel B. Emerson , Francis R. Day and Clifford B. Wood , played an integral role during the bubonic plague outbreak that started in 1899. The situation had become so dire in Honolulu that Emerson, Day and Wood were afforded absolute dictatorial authority over Hawaii. This was the result of an agreement between the President of the Provisional Hawaiian Government, Mr. Sanford Ballard Dole , and the Attorney General, Mr. Henry E. Cooper , who concurred that nothing should impede the battle of the "dread disease". Cooper also served as the President of the Board of Health. According to the Annual Reports published by the Hawaii State Department of Health , the first case of the bubonic plague was Yon Chong, a 22-year-old Chinese man who worked as a bookkeeper in Chinatown. Chong fell sick on December 9, 1899, and formed buboes , leading his attending physician to suspect the plague. A jointly-conducted diagnostic exam was performed by other doctors, who confirmed the suspicion. Their diagnosis was reported to Board President Cooper on December 11, 1899. Yon Chong died the following day, and Cooper made an announcement to the public about this first bubonic plague death. After the public announcement, Cooper ordered an immediate military quarantine of the Chinatown area. In hopes of containing the plague in Honolulu, the Board of Health also closed Honolulu Harbor to both incoming and outgoing vessels. According to the official Board of Health records, only three human cases of the plague were recorded during the quarantine. On December 19, 1899, the quarantine of Chinatown and Honolulu Harbor was lifted. However, only five days after the quarantine was lifted, nine more cases were reported by the Board of Health. Of those 12 reported cases, 11 would die. The epidemic continued until March 31, 1900. By the end, a total of 71 cases and 61 fatalities were reported by Board of Health. Yersinia pestis , the bacterium that causes bubonic plague , is transmitted by the oriental rat flea and has been historically propagated along various trade routes to the west from China. The original introduction of the oriental rat flea to Hawaii is unknown. In 1899, the Nippon Maru anchored in Honolulu Harbor en route to San Francisco, and reported the death of a Chinese passenger. After inspection, the ship had been confined to Quarantine Island, better known today as Sand Island . After a week-long stay there, the ship had been cleared to travel on to San Francisco. According to one record, due diligence was executed on the part of the Board of Health with respect to the passengers and goods, though little attention was paid to the chance of rats escaping and going ashore. This is because it was not yet widely known that the rodents were the carriers of the flea vector that transmits Yersinia pestis . The bubonic plague was introduced into Honolulu on October 20, 1899, by an offloaded shipment of rice from the America Maru , which had also been carrying rats. [ citation needed ] At that time, Chinese immigration to Hawaii had resulted in crowded residences in Chinatown with poor living conditions and sewage disposal. [ citation needed ] The Board of Health responded by incinerating garbage, renovating the sewer system, putting Chinatown under quarantine, and most of all burning affected buildings. Forty-one fires were set in total, and on January 20, 1900, winds picked up one fire and spread it to other buildings. The fire burned out of control for seventeen days and scorched 38 acres (15 ha) of Honolulu. There were another 31 controlled burns after the incident. The 7,000 residents rendered homeless were housed in detention camps to maintain the quarantine until April 30. White residents who had gathered to watch the fire escorted the victims to refugee camps by force, using baseball bats and pick handles to ensure compliance. Critics accused the government of Sinophobia . An exodus occurred. While the former residents rebuilt Chinatown, many moved to the suburbs, hoping not to relive a similar incident. The post-fire architecture used masonry rather than wood, since stone and brick buildings were fire resistant. Many of the people who filed damage claims were represented by lawyer Paul Neumann , but he died before the cases went to court. After World War II the area fell into disrepair and became a red-light district . During the administrations of mayors Frank Fasi and Jeremy Harris the area was targeted for revitalization. Restrictions on lighting and signs were relaxed to promote nightlife. Special zoning rules were adopted for the area. The Hawaii National Bank was founded in the district in 1960, and has its headquarters there. About 36 acres (15 ha) of the district was added to the National Register of Historic Places listings in Oahu on January 17, 1973, as site 73000658. On the eastern edge of the district, the Hawaii Theatre was restored and re-opened in 1996. The area around the theatre is called the Arts District . In 2005 a small park near the theatre at the corner of Hotel and Bethel streets was opened and named Chinatown Gateway Park. In November 2007 the park was renamed to honor Sun Yat-sen , who came to Chinatown in 1879; he was educated and planned the Chinese Revolution of 1911 during his Hawaiian stay. Honolulu Chinatown was included in the Preserve America program. King Kamehameha III created the Board of Health on December 13, 1850. This became the first Board of Health in the United States. It was established to supervise the public health of the people of Hawaii, and to protect them against epidemic diseases. The Board of Health, which at that time was under the control of three physicians, Nathaniel B. Emerson , Francis R. Day and Clifford B. Wood , played an integral role during the bubonic plague outbreak that started in 1899. The situation had become so dire in Honolulu that Emerson, Day and Wood were afforded absolute dictatorial authority over Hawaii. This was the result of an agreement between the President of the Provisional Hawaiian Government, Mr. Sanford Ballard Dole , and the Attorney General, Mr. Henry E. Cooper , who concurred that nothing should impede the battle of the "dread disease". Cooper also served as the President of the Board of Health. According to the Annual Reports published by the Hawaii State Department of Health , the first case of the bubonic plague was Yon Chong, a 22-year-old Chinese man who worked as a bookkeeper in Chinatown. Chong fell sick on December 9, 1899, and formed buboes , leading his attending physician to suspect the plague. A jointly-conducted diagnostic exam was performed by other doctors, who confirmed the suspicion. Their diagnosis was reported to Board President Cooper on December 11, 1899. Yon Chong died the following day, and Cooper made an announcement to the public about this first bubonic plague death. After the public announcement, Cooper ordered an immediate military quarantine of the Chinatown area. In hopes of containing the plague in Honolulu, the Board of Health also closed Honolulu Harbor to both incoming and outgoing vessels. According to the official Board of Health records, only three human cases of the plague were recorded during the quarantine. On December 19, 1899, the quarantine of Chinatown and Honolulu Harbor was lifted. However, only five days after the quarantine was lifted, nine more cases were reported by the Board of Health. Of those 12 reported cases, 11 would die. The epidemic continued until March 31, 1900. By the end, a total of 71 cases and 61 fatalities were reported by Board of Health.Yersinia pestis , the bacterium that causes bubonic plague , is transmitted by the oriental rat flea and has been historically propagated along various trade routes to the west from China. The original introduction of the oriental rat flea to Hawaii is unknown. In 1899, the Nippon Maru anchored in Honolulu Harbor en route to San Francisco, and reported the death of a Chinese passenger. After inspection, the ship had been confined to Quarantine Island, better known today as Sand Island . After a week-long stay there, the ship had been cleared to travel on to San Francisco. According to one record, due diligence was executed on the part of the Board of Health with respect to the passengers and goods, though little attention was paid to the chance of rats escaping and going ashore. This is because it was not yet widely known that the rodents were the carriers of the flea vector that transmits Yersinia pestis . The bubonic plague was introduced into Honolulu on October 20, 1899, by an offloaded shipment of rice from the America Maru , which had also been carrying rats. [ citation needed ] At that time, Chinese immigration to Hawaii had resulted in crowded residences in Chinatown with poor living conditions and sewage disposal. [ citation needed ] The Board of Health responded by incinerating garbage, renovating the sewer system, putting Chinatown under quarantine, and most of all burning affected buildings. Forty-one fires were set in total, and on January 20, 1900, winds picked up one fire and spread it to other buildings. The fire burned out of control for seventeen days and scorched 38 acres (15 ha) of Honolulu. There were another 31 controlled burns after the incident. The 7,000 residents rendered homeless were housed in detention camps to maintain the quarantine until April 30. White residents who had gathered to watch the fire escorted the victims to refugee camps by force, using baseball bats and pick handles to ensure compliance. Critics accused the government of Sinophobia . An exodus occurred. While the former residents rebuilt Chinatown, many moved to the suburbs, hoping not to relive a similar incident. The post-fire architecture used masonry rather than wood, since stone and brick buildings were fire resistant. Many of the people who filed damage claims were represented by lawyer Paul Neumann , but he died before the cases went to court. After World War II the area fell into disrepair and became a red-light district . During the administrations of mayors Frank Fasi and Jeremy Harris the area was targeted for revitalization. Restrictions on lighting and signs were relaxed to promote nightlife. Special zoning rules were adopted for the area. The Hawaii National Bank was founded in the district in 1960, and has its headquarters there. About 36 acres (15 ha) of the district was added to the National Register of Historic Places listings in Oahu on January 17, 1973, as site 73000658. On the eastern edge of the district, the Hawaii Theatre was restored and re-opened in 1996. The area around the theatre is called the Arts District . In 2005 a small park near the theatre at the corner of Hotel and Bethel streets was opened and named Chinatown Gateway Park. In November 2007 the park was renamed to honor Sun Yat-sen , who came to Chinatown in 1879; he was educated and planned the Chinese Revolution of 1911 during his Hawaiian stay. Honolulu Chinatown was included in the Preserve America program. The Chinatown-Downtown Honolulu Neighborhood Board is an elected nine-member volunteer organization dedicated to improving the governance of this specially designated region. It is a part of the City and County of Honolulu Neighborhood Commission Office. Currently, the Board is chaired by Ernest Caravalho and meets on the first Thursday of each month at 6 p.m. at the Keʻelikolani Middle School Cafeteria 1302 Queen Emma Street, Honolulu, Hawaii. The downtown police substation of the Honolulu Police Department is located in Chinatown. Officials broke ground for the substation on Friday September 18, 1998. Mayor Jeremy Harris said that he wanted a police station built at that location because the presence of a police station would deter crime. The Skyline rail system is anticipated to extend service to Chinatown by 2031; the future Hōlau station will be built in the median of Nimitz Highway between River and Kekaulike.

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Sámi peoples

The Sámi ( / ˈ s ɑː m i / SAH -mee ; also spelled Sami or Saami ) are the traditionally Sámi -speaking peoples inhabiting the region of Sápmi , which today encompasses large northern parts of Norway , Sweden , Finland , and of the Kola Peninsula in Russia . The region of Sápmi was formerly known as Lapland, and the Sámi have historically been known in English as Lapps or Laplanders , but these terms are regarded as offensive by the Sámi, who prefer the area's name in their own languages, e.g. Northern Sámi Sápmi . Their traditional languages are the Sámi languages , which are classified as a branch of the Uralic language family . Traditionally, the Sámi have pursued a variety of livelihoods, including coastal fishing, fur trapping , and sheep herding . Their best-known means of livelihood is semi-nomadic reindeer herding . As of 2007 [ update ] about 10% of the Sámi were connected to reindeer herding, which provides them with meat, fur, and transportation; around 2,800 Sámi people were actively involved in reindeer herding on a full-time basis in Norway. For traditional, environmental, cultural, and political reasons, reindeer herding is legally reserved for only Sámi in some regions of the Nordic countries. Speakers of Northern Sámi refer to themselves as Sámit (the Sámis) or Sápmelaš (of Sámi kin), the word Sápmi being inflected into various grammatical forms. Other Sámi languages use cognate words. As of around 2014, the current consensus among specialists was that the word Sámi was borrowed from the Proto-Baltic word * žēmē , meaning 'land' ( cognate with Slavic zemlja ( земля ), of the same meaning). The word Sámi has at least one cognate word in Finnish : Proto-Baltic * žēmē was also borrowed into Proto-Finnic , as * šämä . This word became modern Finnish Häme (Finnish for the region of Tavastia ; the second ä of * šämä is still found in the adjective häm ä läinen ). The Finnish word for Finland, Suomi , is also thought probably to derive ultimately from Proto-Baltic * žēmē , though the precise route is debated and proposals usually involve complex processes of borrowing and reborrowing. Suomi and its adjectival form suom a lainen must come from * sōme- / sōma- . In one proposal, this Finnish word comes from a Proto-Germanic word * sōma- , itself from Proto-Baltic * sāma- , in turn borrowed from Proto-Finnic * šämä , which was borrowed from * žēmē . The Sámi institutions—notably the parliaments , radio and TV stations, theatres, etc.—all use the term Sámi , including when addressing outsiders in Norwegian, Swedish, Finnish, or English. In Norwegian and Swedish, the Sámi are today referred to by the localized form Same . The first probable historical mention of the Sámi, naming them Fenni , was by Tacitus , about AD 98. Variants of Finn or Fenni were in wide use in ancient times, judging from the names Fenni and Φίννοι ( Phinnoi ) in classical Roman and Greek works . Finn (or variants, such as skridfinn , 'striding Finn') was the name originally used by Norse speakers (and their proto-Norse speaking ancestors) to refer to the Sámi, as attested in the Icelandic Eddas and Norse sagas (11th to 14th centuries). The etymology is somewhat uncertain, but the consensus seems to be that it is related to Old Norse finna , from proto-Germanic * finþanan ('to find'), the logic being that the Sámi, as hunter-gatherers "found" their food, rather than grew it. This etymology has superseded older speculations that the word might be related to fen . As Old Norse gradually developed into the separate Scandinavian languages, Swedes apparently took to using Finn to refer to inhabitants of what is now Finland, while the Sámi came to be called Lapps . In Norway, however, Sámi were still called Finns at least until the modern era (reflected in toponyms like Finnmark , Finnsnes , Finnfjord and Finnøy ), and some northern Norwegians will still occasionally use Finn to refer to Sámi people, although the Sámi themselves now consider this to be an inappropriate term. Finnish immigrants to Northern Norway in the 18th and 19th centuries were referred to as Kvens to distinguish them from the Sámi "Finns". Ethnic Finns ( suomalaiset ) are a group related to the Sámi, but distinct from them . The word Lapp can be traced to Old Swedish lapper , Icelandic lappir (plural) perhaps of Finnish origin; compare Finnish lappalainen "Lapp", Lappi "Lapland" (possibly meaning "wilderness in the north"), the original meaning being unknown. It is unknown how the word Lapp came into the Norse language , but one of the first written mentions of the term is in the Gesta Danorum by the twelfth-century Danish historian Saxo Grammaticus , who referred to 'the two Lappias', although he still referred to the Sámi as (Skrid-)Finn s. In fact, Saxo never explicitly connects the Sámi with the "two Laplands". The term "Lapp" was popularized and became the standard terminology by the work of Johannes Schefferus , Acta Lapponica (1673). The Sámi are often known in other languages by the exonyms Lap , Lapp , or Laplanders , although these are considered derogatory terms by some, while others accept at least the name Lappland . Variants of the name Lapp were originally used in Sweden and Finland and, through Swedish, adopted by many major European languages: English: Lapps ; German, Dutch : Lappen ; French : Lapons ; Greek : Λάπωνες ( Lápōnes ); Hungarian : lappok ; Italian : Lapponi ; Polish : Lapończycy ; Portuguese : Lapões ; Spanish : Lapones ; Romanian : laponi ; Turkish : Lapon . In Russian the corresponding term is лопари́ ( lopari ) and in Ukrainian лопарі́ ( lopari ). In Finland and Sweden, Lapp is common in place names, such as Lappi ( Satakunta ), Lappeenranta ( South Karelia ) and Lapinlahti ( North Savo ) in Finland; and Lapp ( Stockholm County ), Lappe ( Södermanland ) and Lappabo ( Småland ) in Sweden. As already mentioned, Finn is a common element in Norwegian (particularly Northern Norwegian) place names, whereas Lapp is exceedingly rare. Terminological issues in Finnish are somewhat different. Finns living in Finnish Lapland generally call themselves lapp i lainen , whereas the similar word for the Sámi people is lapp a lainen . This can be confusing for foreign visitors because of the similar lives Finns and Sámi people live today in Lapland. Lappalainen is also a common family name in Finland. In Finnish, saamelainen is the most commonly used word nowadays, especially in official contexts.Speakers of Northern Sámi refer to themselves as Sámit (the Sámis) or Sápmelaš (of Sámi kin), the word Sápmi being inflected into various grammatical forms. Other Sámi languages use cognate words. As of around 2014, the current consensus among specialists was that the word Sámi was borrowed from the Proto-Baltic word * žēmē , meaning 'land' ( cognate with Slavic zemlja ( земля ), of the same meaning). The word Sámi has at least one cognate word in Finnish : Proto-Baltic * žēmē was also borrowed into Proto-Finnic , as * šämä . This word became modern Finnish Häme (Finnish for the region of Tavastia ; the second ä of * šämä is still found in the adjective häm ä läinen ). The Finnish word for Finland, Suomi , is also thought probably to derive ultimately from Proto-Baltic * žēmē , though the precise route is debated and proposals usually involve complex processes of borrowing and reborrowing. Suomi and its adjectival form suom a lainen must come from * sōme- / sōma- . In one proposal, this Finnish word comes from a Proto-Germanic word * sōma- , itself from Proto-Baltic * sāma- , in turn borrowed from Proto-Finnic * šämä , which was borrowed from * žēmē . The Sámi institutions—notably the parliaments , radio and TV stations, theatres, etc.—all use the term Sámi , including when addressing outsiders in Norwegian, Swedish, Finnish, or English. In Norwegian and Swedish, the Sámi are today referred to by the localized form Same .The first probable historical mention of the Sámi, naming them Fenni , was by Tacitus , about AD 98. Variants of Finn or Fenni were in wide use in ancient times, judging from the names Fenni and Φίννοι ( Phinnoi ) in classical Roman and Greek works . Finn (or variants, such as skridfinn , 'striding Finn') was the name originally used by Norse speakers (and their proto-Norse speaking ancestors) to refer to the Sámi, as attested in the Icelandic Eddas and Norse sagas (11th to 14th centuries). The etymology is somewhat uncertain, but the consensus seems to be that it is related to Old Norse finna , from proto-Germanic * finþanan ('to find'), the logic being that the Sámi, as hunter-gatherers "found" their food, rather than grew it. This etymology has superseded older speculations that the word might be related to fen . As Old Norse gradually developed into the separate Scandinavian languages, Swedes apparently took to using Finn to refer to inhabitants of what is now Finland, while the Sámi came to be called Lapps . In Norway, however, Sámi were still called Finns at least until the modern era (reflected in toponyms like Finnmark , Finnsnes , Finnfjord and Finnøy ), and some northern Norwegians will still occasionally use Finn to refer to Sámi people, although the Sámi themselves now consider this to be an inappropriate term. Finnish immigrants to Northern Norway in the 18th and 19th centuries were referred to as Kvens to distinguish them from the Sámi "Finns". Ethnic Finns ( suomalaiset ) are a group related to the Sámi, but distinct from them .The word Lapp can be traced to Old Swedish lapper , Icelandic lappir (plural) perhaps of Finnish origin; compare Finnish lappalainen "Lapp", Lappi "Lapland" (possibly meaning "wilderness in the north"), the original meaning being unknown. It is unknown how the word Lapp came into the Norse language , but one of the first written mentions of the term is in the Gesta Danorum by the twelfth-century Danish historian Saxo Grammaticus , who referred to 'the two Lappias', although he still referred to the Sámi as (Skrid-)Finn s. In fact, Saxo never explicitly connects the Sámi with the "two Laplands". The term "Lapp" was popularized and became the standard terminology by the work of Johannes Schefferus , Acta Lapponica (1673). The Sámi are often known in other languages by the exonyms Lap , Lapp , or Laplanders , although these are considered derogatory terms by some, while others accept at least the name Lappland . Variants of the name Lapp were originally used in Sweden and Finland and, through Swedish, adopted by many major European languages: English: Lapps ; German, Dutch : Lappen ; French : Lapons ; Greek : Λάπωνες ( Lápōnes ); Hungarian : lappok ; Italian : Lapponi ; Polish : Lapończycy ; Portuguese : Lapões ; Spanish : Lapones ; Romanian : laponi ; Turkish : Lapon . In Russian the corresponding term is лопари́ ( lopari ) and in Ukrainian лопарі́ ( lopari ). In Finland and Sweden, Lapp is common in place names, such as Lappi ( Satakunta ), Lappeenranta ( South Karelia ) and Lapinlahti ( North Savo ) in Finland; and Lapp ( Stockholm County ), Lappe ( Södermanland ) and Lappabo ( Småland ) in Sweden. As already mentioned, Finn is a common element in Norwegian (particularly Northern Norwegian) place names, whereas Lapp is exceedingly rare. Terminological issues in Finnish are somewhat different. Finns living in Finnish Lapland generally call themselves lapp i lainen , whereas the similar word for the Sámi people is lapp a lainen . This can be confusing for foreign visitors because of the similar lives Finns and Sámi people live today in Lapland. Lappalainen is also a common family name in Finland. In Finnish, saamelainen is the most commonly used word nowadays, especially in official contexts.The western Uralic languages are believed to have spread from the original Proto-Uralic homeland along the Volga , which is the longest river in Europe. The speakers of Finnic and Sámi languages have their roots in the middle and upper Volga region in the Corded Ware culture . These groups presumably started to move to the northwest from the homeland of the early Uralic peoples in the second and third quarters of the 2nd millennium BC. On their journey, they used the ancient river routes of northern Russia. Some of these peoples, who may have originally spoken the same western Uralic language, stopped and stayed in the regions between Karelia , Ladoga and Lake Ilmen , and even further to the east and to the southeast. The groups of these peoples that ended up in the Finnish Lakeland from 1600 to 1500 BC later "became" the Sámi. The Sámi people arrived in their current homeland some time after the beginning of the Common Era . The Sámi language first developed on the southern side of Lake Onega and Lake Ladoga and spread from there. When the speakers of this language extended to the area of modern-day Finland, they encountered groups of peoples who spoke a number of smaller ancient languages ( Paleo-Laplandic languages ), which later became extinct. However, these languages left traces in the Sámi language ( Pre-Finnic substrate ). As the language spread further, it became segmented into dialects. The geographical distribution of the Sámi has evolved over the course of history. From the Bronze Age , the Sámi occupied the area along the coast of Finnmark and the Kola Peninsula . This coincides with the arrival of the Siberian genome to Estonia and Finland, which may correspond with the introduction of the Finno-Ugric languages in the region. Petroglyphs and archeological findings such as settlements, dating from about 10,000 BC can be found in Lapland and Finnmark, although these have not been demonstrated to be related to the Sámi people. These hunter-gatherers of the late Paleolithic and early Mesolithic were named Komsa by the researchers. The Sámi have a complex relationship with the Scandinavians (known as Norse people in the medieval era), the dominant peoples of Scandinavia, who speak Scandinavian languages and who founded and thus dominated the kingdoms of Norway and Sweden in which most Sámi people live. While the Sámi have lived in Fennoscandia for around 3,500 years, Sámi settlement of Scandinavia does not predate Norse/Scandinavian settlement of Scandinavia, as sometimes popularly assumed. The migration of Germanic-speaking peoples to Southern Scandinavia happened independently and separate from the later Sámi migrations into the northern regions. For centuries, the Sámi and the Scandinavians had relatively little contact; the Sámi primarily lived in the inland of northern Fennoscandia, while Scandinavians lived in southern Scandinavia and gradually colonised the Norwegian coast; from the 18th and especially the 19th century, the governments of Norway and Sweden started to assert sovereignty more aggressively in the north, and targeted the Sámi with Scandinavization policies aimed at forced assimilation from the 19th century. Before the era of forced Scandinavization policies, the Norwegian and Swedish authorities had largely ignored the Sámi and did not interfere much in their way of life. While Norwegians moved north to gradually colonise the coast of modern-day Troms and Finnmark to engage in an export-driven fisheries industry prior to the 19th century, they showed little interest in the harsh and non-arable inland populated by reindeer-herding Sámi. Unlike the Norwegians on the coast who were strongly dependent on their trade with the south, the Sámi in the inland lived off the land. From the 19th century Norwegian and Swedish authorities started to regard the Sámi as a "backward" and "primitive" people in need of being "civilized", imposing the Scandinavian languages as the only valid languages of the kingdoms and effectively banning Sámi language and culture in many contexts, particularly schools. How far south the Sámi extended in the past has been debated among historians and archeologists for many years. The Norwegian historian Yngvar Nielsen , commissioned by the Norwegian government in 1889 to determine this question in order to settle contemporary questions of Sámi land rights, concluded that the Sámi had lived no farther south than Lierne in Nord-Trøndelag county until around 1500, when they started moving south, reaching the area around Lake Femund in the 18th century. This hypothesis is still accepted among many historians, but has been the subject of scholarly debate in the 21st century. In recent years, several archaeological finds indicate a Sámi presence in southern Norway in the Middle Ages, and in southern Sweden, including finds in Lesja , in Vang , in Valdres and in Hol and à l in Hallingdal . Proponents of the Sámi interpretations of these finds assume a mixed population of Norse and Sámi people in the mountainous areas of southern Norway in the Middle Ages. Until the arrival of bubonic plague in northern Norway in 1349, the Sámi and the Norwegians occupied very separate economic niches . The Sámi hunted reindeer and fished for their livelihood. The Norwegians, who were concentrated on the outer islands and near the mouths of the fjords , had access to the major European trade routes so that, in addition to marginal farming in the Nordland , Troms , and Finnmark counties, they were able to establish commerce, trading fish for products from the south. According to old Nordic texts, the Sea Sámi and the Mountain Sámi are two classes of the same people and not two different ethnic groups, as had been erroneously believed. This socioeconomic balance greatly changed when bubonic plague came to northern Norway in December 1349. The Norwegians were closely connected to the greater European trade routes, along which the plague traveled; consequently, they were infected and died at a far higher rate than Sámi in the interior. Of all the states in the region, Norway suffered the most from this plague . Depending on the parish , 60 to 76 percent of northern Norwegian farms were abandoned following the plague, while land-rents, another measure of population, dropped to 9–28% of pre-plague levels. Although the population of northern Norway is sparse compared to southern Europe, the disease spread just as fast. The spread of the plague-carrying flea ( Xenopsylla cheopsis ) from the south was facilitated by the transport of wooden barrels holding wheat, rye, or wool, where the fleas were able to live, and even reproduce, for several months at a time. The Sámi lived on fish and reindeer meat, and did not eat wheat or rye. They lived in communities detached from the Norwegians; being only loosely connected to the European trade routes, they fared far better than the Norwegians. Fishing has always been the main livelihood for the many Sámi living permanently in coastal areas. Archeological research shows that the Sámi have lived along the coast and once lived much farther south in the past, and they were also involved in work other than reindeer herding (e.g., fishing, agriculture, iron work). The fishing along the north Norwegian coast, especially in the Lofoten and Vesterålen islands, is quite productive, with a variety of fish; during medieval times, it was a major source of income for both the fishermen and the Norwegian monarchy . With such massive population drops caused by the Black Death , the tax revenues from this industry greatly diminished. Because of the huge profits that could be had from these fisheries, the local authorities offered incentives to the Sámi—faced with their own population pressures—to settle on the newly vacant farms. This started the economic division between the Sea Sámi ( sjøsamene ), who fished extensively off the coast, and the Mountain Sámi ( fjellsamene, innlandssamene ), who continued to hunt reindeer and small-game animals. They later herded reindeer. Even as late as the early 18th century, there were many Sámi who were still settling on these farms left abandoned from the 1350s. After many years of continuous migration, these Sea Sámi became far more numerous than the reindeer-herding mountain Sámi, who today only make up 10% of all Sámi. In contemporary times, there are also ongoing consultations between the Government of Norway and the Sámi Parliament regarding the right of the coastal Sámi to fish in the seas on the basis of historical use and international law. State regulation of sea fisheries underwent drastic change in the late 1980s. The regulation linked quotas to vessels and not to fishers. These newly calculated quotas were distributed free of charge to larger vessels on the basis of the amount of the catch in previous years, resulting in small vessels in Sámi districts falling outside the new quota system to a large degree. As the Sea Sámi settled along Norway's fjords and inland waterways, pursuing a combination of farming, cattle raising, trapping and fishing, the minority Mountain Sámi continued to hunt wild reindeer . Around 1500, they started to tame these animals into herding groups, becoming the well-known reindeer nomads , often portrayed by outsiders as following the traditional Sámi lifestyle. The Mountain Sámi had to pay taxes to three states, Norway , Sweden and Russia , as they crossed each border while following the annual reindeer migrations; this caused much resentment over the years. Between 1635 and 1659, the Swedish crown forced Swedish conscripts and Sámi cart drivers to work in the Nasa silver mine , causing many Sámis to emigrate from the area to avoid forced labour. As a result, the population of Pite - and Lule -speaking Sámi decreased greatly. For long periods of time, the Sámi lifestyle thrived because of its adaptation to the Arctic environment. Indeed, throughout the 18th century, as Norwegians of Northern Norway suffered from low fish prices and consequent depopulation, the Sámi cultural element was strengthened, since the Sámi were mostly independent of supplies from Southern Norway. During the 19th century, the pressure of Christianization of the Sámi increased, with some Sámi adopting Laestadianism . With the introduction of seven compulsory years of school in 1889, the Sámi language and traditional way of life came increasingly under pressure from forced cultural normalization. Strong economic development of the north also ensued, giving Norwegian culture and language higher status. [ citation needed ] On the Swedish and Finnish sides, the authorities were less militant, although the Sámi language was forbidden in schools and strong economic development in the north led to weakened cultural and economic status for the Sámi. From 1913 to 1920, the Swedish race-segregation political movement created a race-based biological institute that collected research material from living people and graves. Throughout history, Swedish settlers were encouraged to move to the northern regions through incentives such as land and water rights, tax allowances, and military exemptions. The strongest pressure took place from around 1900 to 1940, when Norway invested considerable money and effort to assimilate Sámi culture. Anyone who wanted to buy or lease state lands for agriculture in Finnmark had to prove knowledge of the Norwegian language and had to register with a Norwegian name. This partly caused the dislocation of Sámi people in the 1920s, which increased the gap between local Sámi groups (something still present today) that sometimes has the character of an internal Sámi ethnic conflict. Another example of forced displacement occurred between 1919 and 1920 in Norway and Sweden. This has been the topic of a recent work of journalism by Sámi author Elin Anna Labba , translated into English in 2023 under the title The Rocks Will Echo Our Sorrow: The Forced Displacement of the Northern Sámi . In 1913, the Norwegian parliament passed a bill on "native act land" to allocate the best and most useful lands to Norwegian settlers. Another factor was the scorched earth policy conducted by the German army, resulting in heavy war destruction in northern Finland and northern Norway in 1944–45, destroying all existing houses, or kota , and visible traces of Sámi culture. After World War II , the pressure was relaxed, though the legacy was evident into recent times, such as the 1970s law limiting the size of any house Sámi people were allowed to build. [ citation needed ] The controversy over the construction of the hydro-electric power station in Alta in 1979 brought Sámi rights onto the political agenda. In August 1986, the national anthem (" Sámi soga lávlla ") and flag ( Sámi flag ) of the Sámi people were created. In 1989, the first Sámi parliament in Norway was elected. In 2005, the Finnmark Act was passed in the Norwegian parliament giving the Sámi parliament and the Finnmark Provincial council a joint responsibility of administering the land areas previously considered state property. These areas (96% of the provincial area), which have always been used primarily by the Sámi, now belong officially to the people of the province, whether Sámi or Norwegian, and not to the Norwegian state. The indigenous Sámi population is a mostly urbanised demographic, but a substantial number live in villages in the high Arctic. The Sámi are still coping with the cultural consequences of language and culture loss caused by generations of Sámi children being taken to missionary and/or state-run boarding schools and the legacy of laws that were created to deny the Sámi rights (e.g., to their beliefs, language, land and to the practice of traditional livelihoods). The Sámi are experiencing cultural and environmental threats, including: oil exploration, mining, dam building, logging, climate change, military bombing ranges, tourism and commercial development. Sápmi is rich in precious metals, oil, and natural gas. Mining activities and prospecting to extract these resources from the region often interfere with reindeer grazing and calving areas and other aspects of traditional Sámi life. Some active mining locations include ancient Sámi spaces that are designated as ecologically protected areas, such as the Vindelfjällen Nature Reserve . The Sámi Parliament has opposed and rejected mining projects in the Finnmark area, and demanded that resources and mineral exploration benefit local Sámi communities and populations, as the proposed mines are in Sámi lands and will affect their ability to maintain their traditional livelihood. In Kallak (Sámi: Gállok ) a group of indigenous and non-indigenous activists protested against the UK-based mining company Beowulf which operated a drilling program in lands used for grazing reindeer during the winter. There is often local opposition to new mining projects where environmental impacts are perceived to be very large, as very few plans for mine reclamation have been made. In Sweden, taxes on minerals are intentionally low in an effort to increase mineral exploration for economic benefit, though this policy is at the expense of Sámi populations. ILO Convention No. 169 would grant rights to the Sámi people to their land and give them power in matters that affect their future. In Russia's Kola Peninsula, vast areas have already been destroyed by mining and smelting activities, and further development is imminent. This includes oil and natural gas exploration in the Barents Sea . Oil spills affect fishing and the construction of roads. There is a gas pipeline that stretches across the Kola Peninsula, and power lines cut off access to reindeer calving grounds and sacred sites. [ failed verification ] In northern Finland, there has been a longstanding dispute over the destruction of forests, which prevents reindeer from migrating between seasonal feeding grounds and destroys supplies of lichen that grow on the upper branches of older trees. This lichen is the reindeer's only source of sustenance during the winter months, when snow is deep. The logging has been under the control of the state-run forest system. Greenpeace , reindeer herders, and Sámi organisations carried out a historic joint campaign, and in 2010, Sámi reindeer herders won some time as a result of these court cases. Industrial logging has now been pushed back from the most important forest areas either permanently or for the next 20 years, though there are still threats, such as mining and construction plans of holiday resorts on the protected shorelines of Lake Inari. The Swedish government has allowed the world's largest onshore wind farm to be built in Piteå, in the Arctic region where the Eastern Kikkejaure village has its winter reindeer pastures. The wind farm will consist of more than 1,000 wind turbines and an extensive road infrastructure, which means that the feasibility of using the area for winter grazing in practice is impossible. Sweden has received strong international criticism, including by the UN Racial Discrimination Committee and the Human Rights Committee, that Sweden violates Sámi landrättigheter ( land rights ), including by not regulating industry. In Norway some Sámi politicians (for example—Aili Keskitalo) suggest giving the Sámi Parliament a special veto right on planned mining projects. Government authorities and NATO have built bombing-practice ranges in Sámi areas in northern Norway and Sweden. These regions have served as reindeer calving and summer grounds for thousands of years, and contain many ancient Sámi sacred sites. State regulation of sea fisheries underwent drastic change in the late 1980s. The regulation linked quotas to vessels and not to fishers. These newly calculated quotas were distributed free of cost to larger vessels on the basis of the amount of the catch in previous years, resulting in small vessels in Sámi districts falling outside the new quota system to a large degree. The Sámi recently stopped a water-prospecting venture that threatened to turn an ancient sacred site and natural spring called Suttesaja into a large-scale water-bottling plant for the world market—without notification or consultation with the local Sámi people, who make up 70 percent of the population. The Finnish National Board of Antiquities has registered the area as a heritage site of cultural and historical significance, and the stream itself is part of the Deatnu/Tana watershed, which is home to Europe's largest salmon river, an important source of Sámi livelihood. In Norway, government plans for the construction of a hydroelectric power plant in the Alta river in Finnmark in northern Norway led to a political controversy and the rallying of the Sámi popular movement in the late 1970s and early 1980s. As a result, the opposition in the Alta controversy brought attention to not only environmental issues but also the issue of Sámi rights. Reindeer have major cultural and economic significance for indigenous peoples of the North. The human-ecological systems in the North, like reindeer pastoralism, are sensitive to change, perhaps more than in virtually any other region of the globe, due in part to the variability of the Arctic climate and ecosystem and the characteristic ways of life of indigenous Arctic peoples. The 1986 Chernobyl nuclear disaster caused nuclear fallout in the sensitive Arctic ecosystems and poisoned fish, meat and berries. Lichens and mosses are two of the main forms of vegetation in the Arctic and are highly susceptible to airborne pollutants and heavy metals. Since many do not have roots, they absorb nutrients, and toxic compounds, through their leaves. The lichens accumulated airborne radiation, and 73,000 reindeer had to be killed as "unfit" for human consumption in Sweden alone. The government promised Sámi indemnification, which was not acted upon by government. Radioactive wastes and spent nuclear fuel have been stored in the waters off the Kola Peninsula, including locations that are only "two kilometers" from places where Sámi live. There are a minimum of five "dumps" where spent nuclear fuel and other radioactive waste are being deposited in the Kola Peninsula, often with little concern for the surrounding environment or population. The tourism industry in Finland has been criticized for turning Sámi culture into a marketing tool by promoting opportunities to experience "authentic" Sámi ceremonies and lifestyle. At many tourist locales, non-Sámi dress in inaccurate replicas of Sámi traditional clothing, and gift shops sell crude reproductions of Sámi handicraft. One popular "ceremony", crossing the Arctic Circle, actually has no significance in Sámi spirituality. To some Sámi, this is an insulting display of cultural exploitation. The Sámi have a complex relationship with the Scandinavians (known as Norse people in the medieval era), the dominant peoples of Scandinavia, who speak Scandinavian languages and who founded and thus dominated the kingdoms of Norway and Sweden in which most Sámi people live. While the Sámi have lived in Fennoscandia for around 3,500 years, Sámi settlement of Scandinavia does not predate Norse/Scandinavian settlement of Scandinavia, as sometimes popularly assumed. The migration of Germanic-speaking peoples to Southern Scandinavia happened independently and separate from the later Sámi migrations into the northern regions. For centuries, the Sámi and the Scandinavians had relatively little contact; the Sámi primarily lived in the inland of northern Fennoscandia, while Scandinavians lived in southern Scandinavia and gradually colonised the Norwegian coast; from the 18th and especially the 19th century, the governments of Norway and Sweden started to assert sovereignty more aggressively in the north, and targeted the Sámi with Scandinavization policies aimed at forced assimilation from the 19th century. Before the era of forced Scandinavization policies, the Norwegian and Swedish authorities had largely ignored the Sámi and did not interfere much in their way of life. While Norwegians moved north to gradually colonise the coast of modern-day Troms and Finnmark to engage in an export-driven fisheries industry prior to the 19th century, they showed little interest in the harsh and non-arable inland populated by reindeer-herding Sámi. Unlike the Norwegians on the coast who were strongly dependent on their trade with the south, the Sámi in the inland lived off the land. From the 19th century Norwegian and Swedish authorities started to regard the Sámi as a "backward" and "primitive" people in need of being "civilized", imposing the Scandinavian languages as the only valid languages of the kingdoms and effectively banning Sámi language and culture in many contexts, particularly schools. How far south the Sámi extended in the past has been debated among historians and archeologists for many years. The Norwegian historian Yngvar Nielsen , commissioned by the Norwegian government in 1889 to determine this question in order to settle contemporary questions of Sámi land rights, concluded that the Sámi had lived no farther south than Lierne in Nord-Trøndelag county until around 1500, when they started moving south, reaching the area around Lake Femund in the 18th century. This hypothesis is still accepted among many historians, but has been the subject of scholarly debate in the 21st century. In recent years, several archaeological finds indicate a Sámi presence in southern Norway in the Middle Ages, and in southern Sweden, including finds in Lesja , in Vang , in Valdres and in Hol and à l in Hallingdal . Proponents of the Sámi interpretations of these finds assume a mixed population of Norse and Sámi people in the mountainous areas of southern Norway in the Middle Ages. Until the arrival of bubonic plague in northern Norway in 1349, the Sámi and the Norwegians occupied very separate economic niches . The Sámi hunted reindeer and fished for their livelihood. The Norwegians, who were concentrated on the outer islands and near the mouths of the fjords , had access to the major European trade routes so that, in addition to marginal farming in the Nordland , Troms , and Finnmark counties, they were able to establish commerce, trading fish for products from the south. According to old Nordic texts, the Sea Sámi and the Mountain Sámi are two classes of the same people and not two different ethnic groups, as had been erroneously believed. This socioeconomic balance greatly changed when bubonic plague came to northern Norway in December 1349. The Norwegians were closely connected to the greater European trade routes, along which the plague traveled; consequently, they were infected and died at a far higher rate than Sámi in the interior. Of all the states in the region, Norway suffered the most from this plague . Depending on the parish , 60 to 76 percent of northern Norwegian farms were abandoned following the plague, while land-rents, another measure of population, dropped to 9–28% of pre-plague levels. Although the population of northern Norway is sparse compared to southern Europe, the disease spread just as fast. The spread of the plague-carrying flea ( Xenopsylla cheopsis ) from the south was facilitated by the transport of wooden barrels holding wheat, rye, or wool, where the fleas were able to live, and even reproduce, for several months at a time. The Sámi lived on fish and reindeer meat, and did not eat wheat or rye. They lived in communities detached from the Norwegians; being only loosely connected to the European trade routes, they fared far better than the Norwegians. Fishing has always been the main livelihood for the many Sámi living permanently in coastal areas. Archeological research shows that the Sámi have lived along the coast and once lived much farther south in the past, and they were also involved in work other than reindeer herding (e.g., fishing, agriculture, iron work). The fishing along the north Norwegian coast, especially in the Lofoten and Vesterålen islands, is quite productive, with a variety of fish; during medieval times, it was a major source of income for both the fishermen and the Norwegian monarchy . With such massive population drops caused by the Black Death , the tax revenues from this industry greatly diminished. Because of the huge profits that could be had from these fisheries, the local authorities offered incentives to the Sámi—faced with their own population pressures—to settle on the newly vacant farms. This started the economic division between the Sea Sámi ( sjøsamene ), who fished extensively off the coast, and the Mountain Sámi ( fjellsamene, innlandssamene ), who continued to hunt reindeer and small-game animals. They later herded reindeer. Even as late as the early 18th century, there were many Sámi who were still settling on these farms left abandoned from the 1350s. After many years of continuous migration, these Sea Sámi became far more numerous than the reindeer-herding mountain Sámi, who today only make up 10% of all Sámi. In contemporary times, there are also ongoing consultations between the Government of Norway and the Sámi Parliament regarding the right of the coastal Sámi to fish in the seas on the basis of historical use and international law. State regulation of sea fisheries underwent drastic change in the late 1980s. The regulation linked quotas to vessels and not to fishers. These newly calculated quotas were distributed free of charge to larger vessels on the basis of the amount of the catch in previous years, resulting in small vessels in Sámi districts falling outside the new quota system to a large degree. As the Sea Sámi settled along Norway's fjords and inland waterways, pursuing a combination of farming, cattle raising, trapping and fishing, the minority Mountain Sámi continued to hunt wild reindeer . Around 1500, they started to tame these animals into herding groups, becoming the well-known reindeer nomads , often portrayed by outsiders as following the traditional Sámi lifestyle. The Mountain Sámi had to pay taxes to three states, Norway , Sweden and Russia , as they crossed each border while following the annual reindeer migrations; this caused much resentment over the years. Between 1635 and 1659, the Swedish crown forced Swedish conscripts and Sámi cart drivers to work in the Nasa silver mine , causing many Sámis to emigrate from the area to avoid forced labour. As a result, the population of Pite - and Lule -speaking Sámi decreased greatly. Until the arrival of bubonic plague in northern Norway in 1349, the Sámi and the Norwegians occupied very separate economic niches . The Sámi hunted reindeer and fished for their livelihood. The Norwegians, who were concentrated on the outer islands and near the mouths of the fjords , had access to the major European trade routes so that, in addition to marginal farming in the Nordland , Troms , and Finnmark counties, they were able to establish commerce, trading fish for products from the south. According to old Nordic texts, the Sea Sámi and the Mountain Sámi are two classes of the same people and not two different ethnic groups, as had been erroneously believed. This socioeconomic balance greatly changed when bubonic plague came to northern Norway in December 1349. The Norwegians were closely connected to the greater European trade routes, along which the plague traveled; consequently, they were infected and died at a far higher rate than Sámi in the interior. Of all the states in the region, Norway suffered the most from this plague . Depending on the parish , 60 to 76 percent of northern Norwegian farms were abandoned following the plague, while land-rents, another measure of population, dropped to 9–28% of pre-plague levels. Although the population of northern Norway is sparse compared to southern Europe, the disease spread just as fast. The spread of the plague-carrying flea ( Xenopsylla cheopsis ) from the south was facilitated by the transport of wooden barrels holding wheat, rye, or wool, where the fleas were able to live, and even reproduce, for several months at a time. The Sámi lived on fish and reindeer meat, and did not eat wheat or rye. They lived in communities detached from the Norwegians; being only loosely connected to the European trade routes, they fared far better than the Norwegians. Fishing has always been the main livelihood for the many Sámi living permanently in coastal areas. Archeological research shows that the Sámi have lived along the coast and once lived much farther south in the past, and they were also involved in work other than reindeer herding (e.g., fishing, agriculture, iron work). The fishing along the north Norwegian coast, especially in the Lofoten and Vesterålen islands, is quite productive, with a variety of fish; during medieval times, it was a major source of income for both the fishermen and the Norwegian monarchy . With such massive population drops caused by the Black Death , the tax revenues from this industry greatly diminished. Because of the huge profits that could be had from these fisheries, the local authorities offered incentives to the Sámi—faced with their own population pressures—to settle on the newly vacant farms. This started the economic division between the Sea Sámi ( sjøsamene ), who fished extensively off the coast, and the Mountain Sámi ( fjellsamene, innlandssamene ), who continued to hunt reindeer and small-game animals. They later herded reindeer. Even as late as the early 18th century, there were many Sámi who were still settling on these farms left abandoned from the 1350s. After many years of continuous migration, these Sea Sámi became far more numerous than the reindeer-herding mountain Sámi, who today only make up 10% of all Sámi. In contemporary times, there are also ongoing consultations between the Government of Norway and the Sámi Parliament regarding the right of the coastal Sámi to fish in the seas on the basis of historical use and international law. State regulation of sea fisheries underwent drastic change in the late 1980s. The regulation linked quotas to vessels and not to fishers. These newly calculated quotas were distributed free of charge to larger vessels on the basis of the amount of the catch in previous years, resulting in small vessels in Sámi districts falling outside the new quota system to a large degree. As the Sea Sámi settled along Norway's fjords and inland waterways, pursuing a combination of farming, cattle raising, trapping and fishing, the minority Mountain Sámi continued to hunt wild reindeer . Around 1500, they started to tame these animals into herding groups, becoming the well-known reindeer nomads , often portrayed by outsiders as following the traditional Sámi lifestyle. The Mountain Sámi had to pay taxes to three states, Norway , Sweden and Russia , as they crossed each border while following the annual reindeer migrations; this caused much resentment over the years. Between 1635 and 1659, the Swedish crown forced Swedish conscripts and Sámi cart drivers to work in the Nasa silver mine , causing many Sámis to emigrate from the area to avoid forced labour. As a result, the population of Pite - and Lule -speaking Sámi decreased greatly. For long periods of time, the Sámi lifestyle thrived because of its adaptation to the Arctic environment. Indeed, throughout the 18th century, as Norwegians of Northern Norway suffered from low fish prices and consequent depopulation, the Sámi cultural element was strengthened, since the Sámi were mostly independent of supplies from Southern Norway. During the 19th century, the pressure of Christianization of the Sámi increased, with some Sámi adopting Laestadianism . With the introduction of seven compulsory years of school in 1889, the Sámi language and traditional way of life came increasingly under pressure from forced cultural normalization. Strong economic development of the north also ensued, giving Norwegian culture and language higher status. [ citation needed ] On the Swedish and Finnish sides, the authorities were less militant, although the Sámi language was forbidden in schools and strong economic development in the north led to weakened cultural and economic status for the Sámi. From 1913 to 1920, the Swedish race-segregation political movement created a race-based biological institute that collected research material from living people and graves. Throughout history, Swedish settlers were encouraged to move to the northern regions through incentives such as land and water rights, tax allowances, and military exemptions. The strongest pressure took place from around 1900 to 1940, when Norway invested considerable money and effort to assimilate Sámi culture. Anyone who wanted to buy or lease state lands for agriculture in Finnmark had to prove knowledge of the Norwegian language and had to register with a Norwegian name. This partly caused the dislocation of Sámi people in the 1920s, which increased the gap between local Sámi groups (something still present today) that sometimes has the character of an internal Sámi ethnic conflict. Another example of forced displacement occurred between 1919 and 1920 in Norway and Sweden. This has been the topic of a recent work of journalism by Sámi author Elin Anna Labba , translated into English in 2023 under the title The Rocks Will Echo Our Sorrow: The Forced Displacement of the Northern Sámi . In 1913, the Norwegian parliament passed a bill on "native act land" to allocate the best and most useful lands to Norwegian settlers. Another factor was the scorched earth policy conducted by the German army, resulting in heavy war destruction in northern Finland and northern Norway in 1944–45, destroying all existing houses, or kota , and visible traces of Sámi culture. After World War II , the pressure was relaxed, though the legacy was evident into recent times, such as the 1970s law limiting the size of any house Sámi people were allowed to build. [ citation needed ] The controversy over the construction of the hydro-electric power station in Alta in 1979 brought Sámi rights onto the political agenda. In August 1986, the national anthem (" Sámi soga lávlla ") and flag ( Sámi flag ) of the Sámi people were created. In 1989, the first Sámi parliament in Norway was elected. In 2005, the Finnmark Act was passed in the Norwegian parliament giving the Sámi parliament and the Finnmark Provincial council a joint responsibility of administering the land areas previously considered state property. These areas (96% of the provincial area), which have always been used primarily by the Sámi, now belong officially to the people of the province, whether Sámi or Norwegian, and not to the Norwegian state.The indigenous Sámi population is a mostly urbanised demographic, but a substantial number live in villages in the high Arctic. The Sámi are still coping with the cultural consequences of language and culture loss caused by generations of Sámi children being taken to missionary and/or state-run boarding schools and the legacy of laws that were created to deny the Sámi rights (e.g., to their beliefs, language, land and to the practice of traditional livelihoods). The Sámi are experiencing cultural and environmental threats, including: oil exploration, mining, dam building, logging, climate change, military bombing ranges, tourism and commercial development. Sápmi is rich in precious metals, oil, and natural gas. Mining activities and prospecting to extract these resources from the region often interfere with reindeer grazing and calving areas and other aspects of traditional Sámi life. Some active mining locations include ancient Sámi spaces that are designated as ecologically protected areas, such as the Vindelfjällen Nature Reserve . The Sámi Parliament has opposed and rejected mining projects in the Finnmark area, and demanded that resources and mineral exploration benefit local Sámi communities and populations, as the proposed mines are in Sámi lands and will affect their ability to maintain their traditional livelihood. In Kallak (Sámi: Gállok ) a group of indigenous and non-indigenous activists protested against the UK-based mining company Beowulf which operated a drilling program in lands used for grazing reindeer during the winter. There is often local opposition to new mining projects where environmental impacts are perceived to be very large, as very few plans for mine reclamation have been made. In Sweden, taxes on minerals are intentionally low in an effort to increase mineral exploration for economic benefit, though this policy is at the expense of Sámi populations. ILO Convention No. 169 would grant rights to the Sámi people to their land and give them power in matters that affect their future. In Russia's Kola Peninsula, vast areas have already been destroyed by mining and smelting activities, and further development is imminent. This includes oil and natural gas exploration in the Barents Sea . Oil spills affect fishing and the construction of roads. There is a gas pipeline that stretches across the Kola Peninsula, and power lines cut off access to reindeer calving grounds and sacred sites. [ failed verification ] In northern Finland, there has been a longstanding dispute over the destruction of forests, which prevents reindeer from migrating between seasonal feeding grounds and destroys supplies of lichen that grow on the upper branches of older trees. This lichen is the reindeer's only source of sustenance during the winter months, when snow is deep. The logging has been under the control of the state-run forest system. Greenpeace , reindeer herders, and Sámi organisations carried out a historic joint campaign, and in 2010, Sámi reindeer herders won some time as a result of these court cases. Industrial logging has now been pushed back from the most important forest areas either permanently or for the next 20 years, though there are still threats, such as mining and construction plans of holiday resorts on the protected shorelines of Lake Inari. The Swedish government has allowed the world's largest onshore wind farm to be built in Piteå, in the Arctic region where the Eastern Kikkejaure village has its winter reindeer pastures. The wind farm will consist of more than 1,000 wind turbines and an extensive road infrastructure, which means that the feasibility of using the area for winter grazing in practice is impossible. Sweden has received strong international criticism, including by the UN Racial Discrimination Committee and the Human Rights Committee, that Sweden violates Sámi landrättigheter ( land rights ), including by not regulating industry. In Norway some Sámi politicians (for example—Aili Keskitalo) suggest giving the Sámi Parliament a special veto right on planned mining projects. Government authorities and NATO have built bombing-practice ranges in Sámi areas in northern Norway and Sweden. These regions have served as reindeer calving and summer grounds for thousands of years, and contain many ancient Sámi sacred sites. State regulation of sea fisheries underwent drastic change in the late 1980s. The regulation linked quotas to vessels and not to fishers. These newly calculated quotas were distributed free of cost to larger vessels on the basis of the amount of the catch in previous years, resulting in small vessels in Sámi districts falling outside the new quota system to a large degree. The Sámi recently stopped a water-prospecting venture that threatened to turn an ancient sacred site and natural spring called Suttesaja into a large-scale water-bottling plant for the world market—without notification or consultation with the local Sámi people, who make up 70 percent of the population. The Finnish National Board of Antiquities has registered the area as a heritage site of cultural and historical significance, and the stream itself is part of the Deatnu/Tana watershed, which is home to Europe's largest salmon river, an important source of Sámi livelihood. In Norway, government plans for the construction of a hydroelectric power plant in the Alta river in Finnmark in northern Norway led to a political controversy and the rallying of the Sámi popular movement in the late 1970s and early 1980s. As a result, the opposition in the Alta controversy brought attention to not only environmental issues but also the issue of Sámi rights. Reindeer have major cultural and economic significance for indigenous peoples of the North. The human-ecological systems in the North, like reindeer pastoralism, are sensitive to change, perhaps more than in virtually any other region of the globe, due in part to the variability of the Arctic climate and ecosystem and the characteristic ways of life of indigenous Arctic peoples. The 1986 Chernobyl nuclear disaster caused nuclear fallout in the sensitive Arctic ecosystems and poisoned fish, meat and berries. Lichens and mosses are two of the main forms of vegetation in the Arctic and are highly susceptible to airborne pollutants and heavy metals. Since many do not have roots, they absorb nutrients, and toxic compounds, through their leaves. The lichens accumulated airborne radiation, and 73,000 reindeer had to be killed as "unfit" for human consumption in Sweden alone. The government promised Sámi indemnification, which was not acted upon by government. Radioactive wastes and spent nuclear fuel have been stored in the waters off the Kola Peninsula, including locations that are only "two kilometers" from places where Sámi live. There are a minimum of five "dumps" where spent nuclear fuel and other radioactive waste are being deposited in the Kola Peninsula, often with little concern for the surrounding environment or population. The tourism industry in Finland has been criticized for turning Sámi culture into a marketing tool by promoting opportunities to experience "authentic" Sámi ceremonies and lifestyle. At many tourist locales, non-Sámi dress in inaccurate replicas of Sámi traditional clothing, and gift shops sell crude reproductions of Sámi handicraft. One popular "ceremony", crossing the Arctic Circle, actually has no significance in Sámi spirituality. To some Sámi, this is an insulting display of cultural exploitation. Sápmi is rich in precious metals, oil, and natural gas. Mining activities and prospecting to extract these resources from the region often interfere with reindeer grazing and calving areas and other aspects of traditional Sámi life. Some active mining locations include ancient Sámi spaces that are designated as ecologically protected areas, such as the Vindelfjällen Nature Reserve . The Sámi Parliament has opposed and rejected mining projects in the Finnmark area, and demanded that resources and mineral exploration benefit local Sámi communities and populations, as the proposed mines are in Sámi lands and will affect their ability to maintain their traditional livelihood. In Kallak (Sámi: Gállok ) a group of indigenous and non-indigenous activists protested against the UK-based mining company Beowulf which operated a drilling program in lands used for grazing reindeer during the winter. There is often local opposition to new mining projects where environmental impacts are perceived to be very large, as very few plans for mine reclamation have been made. In Sweden, taxes on minerals are intentionally low in an effort to increase mineral exploration for economic benefit, though this policy is at the expense of Sámi populations. ILO Convention No. 169 would grant rights to the Sámi people to their land and give them power in matters that affect their future. In Russia's Kola Peninsula, vast areas have already been destroyed by mining and smelting activities, and further development is imminent. This includes oil and natural gas exploration in the Barents Sea . Oil spills affect fishing and the construction of roads. There is a gas pipeline that stretches across the Kola Peninsula, and power lines cut off access to reindeer calving grounds and sacred sites. [ failed verification ] In northern Finland, there has been a longstanding dispute over the destruction of forests, which prevents reindeer from migrating between seasonal feeding grounds and destroys supplies of lichen that grow on the upper branches of older trees. This lichen is the reindeer's only source of sustenance during the winter months, when snow is deep. The logging has been under the control of the state-run forest system. Greenpeace , reindeer herders, and Sámi organisations carried out a historic joint campaign, and in 2010, Sámi reindeer herders won some time as a result of these court cases. Industrial logging has now been pushed back from the most important forest areas either permanently or for the next 20 years, though there are still threats, such as mining and construction plans of holiday resorts on the protected shorelines of Lake Inari. The Swedish government has allowed the world's largest onshore wind farm to be built in Piteå, in the Arctic region where the Eastern Kikkejaure village has its winter reindeer pastures. The wind farm will consist of more than 1,000 wind turbines and an extensive road infrastructure, which means that the feasibility of using the area for winter grazing in practice is impossible. Sweden has received strong international criticism, including by the UN Racial Discrimination Committee and the Human Rights Committee, that Sweden violates Sámi landrättigheter ( land rights ), including by not regulating industry. In Norway some Sámi politicians (for example—Aili Keskitalo) suggest giving the Sámi Parliament a special veto right on planned mining projects. Government authorities and NATO have built bombing-practice ranges in Sámi areas in northern Norway and Sweden. These regions have served as reindeer calving and summer grounds for thousands of years, and contain many ancient Sámi sacred sites. State regulation of sea fisheries underwent drastic change in the late 1980s. The regulation linked quotas to vessels and not to fishers. These newly calculated quotas were distributed free of cost to larger vessels on the basis of the amount of the catch in previous years, resulting in small vessels in Sámi districts falling outside the new quota system to a large degree. The Sámi recently stopped a water-prospecting venture that threatened to turn an ancient sacred site and natural spring called Suttesaja into a large-scale water-bottling plant for the world market—without notification or consultation with the local Sámi people, who make up 70 percent of the population. The Finnish National Board of Antiquities has registered the area as a heritage site of cultural and historical significance, and the stream itself is part of the Deatnu/Tana watershed, which is home to Europe's largest salmon river, an important source of Sámi livelihood. In Norway, government plans for the construction of a hydroelectric power plant in the Alta river in Finnmark in northern Norway led to a political controversy and the rallying of the Sámi popular movement in the late 1970s and early 1980s. As a result, the opposition in the Alta controversy brought attention to not only environmental issues but also the issue of Sámi rights.Reindeer have major cultural and economic significance for indigenous peoples of the North. The human-ecological systems in the North, like reindeer pastoralism, are sensitive to change, perhaps more than in virtually any other region of the globe, due in part to the variability of the Arctic climate and ecosystem and the characteristic ways of life of indigenous Arctic peoples. The 1986 Chernobyl nuclear disaster caused nuclear fallout in the sensitive Arctic ecosystems and poisoned fish, meat and berries. Lichens and mosses are two of the main forms of vegetation in the Arctic and are highly susceptible to airborne pollutants and heavy metals. Since many do not have roots, they absorb nutrients, and toxic compounds, through their leaves. The lichens accumulated airborne radiation, and 73,000 reindeer had to be killed as "unfit" for human consumption in Sweden alone. The government promised Sámi indemnification, which was not acted upon by government. Radioactive wastes and spent nuclear fuel have been stored in the waters off the Kola Peninsula, including locations that are only "two kilometers" from places where Sámi live. There are a minimum of five "dumps" where spent nuclear fuel and other radioactive waste are being deposited in the Kola Peninsula, often with little concern for the surrounding environment or population. The tourism industry in Finland has been criticized for turning Sámi culture into a marketing tool by promoting opportunities to experience "authentic" Sámi ceremonies and lifestyle. At many tourist locales, non-Sámi dress in inaccurate replicas of Sámi traditional clothing, and gift shops sell crude reproductions of Sámi handicraft. One popular "ceremony", crossing the Arctic Circle, actually has no significance in Sámi spirituality. To some Sámi, this is an insulting display of cultural exploitation. The Sámi have for centuries, even today, been the subject of discrimination and abuse by the dominant cultures in the nations they have historically inhabited. They have never been a single community in a single region of Sápmi, which until recently was considered only a cultural region. Norway has been criticized internationally for the politics of Norwegianization of and discrimination against the Sámi. On 8 April 2011, recommendations from the UN Racial Discrimination Committee were delivered to Norway, addressing many issues related to the legacy of Norwegianization policies, including the need for more Sámi language education, interpreters, and cultural support. One committee recommendation was that discrimination against someone based upon their language be added to Article 1 of the Norwegian Discrimination and Accessibility Act. A new present status report was to have been ready by the end of 2012. In 2018, The Storting commissioned The Truth and Reconciliation Commission to lay the foundation for recognition of the experiences of the Sámi subject to Norwegianization and the subsequent consequences. Sweden has faced similar criticism for its Swedification policies, which began in the 1800s and lasted until the 1970s. In 2020, Sweden funded the establishment of an independent truth commission to examine and document past abuse of Sámi by the Swedish state. In 2021, the Church of Sweden made a formal apology to Sweden's Sámi population for its role in forced conversions and Swedification efforts, outlining a multiyear reconciliation plan. In Finland, where Sámi children, like all Finnish children, are entitled to day care and language instruction in their own language, the Finnish government has denied funding for these rights in most of the country, including in Rovaniemi , the largest municipality in Finnish Lapland. Sámi activists have pushed for nationwide application of these basic rights. [ obsolete source ] The city of Rovaniemi offers day care and preschool education in the Sámi language, and then as basic education first as supplementary native language education starting from the first grade and as a voluntary subject on its own starting from the fourth grade. As in the other countries claiming sovereignty over Sámi lands, Sámi activists' efforts in Finland in the 20th century achieved limited government recognition of the Sámis' rights as a recognized minority, but the Finnish government has maintained its legally enforced premise that the Sámi must prove their land ownership, an idea incompatible with and antithetical to the traditional reindeer-herding Sámi way of life. This has effectively allowed the Finnish government to take without compensation, motivated by economic gain, land occupied by the Sámi for centuries. Non-Sámi Finns began to move to Lapland in the 1550s. The Sámi have been recognized as an indigenous people in Norway (1990 according to ILO convention 169 as described below), and therefore, according to international law, the Sámi people in Norway are entitled special protection and rights. The legal foundation of the Sámi policy is: The constitutional amendment states: "It is the responsibility of the authorities of the State to create conditions enabling the Sámi people to preserve and develop its language, culture and way of life." This provides a legal and political protection of the Sámi language, culture and society. In addition the "amendment implies a legal, political and moral obligation for Norwegian authorities to create an environment conducive to the Sámis themselves influencing on the development of the Sámi community". The Sámi Act provides special rights for the Sámi people: "... the Sámis shall have their own national Sámi Parliament elected by and amongst the Sámis" (Chapter 1–2). The Sámi people shall decide the area of activity of the Norwegian Sámi Parliament. The Sámi and Norwegian languages have equal standing in Norway (section 15; Chapter 3 contains details with regards to the use of the Sámi language). The Norwegian Sámi Parliament also elects 50% of the members to the board of the Finnmark Estate , which controls 95% of the land in the county of Finnmark. In addition, the Sámi have special rights to reindeer husbandry. In 2007, the Norwegian Parliament passed the new Reindeer Herding Act acknowledging siida as the basic institution regarding land rights, organization, and daily herding management. Norway has also accepted international conventions, declarations and agreements applicable to the Sámi as a minority and indigenous people including: The International Covenant on Civil and Political Right (1966). Article 27 protects minorities, and indigenous peoples, against discrimination: "In those states in which ethnic, religious or linguistic minorities exist, persons belonging to such minorities, shall not be denied the right, in community with the other members of their group, to enjoy their own culture, to profess and practice their own religion, or use their own language." ILO Convention No. 169 concerning Indigenous and Tribal Peoples in Independent Countries (1989). The convention states that rights for the indigenous peoples to land and natural resources are recognized as central for their material and cultural survival. In addition, indigenous peoples should be entitled to exercise control over, and manage, their own institutions, ways of life and economic development in order to maintain and develop their identities, languages and religions, within the framework of the states in which they live. The International Convention on the Elimination of All Forms of Racial Discrimination (1965). The UN Convention on the Rights of the Child (1989). The UN Convention on the Elimination of All Forms of Discrimination against Women (1979). The Council of Europe's Framework Convention for the Protection of National Minorities (1995). The Council of Europe's Charter for Regional and Minority Languages (1992). The UN Declaration on the Rights of Indigenous Peoples (2007). Sweden recognised the existence of the "Sámi nation" in 1989, but the ILO Indigenous and Tribal Peoples Convention, C169 has not been adopted. The Sametingslag was established as the Swedish Sámi Parliament on 1 January 1993. In 1998, Sweden formally apologized for the wrongs committed against the Sámi. Sámi is one of five national minority languages recognized by Swedish law. The Compulsory School Ordinance states that Sámi pupils are entitled to be taught in their native language; however, a municipality is only obliged to arrange mother-tongue teaching in Sámi if a suitable teacher is available and the pupil has a basic knowledge of Sámi. In 2010, after 15 years of negotiation, Laponiatjuottjudus, an association with Sámi majority control, will govern the UNESCO World Heritage Site Laponia . The reindeer-herding law will apply in the area as well. The act establishing the Finnish Sámi Parliament (Finnish: Saamelaiskäräjät) was passed on 9 November 1973. Sámi people have had very little representation in Finnish national politics. In fact, in 2007, Janne Seurujärvi , a Finnish Centre Party representative, became the first Sámi ever to be elected to the Finnish Parliament. Finland ratified the 1966 U.N. Covenant on Civil and Political Rights though several cases have been brought before the U.N. Human Rights Committee . Of those, 36 cases involved a determination of the rights of individual Sámi in Finland and Sweden. The committee decisions clarify that Sámi are members of a minority within the meaning of Article 27 and that deprivation or erosion of their rights to practice traditional activities that are an essential element of their culture do come within the scope of Article 27. Finland recognized the Sámi as a "people" in 1995, but has yet to ratify ILO Convention 169 Concerning Indigenous and Tribal Peoples. Sámi in Finland have had access to Sámi language instruction in some schools since the 1970s, and language rights were established in 1992. There are three Sámi languages spoken in Finland: North Sámi , Skolt Sámi and Inari Sámi . Of these languages, Inari Sámi, which is spoken by about 350 speakers, is the only one that is used entirely within the borders of Finland, mainly in the municipality of Inari. The case of J. Lansman versus Finland concerned a challenge by Sámi reindeer herders in northern Finland to the Finnish Central Forestry Board's plans to approve logging and construction of roads in an area used by the herdsmen as winter pasture and spring calving grounds. Finland has denied any aboriginal rights or land rights to the Sámi people; in Finland, non-Sámi can herd reindeer. The 1822 Statute of Administration of Non-Russians in Siberia asserted state ownership over all the land in Siberia and then "granted" possessory rights to the natives. Governance of indigenous groups, and especially collection of taxes from them, necessitated protection of indigenous peoples against exploitation by traders and settlers. During the Soviet era, the inhabitants of the Kola tundra were forcibly relocated to kolkhoz'es (collective communities) by the state; most Sámi were settled at Lujávri ( Lovozero ). The 1993 Constitution, Article 69 states, "The Russian Federation guarantees the rights of small indigenous peoples in accordance with the generally accepted principles and standards of international law and international treaties of the Russian Federation." For the first time in Russia, the rights of indigenous minorities were established in the 1993 Constitution. The Russian Federation ratified the 1966 U.N. Covenant on Civil and Political Rights; Section 2 explicitly forbids depriving a people of "its own means of subsistence." The Russian Duma (parliament) has adopted partial measures to implement it. The Russian Federation lists distinct indigenous peoples as having special rights and protections under the Constitution and federal laws and decrees. These rights are linked to the category known since Soviet times as the malochislennye narody ("small-numbered peoples"), a term that is often translated as "indigenous minorities", which include Arctic peoples such as the Sámi, Nenets , Evenki , and Chukchi . In April 1999, the Russian Duma passed a law that guarantees socio-economic and cultural development to all indigenous minorities, protecting traditional living places and acknowledging some form of limited ownership of territories that have traditionally been used for hunting, herding, fishing, and gathering activities. The law, however, does not anticipate the transfer of title in fee simply to indigenous minorities. The law does not recognize development rights, some proprietary rights including compensation for damage to the property, and limited exclusionary rights. It is not clear, however, whether protection of nature in the traditional places of inhabitation implies a right to exclude conflicting uses that are destructive to nature or whether they have the right to veto development. The Russian Federation's Land Code reinforces the rights of numerically small peoples ("indigenous minorities") to use places they inhabit and to continue traditional economic activities without being charged rent. Such lands cannot be allocated for unrelated activities (which might include oil, gas, and mineral development or tourism) without the consent of the indigenous peoples. Furthermore, indigenous minorities and ethnic groups are allowed to use environmentally protected lands and lands set aside as nature preserves to engage in their traditional modes of land use. Regional law, Code of the Murmansk Oblast , calls on the organs of state power of the oblast to facilitate the native peoples of the Kola North, specifically naming the Sámi, "in realization of their rights for preservation and development of their native language, national culture, traditions and customs." The third section of Article 21 states: "In historically established areas of habitation, Sámi enjoy the rights for traditional use of nature and [traditional] activities." Throughout the Russian North, indigenous and local people have difficulties with exercising control over resources upon which they and their ancestors have depended for centuries. The failure to protect indigenous ways, however, stems not from inadequacy of the written law, but rather from the failure to implement existing laws. Violations of the rights of indigenous peoples continue, and oil, gas, and mineral development and other activities, (mining, timber cutting, commercial fishing, and tourism) that bring foreign currency into the Russian economy. The life ways and economy of indigenous peoples of the Russian North are based upon reindeer herding, fishing, terrestrial and sea mammal hunting, and trapping. Many groups in the Russian Arctic are semi-nomadic, moving seasonally to different hunting and fishing camps. These groups depend upon different types of environment at differing times of the year, rather than upon exploiting a single commodity to exhaustion. Throughout northwestern Siberia, oil and gas development has disturbed pastureland and undermined the ability of indigenous peoples to continue hunting, fishing, trapping, and herding activities. Roads constructed in connection with oil and gas exploration and development destroy and degrade pastureland, ancestral burial grounds, and sacred sites and increase hunting by oil workers on the territory used by indigenous peoples. In the Sámi homeland on the Kola Peninsula in northwestern Russia, regional authorities closed a fifty-mile (eighty-kilometer) stretch of the Ponoi River (and other rivers) to local fishing and granted exclusive fishing rights to a commercial company offering catch-and-release fishing to sport fishers largely from abroad. This deprived the local Sámi (see Article 21 of the Code of the Murmansk Oblast) of food for their families and community and of their traditional economic livelihood. Thus, closing the fishery to locals may have violated the test articulated by the U.N. Human Rights Committee and disregarded the Land Code, other legislative acts, and the 1992 Presidential decree. Sámi are not only forbidden to fish in the eighty-kilometer stretch leased to the Ponoi River Company but are also required by regional laws to pay for licenses to catch a limited number of fish outside the lease area. Residents of remote communities have neither the power nor the resources to demand enforcement of their rights. Here and elsewhere in the circumpolar north, the failure to apply laws for the protection of indigenous peoples leads to "criminalization" of local indigenous populations who cannot survive without "poaching" resources that should be accessible to them legally. Although indigenous leaders in Russia have occasionally asserted indigenous rights to land and resources, to date there has been no serious or sustained discussion of indigenous group rights to ownership of land. Russia has not adopted the ILO Indigenous and Tribal Peoples Convention, C169. On 16 November 2005 in Helsinki , a group of experts, led by former Chief Justice of the Supreme Court of Norway Professor Carsten Smith , submitted a proposal for a Nordic Sámi Convention to the annual joint meeting of the ministers responsible for Sámi affairs in Finland, Norway and Sweden and the presidents of the three Sámi Parliaments from the respective countries. This convention recognizes the Sámi as one indigenous people residing across national borders in all three countries. A set of minimum standards is proposed for the rights of developing the Sámi language and culture and rights to land and water, livelihoods and society. The convention has not yet been ratified in the Nordic countries. The Sámi have been recognized as an indigenous people in Norway (1990 according to ILO convention 169 as described below), and therefore, according to international law, the Sámi people in Norway are entitled special protection and rights. The legal foundation of the Sámi policy is: The constitutional amendment states: "It is the responsibility of the authorities of the State to create conditions enabling the Sámi people to preserve and develop its language, culture and way of life." This provides a legal and political protection of the Sámi language, culture and society. In addition the "amendment implies a legal, political and moral obligation for Norwegian authorities to create an environment conducive to the Sámis themselves influencing on the development of the Sámi community". The Sámi Act provides special rights for the Sámi people: "... the Sámis shall have their own national Sámi Parliament elected by and amongst the Sámis" (Chapter 1–2). The Sámi people shall decide the area of activity of the Norwegian Sámi Parliament. The Sámi and Norwegian languages have equal standing in Norway (section 15; Chapter 3 contains details with regards to the use of the Sámi language). The Norwegian Sámi Parliament also elects 50% of the members to the board of the Finnmark Estate , which controls 95% of the land in the county of Finnmark. In addition, the Sámi have special rights to reindeer husbandry. In 2007, the Norwegian Parliament passed the new Reindeer Herding Act acknowledging siida as the basic institution regarding land rights, organization, and daily herding management. Norway has also accepted international conventions, declarations and agreements applicable to the Sámi as a minority and indigenous people including: The International Covenant on Civil and Political Right (1966). Article 27 protects minorities, and indigenous peoples, against discrimination: "In those states in which ethnic, religious or linguistic minorities exist, persons belonging to such minorities, shall not be denied the right, in community with the other members of their group, to enjoy their own culture, to profess and practice their own religion, or use their own language." ILO Convention No. 169 concerning Indigenous and Tribal Peoples in Independent Countries (1989). The convention states that rights for the indigenous peoples to land and natural resources are recognized as central for their material and cultural survival. In addition, indigenous peoples should be entitled to exercise control over, and manage, their own institutions, ways of life and economic development in order to maintain and develop their identities, languages and religions, within the framework of the states in which they live. The International Convention on the Elimination of All Forms of Racial Discrimination (1965). The UN Convention on the Rights of the Child (1989). The UN Convention on the Elimination of All Forms of Discrimination against Women (1979). The Council of Europe's Framework Convention for the Protection of National Minorities (1995). The Council of Europe's Charter for Regional and Minority Languages (1992). The UN Declaration on the Rights of Indigenous Peoples (2007). Sweden recognised the existence of the "Sámi nation" in 1989, but the ILO Indigenous and Tribal Peoples Convention, C169 has not been adopted. The Sametingslag was established as the Swedish Sámi Parliament on 1 January 1993. In 1998, Sweden formally apologized for the wrongs committed against the Sámi. Sámi is one of five national minority languages recognized by Swedish law. The Compulsory School Ordinance states that Sámi pupils are entitled to be taught in their native language; however, a municipality is only obliged to arrange mother-tongue teaching in Sámi if a suitable teacher is available and the pupil has a basic knowledge of Sámi. In 2010, after 15 years of negotiation, Laponiatjuottjudus, an association with Sámi majority control, will govern the UNESCO World Heritage Site Laponia . The reindeer-herding law will apply in the area as well. The act establishing the Finnish Sámi Parliament (Finnish: Saamelaiskäräjät) was passed on 9 November 1973. Sámi people have had very little representation in Finnish national politics. In fact, in 2007, Janne Seurujärvi , a Finnish Centre Party representative, became the first Sámi ever to be elected to the Finnish Parliament. Finland ratified the 1966 U.N. Covenant on Civil and Political Rights though several cases have been brought before the U.N. Human Rights Committee . Of those, 36 cases involved a determination of the rights of individual Sámi in Finland and Sweden. The committee decisions clarify that Sámi are members of a minority within the meaning of Article 27 and that deprivation or erosion of their rights to practice traditional activities that are an essential element of their culture do come within the scope of Article 27. Finland recognized the Sámi as a "people" in 1995, but has yet to ratify ILO Convention 169 Concerning Indigenous and Tribal Peoples. Sámi in Finland have had access to Sámi language instruction in some schools since the 1970s, and language rights were established in 1992. There are three Sámi languages spoken in Finland: North Sámi , Skolt Sámi and Inari Sámi . Of these languages, Inari Sámi, which is spoken by about 350 speakers, is the only one that is used entirely within the borders of Finland, mainly in the municipality of Inari. The case of J. Lansman versus Finland concerned a challenge by Sámi reindeer herders in northern Finland to the Finnish Central Forestry Board's plans to approve logging and construction of roads in an area used by the herdsmen as winter pasture and spring calving grounds. Finland has denied any aboriginal rights or land rights to the Sámi people; in Finland, non-Sámi can herd reindeer.The 1822 Statute of Administration of Non-Russians in Siberia asserted state ownership over all the land in Siberia and then "granted" possessory rights to the natives. Governance of indigenous groups, and especially collection of taxes from them, necessitated protection of indigenous peoples against exploitation by traders and settlers. During the Soviet era, the inhabitants of the Kola tundra were forcibly relocated to kolkhoz'es (collective communities) by the state; most Sámi were settled at Lujávri ( Lovozero ). The 1993 Constitution, Article 69 states, "The Russian Federation guarantees the rights of small indigenous peoples in accordance with the generally accepted principles and standards of international law and international treaties of the Russian Federation." For the first time in Russia, the rights of indigenous minorities were established in the 1993 Constitution. The Russian Federation ratified the 1966 U.N. Covenant on Civil and Political Rights; Section 2 explicitly forbids depriving a people of "its own means of subsistence." The Russian Duma (parliament) has adopted partial measures to implement it. The Russian Federation lists distinct indigenous peoples as having special rights and protections under the Constitution and federal laws and decrees. These rights are linked to the category known since Soviet times as the malochislennye narody ("small-numbered peoples"), a term that is often translated as "indigenous minorities", which include Arctic peoples such as the Sámi, Nenets , Evenki , and Chukchi . In April 1999, the Russian Duma passed a law that guarantees socio-economic and cultural development to all indigenous minorities, protecting traditional living places and acknowledging some form of limited ownership of territories that have traditionally been used for hunting, herding, fishing, and gathering activities. The law, however, does not anticipate the transfer of title in fee simply to indigenous minorities. The law does not recognize development rights, some proprietary rights including compensation for damage to the property, and limited exclusionary rights. It is not clear, however, whether protection of nature in the traditional places of inhabitation implies a right to exclude conflicting uses that are destructive to nature or whether they have the right to veto development. The Russian Federation's Land Code reinforces the rights of numerically small peoples ("indigenous minorities") to use places they inhabit and to continue traditional economic activities without being charged rent. Such lands cannot be allocated for unrelated activities (which might include oil, gas, and mineral development or tourism) without the consent of the indigenous peoples. Furthermore, indigenous minorities and ethnic groups are allowed to use environmentally protected lands and lands set aside as nature preserves to engage in their traditional modes of land use. Regional law, Code of the Murmansk Oblast , calls on the organs of state power of the oblast to facilitate the native peoples of the Kola North, specifically naming the Sámi, "in realization of their rights for preservation and development of their native language, national culture, traditions and customs." The third section of Article 21 states: "In historically established areas of habitation, Sámi enjoy the rights for traditional use of nature and [traditional] activities." Throughout the Russian North, indigenous and local people have difficulties with exercising control over resources upon which they and their ancestors have depended for centuries. The failure to protect indigenous ways, however, stems not from inadequacy of the written law, but rather from the failure to implement existing laws. Violations of the rights of indigenous peoples continue, and oil, gas, and mineral development and other activities, (mining, timber cutting, commercial fishing, and tourism) that bring foreign currency into the Russian economy. The life ways and economy of indigenous peoples of the Russian North are based upon reindeer herding, fishing, terrestrial and sea mammal hunting, and trapping. Many groups in the Russian Arctic are semi-nomadic, moving seasonally to different hunting and fishing camps. These groups depend upon different types of environment at differing times of the year, rather than upon exploiting a single commodity to exhaustion. Throughout northwestern Siberia, oil and gas development has disturbed pastureland and undermined the ability of indigenous peoples to continue hunting, fishing, trapping, and herding activities. Roads constructed in connection with oil and gas exploration and development destroy and degrade pastureland, ancestral burial grounds, and sacred sites and increase hunting by oil workers on the territory used by indigenous peoples. In the Sámi homeland on the Kola Peninsula in northwestern Russia, regional authorities closed a fifty-mile (eighty-kilometer) stretch of the Ponoi River (and other rivers) to local fishing and granted exclusive fishing rights to a commercial company offering catch-and-release fishing to sport fishers largely from abroad. This deprived the local Sámi (see Article 21 of the Code of the Murmansk Oblast) of food for their families and community and of their traditional economic livelihood. Thus, closing the fishery to locals may have violated the test articulated by the U.N. Human Rights Committee and disregarded the Land Code, other legislative acts, and the 1992 Presidential decree. Sámi are not only forbidden to fish in the eighty-kilometer stretch leased to the Ponoi River Company but are also required by regional laws to pay for licenses to catch a limited number of fish outside the lease area. Residents of remote communities have neither the power nor the resources to demand enforcement of their rights. Here and elsewhere in the circumpolar north, the failure to apply laws for the protection of indigenous peoples leads to "criminalization" of local indigenous populations who cannot survive without "poaching" resources that should be accessible to them legally. Although indigenous leaders in Russia have occasionally asserted indigenous rights to land and resources, to date there has been no serious or sustained discussion of indigenous group rights to ownership of land. Russia has not adopted the ILO Indigenous and Tribal Peoples Convention, C169.On 16 November 2005 in Helsinki , a group of experts, led by former Chief Justice of the Supreme Court of Norway Professor Carsten Smith , submitted a proposal for a Nordic Sámi Convention to the annual joint meeting of the ministers responsible for Sámi affairs in Finland, Norway and Sweden and the presidents of the three Sámi Parliaments from the respective countries. This convention recognizes the Sámi as one indigenous people residing across national borders in all three countries. A set of minimum standards is proposed for the rights of developing the Sámi language and culture and rights to land and water, livelihoods and society. The convention has not yet been ratified in the Nordic countries. To make up for past suppression, the authorities of Norway, Sweden and Finland now make an effort to build up Sámi cultural institutions and promote Sámi culture and language. Duodji, the Sámi handicraft, originates from the time when the Sámis were self-supporting nomads, believing therefore that an object should first and foremost serve a purpose rather than being primarily decorative. Men mostly use wood, bone, and antlers to make items such as antler-handled scrimshawed Sámi knives , drums , and guksi (burl cups). Women used leather and roots to make items such as gákti (clothing), and birch- and spruce-root woven baskets. Gákti are the traditional clothing worn by the Sámi people. The gákti is worn both in ceremonial contexts and while working, particularly when herding reindeer. Traditionally, the gákti was made from reindeer leather and sinews, but nowadays, it is more common to use wool, cotton, or silk. Women's gákti typically consist of a dress, a fringed shawl that is fastened with 1–3 silver brooches, and boots/shoes made of reindeer fur or leather. Sámi boots (or nutukas ) can have pointed or curled toes and often have band-woven ankle wraps. Eastern Sámi boots have a rounded toe on reindeer-fur boots, lined with felt and with beaded details. There are different gákti for women and men; men's gákti have a shorter "jacket-skirt" than a women's long dress. Traditional gákti are most commonly in variations of red, blue, green, white, medium-brown tanned leather, or reindeer fur. In winter, there is the addition of a reindeer fur coat and leggings, and sometimes a poncho (luhkka) and rope/lasso. The colours, patterns and the jewellery of the gákti indicate where a person is from, if a person is single or married, and sometimes can even be specific to their family. The collar, sleeves and hem usually have appliqués in the form of geometric shapes. Some regions have ribbonwork, others have tin embroidery, and some Eastern Sámi have beading on clothing or collar. Hats vary by sex, season, and region. They can be wool, leather, or fur. They can be embroidered, or in the East, they are more like a beaded cloth crown with a shawl. Some traditional shamanic headgear had animal hides, plaits, and feathers, particularly in East Sápmi. The gákti can be worn with a belt; these are sometimes band-woven belts, woven, or beaded. Leather belts can have scrimshawed antler buttons, silver concho -like buttons, tassels, or brass/copper details such as rings. Belts can also have beaded leather pouches, antler needle cases, accessories for a fire, copper rings, amulets, and often a carved and/or scrimshawed antler-handled knife. Some Eastern Sámi also have a hooded jumper (малиц) from reindeer skins with wool inside and above the knee boots. A characteristic feature of Sámi musical tradition is the singing of joik . Joiks are song-chants and are traditionally sung a cappella , usually sung slowly and deep in the throat with apparent emotional content of sorrow or anger. Joiks can be dedicated to animals and birds in nature, special people or special occasions, and they can be joyous, sad or melancholic. They often are based on syllablic improvisation. In recent years, musical instruments frequently accompany joiks. The only traditional Sámi instruments that were sometimes used to accompany joik are the "fadno" flute (made from reed-like Angelica archangelica stems) and hand drums (frame drums and bowl drums). In addition to Duodji (Sámi handicraft), there is a developing area of contemporary Sámi visual art. Galleries such as Sámi Dáiddaguovddáš (Sami Center for Contemporary Art) are being established. Unlike many other Indigenous peoples, traditional dance is generally not a visible manifestation of Sámi identity. This has led to a common misconception that Sámi, at least in western Sápmi, have no traditional dance culture. The Sámi modern dance company Kompani Nomad looked to old descriptions of shamanistic rituals and behaviors to identify "lost" Sámi dances and reimagine them through contemporary dance. An example is the lihkadus (ecstasy dance) described in sources from the 16th and 17th centuries, but which was adapted by Swedish–Sámi priest Lars Levi Laestadius , who brought it and other Sámi traditions into the Church of Sweden as part of the Laestadianism movement. Partner and group dancing have been a part of Skolt Sámi culture and among Sámi on the Kola Peninsula since at least the second half of the 1800s. These square dances, couple dances, circle dances, and singing games are influenced by Karelian and Northern Russian dance cultures, likely under the influence of Russian traders, military service under the tsar, and the Russian Orthodox Church . This eastern Sápmi dance tradition has been more continuous and has been adapted by modern Sámi dance companies such as Johtti Kompani. Reindeer husbandry has been and still is an important aspect of Sámi culture. Traditionally the Sámi lived and worked in reindeer herding groups called siidat , which consist of several families and their herds. Members of the siida helped each other with the management and husbandry of the herds. During the years of forced assimilation , the areas in which reindeer herding was an important livelihood were among the few where the Sámi culture and language survived. Today in Norway and Sweden, reindeer husbandry is legally protected as an exclusive Sámi livelihood, such that only persons of Sámi descent with a linkage to a reindeer herding family can own, and hence make a living off, reindeer. Presently, about 2,800 people are engaged in reindeer herding in Norway. In Finland, reindeer husbandry is not exclusive and is also practiced to a limited degree by ethnic Finns. Legally, it is restricted to EU / EEA nationals resident in the area. In the north (Lapland), it plays a major role in the local economy, while its economic impact is lesser in the southern parts of the area ( Province of Oulu ). Among the reindeer herders in Sámi villages, the women usually have a higher level of formal education in the area. The Sámi have traditionally played both card games and board games, but few Sámi games have survived, because Christian missionaries and Laestadianists considered such games sinful. Only the rules of three Sámi board games have been preserved into modern times. Sáhkku is a running-fight board game where each player controls a set of soldiers (referred to as "women" and "men") that race across a board in a loop, attempting to eliminate the other player's soldiers. The game is related to South Scandinavian daldøs , Arabian tâb and Indian tablan. Sáhkku differs from these games in several respects, most notably the addition of a piece – "the king" – that changes gameplay radically. Tablut is a pure strategy game in the tafl family. The game features "Swedes" and a "Swedish king" whose goal is to escape, and an army of "Muscovites" whose goal is to capture the king. Tablut is the only tafl game where a relatively intact set of rules have survived into our time. Hence, all modern versions of tafl (commonly called "Hnefatafl" and marketed exclusively as "Norse" or "Viking" games) are based on the Sámi game of tablut. Dablot Prejjesne is a game related to alquerque which differs from most such games (e.g. draughts ) by having pieces of three different ranks. The game's two sides are referred to as "Sámi" (king, prince, warriors) and "Finlenders" (landowners, landowner's son, farmers). Duodji, the Sámi handicraft, originates from the time when the Sámis were self-supporting nomads, believing therefore that an object should first and foremost serve a purpose rather than being primarily decorative. Men mostly use wood, bone, and antlers to make items such as antler-handled scrimshawed Sámi knives , drums , and guksi (burl cups). Women used leather and roots to make items such as gákti (clothing), and birch- and spruce-root woven baskets.Gákti are the traditional clothing worn by the Sámi people. The gákti is worn both in ceremonial contexts and while working, particularly when herding reindeer. Traditionally, the gákti was made from reindeer leather and sinews, but nowadays, it is more common to use wool, cotton, or silk. Women's gákti typically consist of a dress, a fringed shawl that is fastened with 1–3 silver brooches, and boots/shoes made of reindeer fur or leather. Sámi boots (or nutukas ) can have pointed or curled toes and often have band-woven ankle wraps. Eastern Sámi boots have a rounded toe on reindeer-fur boots, lined with felt and with beaded details. There are different gákti for women and men; men's gákti have a shorter "jacket-skirt" than a women's long dress. Traditional gákti are most commonly in variations of red, blue, green, white, medium-brown tanned leather, or reindeer fur. In winter, there is the addition of a reindeer fur coat and leggings, and sometimes a poncho (luhkka) and rope/lasso. The colours, patterns and the jewellery of the gákti indicate where a person is from, if a person is single or married, and sometimes can even be specific to their family. The collar, sleeves and hem usually have appliqués in the form of geometric shapes. Some regions have ribbonwork, others have tin embroidery, and some Eastern Sámi have beading on clothing or collar. Hats vary by sex, season, and region. They can be wool, leather, or fur. They can be embroidered, or in the East, they are more like a beaded cloth crown with a shawl. Some traditional shamanic headgear had animal hides, plaits, and feathers, particularly in East Sápmi. The gákti can be worn with a belt; these are sometimes band-woven belts, woven, or beaded. Leather belts can have scrimshawed antler buttons, silver concho -like buttons, tassels, or brass/copper details such as rings. Belts can also have beaded leather pouches, antler needle cases, accessories for a fire, copper rings, amulets, and often a carved and/or scrimshawed antler-handled knife. Some Eastern Sámi also have a hooded jumper (малиц) from reindeer skins with wool inside and above the knee boots.A characteristic feature of Sámi musical tradition is the singing of joik . Joiks are song-chants and are traditionally sung a cappella , usually sung slowly and deep in the throat with apparent emotional content of sorrow or anger. Joiks can be dedicated to animals and birds in nature, special people or special occasions, and they can be joyous, sad or melancholic. They often are based on syllablic improvisation. In recent years, musical instruments frequently accompany joiks. The only traditional Sámi instruments that were sometimes used to accompany joik are the "fadno" flute (made from reed-like Angelica archangelica stems) and hand drums (frame drums and bowl drums).In addition to Duodji (Sámi handicraft), there is a developing area of contemporary Sámi visual art. Galleries such as Sámi Dáiddaguovddáš (Sami Center for Contemporary Art) are being established.Unlike many other Indigenous peoples, traditional dance is generally not a visible manifestation of Sámi identity. This has led to a common misconception that Sámi, at least in western Sápmi, have no traditional dance culture. The Sámi modern dance company Kompani Nomad looked to old descriptions of shamanistic rituals and behaviors to identify "lost" Sámi dances and reimagine them through contemporary dance. An example is the lihkadus (ecstasy dance) described in sources from the 16th and 17th centuries, but which was adapted by Swedish–Sámi priest Lars Levi Laestadius , who brought it and other Sámi traditions into the Church of Sweden as part of the Laestadianism movement. Partner and group dancing have been a part of Skolt Sámi culture and among Sámi on the Kola Peninsula since at least the second half of the 1800s. These square dances, couple dances, circle dances, and singing games are influenced by Karelian and Northern Russian dance cultures, likely under the influence of Russian traders, military service under the tsar, and the Russian Orthodox Church . This eastern Sápmi dance tradition has been more continuous and has been adapted by modern Sámi dance companies such as Johtti Kompani. Reindeer husbandry has been and still is an important aspect of Sámi culture. Traditionally the Sámi lived and worked in reindeer herding groups called siidat , which consist of several families and their herds. Members of the siida helped each other with the management and husbandry of the herds. During the years of forced assimilation , the areas in which reindeer herding was an important livelihood were among the few where the Sámi culture and language survived. Today in Norway and Sweden, reindeer husbandry is legally protected as an exclusive Sámi livelihood, such that only persons of Sámi descent with a linkage to a reindeer herding family can own, and hence make a living off, reindeer. Presently, about 2,800 people are engaged in reindeer herding in Norway. In Finland, reindeer husbandry is not exclusive and is also practiced to a limited degree by ethnic Finns. Legally, it is restricted to EU / EEA nationals resident in the area. In the north (Lapland), it plays a major role in the local economy, while its economic impact is lesser in the southern parts of the area ( Province of Oulu ). Among the reindeer herders in Sámi villages, the women usually have a higher level of formal education in the area. The Sámi have traditionally played both card games and board games, but few Sámi games have survived, because Christian missionaries and Laestadianists considered such games sinful. Only the rules of three Sámi board games have been preserved into modern times. Sáhkku is a running-fight board game where each player controls a set of soldiers (referred to as "women" and "men") that race across a board in a loop, attempting to eliminate the other player's soldiers. The game is related to South Scandinavian daldøs , Arabian tâb and Indian tablan. Sáhkku differs from these games in several respects, most notably the addition of a piece – "the king" – that changes gameplay radically. Tablut is a pure strategy game in the tafl family. The game features "Swedes" and a "Swedish king" whose goal is to escape, and an army of "Muscovites" whose goal is to capture the king. Tablut is the only tafl game where a relatively intact set of rules have survived into our time. Hence, all modern versions of tafl (commonly called "Hnefatafl" and marketed exclusively as "Norse" or "Viking" games) are based on the Sámi game of tablut. Dablot Prejjesne is a game related to alquerque which differs from most such games (e.g. draughts ) by having pieces of three different ranks. The game's two sides are referred to as "Sámi" (king, prince, warriors) and "Finlenders" (landowners, landowner's son, farmers). Sápmi is located in Northern Europe, includes the northern parts of Fennoscandia and spans four countries: Norway, Sweden, Finland, and Russia. Non-Sámi and many regional maps have often called this same region Lapland as there is considerable regional overlap between Sápmi and the provinces of Lappland in Sweden and Lapland in Finland. Much of Sápmi falls outside of those provinces. Despite the terms use in tourism, Lapland can be either misleading or offensive, or both, to Sámi, depending on the context and where this word is used. Among the Sámi people, Sápmi is strictly used and acceptable. There is no official geographic definition for the boundaries of Sápmi. However, the following counties and provinces are usually included: The municipalities of Gällivare , Jokkmokk and Arjeplog in Swedish Lappland were designated a UNESCO World Heritage Site in 1996 as a "Laponian Area". The Sámi Domicile Area in Finland consists of the municipalities of Enontekiö , Utsjoki and Inari as well as a part of the municipality of Sodankylä . About 3,000 of Finland's about 10,000 people speak Sámi as their mother tongue. Today, a considerable part of the Finnish Sámi live outside the Sápmi region, for example in Helsinki there is a relatively large and active Sámi minority. According to the Sámi Parliament , the Sámi live in 230 municipalities out of a total of 336 municipalities in Finland . 75% of Sámi under the age of 10 live outside the Sápmi region. The following towns and villages have a significant Sámi population or host Sámi institutions (Norwegian, Swedish, Finnish or Russian name in parentheses):There is no official geographic definition for the boundaries of Sápmi. However, the following counties and provinces are usually included: The municipalities of Gällivare , Jokkmokk and Arjeplog in Swedish Lappland were designated a UNESCO World Heritage Site in 1996 as a "Laponian Area". The Sámi Domicile Area in Finland consists of the municipalities of Enontekiö , Utsjoki and Inari as well as a part of the municipality of Sodankylä . About 3,000 of Finland's about 10,000 people speak Sámi as their mother tongue. Today, a considerable part of the Finnish Sámi live outside the Sápmi region, for example in Helsinki there is a relatively large and active Sámi minority. According to the Sámi Parliament , the Sámi live in 230 municipalities out of a total of 336 municipalities in Finland . 75% of Sámi under the age of 10 live outside the Sápmi region. The following towns and villages have a significant Sámi population or host Sámi institutions (Norwegian, Swedish, Finnish or Russian name in parentheses):In the geographical area of Sápmi, the Sámi are a small population. According to some, the estimated total Sámi population is about 70,000. [lower-alpha 2] One problem when attempting to count the population of the Sámi is that there are few common criteria of what "being a Sámi" constitutes. In addition, there are several Sámi languages and additional dialects, and there are several areas in Sapmi where few of the Sámi speak their native language due to the forced cultural assimilation, but still consider themselves Sámi. Other identity markers are kinship (which can be said to, at some level or other, be of high importance for all Sámi), the geographical region of Sápmi where their family came from, and/or protecting or preserving certain aspects of Sámi culture . All the Nordic Sámi Parliaments have included as the "core" criterion for registering as a Sámi the identity in itself—one must declare that one truly considers oneself a Sámi. Objective criteria vary, but are generally related to kinship and/or language. Still, due to the cultural assimilation of the Sámi people that had occurred in the four countries over the centuries, population estimates are difficult to measure precisely. The population has been estimated to be between 80,000 and 135,000 across the whole Nordic region, including urban areas such as Oslo , Norway, traditionally considered outside Sápmi. The Norwegian state recognizes any Norwegian as Sámi if he or she has one great-grandparent whose home language was Sámi, but there is not, and has never been, any registration of the home language spoken by Norwegian people. Roughly half of all Sámi live in Norway, but many live in Sweden, with smaller groups living in the far north of Finland and the Kola Peninsula of Russia. The Sámi in Russia were forced by the Soviet authorities to relocate to a collective called Lovozero /Lujávri, in the central part of the Kola Peninsula. There is no single Sámi language, but a group of ten distinct Sámi languages . Six of these languages have their own written standards. The Sámi languages are relatively closely related, but not mutually intelligible; for instance, speakers of Southern Sámi cannot understand Northern Sámi. Especially earlier, these distinct languages were referred to as "dialects", but today, this is considered misleading due to the deep differences between the varieties. Most Sámi languages are spoken in several countries, because linguistic borders do not correspond to national borders. All Sámi languages are at some degree of endangerment , ranging from what UNESCO defines as "definitely endangered" to "extinct". This is due in part to historic laws prohibiting the use of Sámi languages in schools and at home in Sweden and Norway. Sámi languages, and Sámi song-chants, called joiks, were illegal in Norway from 1773 until 1958. Then, access to Sámi instruction as part of schooling was not available until 1988. Special residential schools that would assimilate the Sámi into the dominant culture were established. These were originally run by missionaries, but later, controlled by the government. For example, in Russia, Sámi children were taken away when aged 1–2 and returned when aged 15–17 with no knowledge of their language and traditional communities. Not all Sámi viewed the schools negatively, and not all of the schools were brutal. However, being taken from home and prohibited from speaking Sámi has resulted in cultural alienation, loss of language, and lowered self-esteem. The Sámi languages belong to the Uralic language family, linguistically related to Finnish, Estonian , and Hungarian . Due to prolonged contact and import of items foreign to Sámi culture from neighboring Scandinavians, there are a number of Germanic loanwords in Sámi, particularly for "urban" objects. The majority of the Sámi now speak the majority languages of the countries they live in, i.e., Swedish, Russian, Finnish and Norwegian. Efforts are being made to further the use of Sámi languages among Sámi and persons of Sámi origin. Despite these changes, the legacy of cultural repression still exists. Many older Sámi still refuse to speak Sámi. In addition, Sámi parents still feel alienated from schools and hence do not participate as much as they could in shaping school curricula and policy. In Norway, the name of the language is samisk , and the name of the people is Same ; in Finland, the name of the language is spelled saame and the name of the people saamelainen . American scientist Michael E. Krauss published in 1997 an estimate of Sámi population and their languages. Southern Sámi Ume Sámi Pite Sámi Lule Sámi Northern Sámi Skolt Sámi Inari Sámi Kildin Sámi Ter Sámi Kemi Sámi language became extinct in the 19th century. Many Sámi do not speak any of the Sámi languages any more due to historical assimilation policies, so the number of Sámi living in each area is much higher. Sápmi is traditionally divided into: Eastern Sápmi (Inari, Skolt, Akkala, Kildin and Teri Sámi in Kola peninsula (Russia) and Inari (Finland, formerly also in eastern Norway) Northern Sápmi (Northern, Lule and Pite Sámi in most of northern parts of Norway, Sweden and Finland) Southern Sápmi (Ume and Southern Sámi in central parts of Sweden and Norway) It should also be noted that many Sámi now live outside Sápmi, in large cities such as Oslo in Norway. A division often used in Northern Sámi is based on occupation and the area of living. This division is also used in many historical texts: Reindeer Sámi or Mountain Sámi (in Northern Sámi boazosapmelash or badjeolmmosh). Previously nomadic Sámi living as reindeer herders. Now most have a permanent residence in the Sámi core areas. Some 10% of Sámi practice reindeer herding, which is seen as a fundamental part of a Sámi culture and, in some parts of the Nordic countries, can be practiced by Sámis only. Sea Sámi (in Northern Sámi mearasapmelash ). These lived traditionally by combining fishing and small-scale farming. Today, often used for all Sámi from the coast regardless of their occupation. Forest Sámi who traditionally lived by combining fishing in inland rivers and lakes with small-scale reindeer-herding. City Sámi who are now probably the largest group of Sámi. According to the Norwegian Sámi Parliament, the Sámi population of Norway is 40,000. If all people who speak Sámi or have a parent, grandparent, or great-grandparent who speaks or spoke Sámi are included, the number reaches 70,000. As of 2021, 20,545 people were registered to vote in the election for the Sámi Parliament in Norway. The bulk of the Sámi live in Finnmark and Northern Troms , but there are also Sámi populations in Southern Troms, Nordland and Trøndelag . Due to recent migration, it has also been claimed that Oslo is the municipality with the largest Sámi population. The Sámi are in a majority only in the municipalities of Guovdageaidnu–Kautokeino , Kárášjohka–Karasjok , Porsáŋgu–Porsanger , Deatnu–Tana and Unjárga–Nesseby in Finnmark, and Gáivuotna–Kåfjord in Northern Troms. This area is also known as the Sámi core area, and Sámi and Norwegian are co-equal administrative languages here. According to the Swedish Sámi Parliament, estimates of the size of the Sámi population of Sweden ranges from 20,000 to 40,000. As of 2021, 9,226 people were registered to vote in elections to the Swedish Sámi Parliament. According to the Finnish Population Registry Center and the Finnish Sámi Parliament, the Sámi population living in Finland was 10,753 in 2019. As of 31 December 2021, only 2,023 people were registered as speaking a Sámi language as their mother tongue. According to the 2010 All-Russia Census , the Sámi population of Russia was 1,771. There are an estimated 30,000 people living in North America who are either Sámi, or descendants of Sámi. Most have settled in areas that are known to have Norwegian, Swedish and Finnish immigrants. Some of these concentrated areas are Minnesota , North Dakota , Iowa , Wisconsin , the Upper Peninsula of Michigan , Illinois , California , Washington , Utah and Alaska; and throughout Canada, including Saskatchewan , Manitoba and Northern Ontario , and the Canadian territories of the Northwest Territories , Yukon and Nunavut . Descendants of these Sámi immigrants typically know little of their heritage because their ancestors purposely hid their indigenous culture to avoid discrimination from the dominating Scandinavian or Nordic culture. Some of these Sámi are part of a diaspora that moved to North America in order to escape assimilation policies in their home countries. There were also several Sámi families that were brought to North America with herds of reindeer by the U.S. and Canadian governments as part of the "Reindeer Project" designed to teach the Inuit about reindeer herding. There is a long history of Sámi in Alaska . Some of these Sámi immigrants and descendants of immigrants are members of the Sami Siida of North America .There is no single Sámi language, but a group of ten distinct Sámi languages . Six of these languages have their own written standards. The Sámi languages are relatively closely related, but not mutually intelligible; for instance, speakers of Southern Sámi cannot understand Northern Sámi. Especially earlier, these distinct languages were referred to as "dialects", but today, this is considered misleading due to the deep differences between the varieties. Most Sámi languages are spoken in several countries, because linguistic borders do not correspond to national borders. All Sámi languages are at some degree of endangerment , ranging from what UNESCO defines as "definitely endangered" to "extinct". This is due in part to historic laws prohibiting the use of Sámi languages in schools and at home in Sweden and Norway. Sámi languages, and Sámi song-chants, called joiks, were illegal in Norway from 1773 until 1958. Then, access to Sámi instruction as part of schooling was not available until 1988. Special residential schools that would assimilate the Sámi into the dominant culture were established. These were originally run by missionaries, but later, controlled by the government. For example, in Russia, Sámi children were taken away when aged 1–2 and returned when aged 15–17 with no knowledge of their language and traditional communities. Not all Sámi viewed the schools negatively, and not all of the schools were brutal. However, being taken from home and prohibited from speaking Sámi has resulted in cultural alienation, loss of language, and lowered self-esteem. The Sámi languages belong to the Uralic language family, linguistically related to Finnish, Estonian , and Hungarian . Due to prolonged contact and import of items foreign to Sámi culture from neighboring Scandinavians, there are a number of Germanic loanwords in Sámi, particularly for "urban" objects. The majority of the Sámi now speak the majority languages of the countries they live in, i.e., Swedish, Russian, Finnish and Norwegian. Efforts are being made to further the use of Sámi languages among Sámi and persons of Sámi origin. Despite these changes, the legacy of cultural repression still exists. Many older Sámi still refuse to speak Sámi. In addition, Sámi parents still feel alienated from schools and hence do not participate as much as they could in shaping school curricula and policy. In Norway, the name of the language is samisk , and the name of the people is Same ; in Finland, the name of the language is spelled saame and the name of the people saamelainen . American scientist Michael E. Krauss published in 1997 an estimate of Sámi population and their languages. Southern Sámi Ume Sámi Pite Sámi Lule Sámi Northern Sámi Skolt Sámi Inari Sámi Kildin Sámi Ter Sámi Kemi Sámi language became extinct in the 19th century. Many Sámi do not speak any of the Sámi languages any more due to historical assimilation policies, so the number of Sámi living in each area is much higher. Sápmi is traditionally divided into: Eastern Sápmi (Inari, Skolt, Akkala, Kildin and Teri Sámi in Kola peninsula (Russia) and Inari (Finland, formerly also in eastern Norway) Northern Sápmi (Northern, Lule and Pite Sámi in most of northern parts of Norway, Sweden and Finland) Southern Sápmi (Ume and Southern Sámi in central parts of Sweden and Norway) It should also be noted that many Sámi now live outside Sápmi, in large cities such as Oslo in Norway.A division often used in Northern Sámi is based on occupation and the area of living. This division is also used in many historical texts: Reindeer Sámi or Mountain Sámi (in Northern Sámi boazosapmelash or badjeolmmosh). Previously nomadic Sámi living as reindeer herders. Now most have a permanent residence in the Sámi core areas. Some 10% of Sámi practice reindeer herding, which is seen as a fundamental part of a Sámi culture and, in some parts of the Nordic countries, can be practiced by Sámis only. Sea Sámi (in Northern Sámi mearasapmelash ). These lived traditionally by combining fishing and small-scale farming. Today, often used for all Sámi from the coast regardless of their occupation. Forest Sámi who traditionally lived by combining fishing in inland rivers and lakes with small-scale reindeer-herding. City Sámi who are now probably the largest group of Sámi.According to the Norwegian Sámi Parliament, the Sámi population of Norway is 40,000. If all people who speak Sámi or have a parent, grandparent, or great-grandparent who speaks or spoke Sámi are included, the number reaches 70,000. As of 2021, 20,545 people were registered to vote in the election for the Sámi Parliament in Norway. The bulk of the Sámi live in Finnmark and Northern Troms , but there are also Sámi populations in Southern Troms, Nordland and Trøndelag . Due to recent migration, it has also been claimed that Oslo is the municipality with the largest Sámi population. The Sámi are in a majority only in the municipalities of Guovdageaidnu–Kautokeino , Kárášjohka–Karasjok , Porsáŋgu–Porsanger , Deatnu–Tana and Unjárga–Nesseby in Finnmark, and Gáivuotna–Kåfjord in Northern Troms. This area is also known as the Sámi core area, and Sámi and Norwegian are co-equal administrative languages here. According to the Swedish Sámi Parliament, estimates of the size of the Sámi population of Sweden ranges from 20,000 to 40,000. As of 2021, 9,226 people were registered to vote in elections to the Swedish Sámi Parliament. According to the Finnish Population Registry Center and the Finnish Sámi Parliament, the Sámi population living in Finland was 10,753 in 2019. As of 31 December 2021, only 2,023 people were registered as speaking a Sámi language as their mother tongue. According to the 2010 All-Russia Census , the Sámi population of Russia was 1,771.There are an estimated 30,000 people living in North America who are either Sámi, or descendants of Sámi. Most have settled in areas that are known to have Norwegian, Swedish and Finnish immigrants. Some of these concentrated areas are Minnesota , North Dakota , Iowa , Wisconsin , the Upper Peninsula of Michigan , Illinois , California , Washington , Utah and Alaska; and throughout Canada, including Saskatchewan , Manitoba and Northern Ontario , and the Canadian territories of the Northwest Territories , Yukon and Nunavut . Descendants of these Sámi immigrants typically know little of their heritage because their ancestors purposely hid their indigenous culture to avoid discrimination from the dominating Scandinavian or Nordic culture. Some of these Sámi are part of a diaspora that moved to North America in order to escape assimilation policies in their home countries. There were also several Sámi families that were brought to North America with herds of reindeer by the U.S. and Canadian governments as part of the "Reindeer Project" designed to teach the Inuit about reindeer herding. There is a long history of Sámi in Alaska . Some of these Sámi immigrants and descendants of immigrants are members of the Sami Siida of North America .Sápmi demonstrates a distinct semi-national identity that transcends the borders between Norway, Sweden, Finland and Russia. There is no movement for sovereign state, but they do seek greater autonomy in respective nation states. The Sámi Parliaments ( Sámediggi in Northern Sámi , Sämitigge in Inari Sámi , Sää'mte'ǧǧ in Skolt Sámi ) founded in Finland (1973), Norway (1989) and Sweden (1993) are the representative bodies for peoples of Sámi heritage. Russia has not recognized the Sámi as a minority and, as a result, recognizes no Sámi parliament, even if the Sámi people there have formed an unrecognised Sámi Parliament of Russia . There is no single, unified Sámi parliament that spans across the Nordic countries. Rather, each of the aforementioned three countries has set up its own separate legislatures for Sámi people, even though the three Sámi Parliaments often work together on cross-border issues. In all three countries, they act as an institution of cultural autonomy for the indigenous Sámi people. The parliaments have very weak political influence, far from autonomy. They are formally public authorities, ruled by the Scandinavian governments, but have democratically elected parliamentarians, whose mission is to work for the Sámi people and culture. Candidates' election promises often get into conflict with the institutions' submission under their governments, but as authorities, they have some influence over the government. The main organisations for Sámi representation in Norway are the siidas . They cover northern and central Norway. The main organisations for Sámi representation in Sweden are the siidas . They cover northern and central Sweden. In contrast to Norway and Sweden, in Finland, a siida ( paliskunta in Finnish) is a reindeer-herding corporation that is not restricted by ethnicity. There are indeed some ethnic Finns who practice reindeer herding, and in principle, all residents of the reindeer herding area (most of Finnish Lapland and parts of Oulu province) who are citizens of EEA countries, i.e., the European Union and Norway, Iceland and Liechtenstein , are allowed to join a paliskunta . In 2010, the Sámi Council supported the establishment of a cultural center in Russia for Arctic peoples. The Center for Northern Peoples aims to promote artistic and cultural cooperation between the Arctic peoples of Russia and the Nordic countries, with particular focus on indigenous peoples and minorities. Sápmi, the Sámi traditional lands, cross four national borders. Traditional summer and winter pastures sometimes lie on different sides of the borders of the nation-states. In addition to that, there is a border drawn for modern-day Sápmi . Some state that the rights (for reindeer herding and, in some parts, even for fishing and hunting) include not only modern Sápmi but areas that are beyond today's Sápmi that reflect older territories. Today's "borders" originate from the 14th to 16th centuries when land-owning conflicts occurred. The establishment of more stable dwelling places and larger towns originates from the 16th century and was performed for strategic defence and economic reasons, both by peoples from Sámi groups themselves and more southern immigrants. Owning land within the borders or being a member of a siida (Sámi corporation) gives rights. A different law enacted in Sweden in the mid-1990s gave the right to anyone to fish and hunt in the region, something that was met with skepticism and anger amongst the siidas . Court proceedings have been common throughout history, and the aim from the Sámi viewpoint is to reclaim territories used earlier in history. Due to a major defeat in 1996, one siida has introduced a sponsorship "Reindeer Godfather" concept to raise funds for further battles in courts. These "internal conflicts" are usually conflicts between non-Sámi land owners and reindeer owners. Cases question the Sámi ancient rights to reindeer pastures. In 2010, Sweden was criticized for its relations with the Sámi in the Universal Periodic Review conducted by the Working Group of the Human Rights Council. The question whether the fjeld 's territory is owned by the governments (crown land) or by the Sámi population is not answered. From an indigenous perspective, people "belong to the land", the land does not belong to people, but this does not mean that hunters, herders, and fishing people do not know where the borders of their territories are located as well as those of their neighbors. The Sámi Parliaments ( Sámediggi in Northern Sámi , Sämitigge in Inari Sámi , Sää'mte'ǧǧ in Skolt Sámi ) founded in Finland (1973), Norway (1989) and Sweden (1993) are the representative bodies for peoples of Sámi heritage. Russia has not recognized the Sámi as a minority and, as a result, recognizes no Sámi parliament, even if the Sámi people there have formed an unrecognised Sámi Parliament of Russia . There is no single, unified Sámi parliament that spans across the Nordic countries. Rather, each of the aforementioned three countries has set up its own separate legislatures for Sámi people, even though the three Sámi Parliaments often work together on cross-border issues. In all three countries, they act as an institution of cultural autonomy for the indigenous Sámi people. The parliaments have very weak political influence, far from autonomy. They are formally public authorities, ruled by the Scandinavian governments, but have democratically elected parliamentarians, whose mission is to work for the Sámi people and culture. Candidates' election promises often get into conflict with the institutions' submission under their governments, but as authorities, they have some influence over the government.The main organisations for Sámi representation in Norway are the siidas . They cover northern and central Norway.The main organisations for Sámi representation in Sweden are the siidas . They cover northern and central Sweden.In contrast to Norway and Sweden, in Finland, a siida ( paliskunta in Finnish) is a reindeer-herding corporation that is not restricted by ethnicity. There are indeed some ethnic Finns who practice reindeer herding, and in principle, all residents of the reindeer herding area (most of Finnish Lapland and parts of Oulu province) who are citizens of EEA countries, i.e., the European Union and Norway, Iceland and Liechtenstein , are allowed to join a paliskunta .In 2010, the Sámi Council supported the establishment of a cultural center in Russia for Arctic peoples. The Center for Northern Peoples aims to promote artistic and cultural cooperation between the Arctic peoples of Russia and the Nordic countries, with particular focus on indigenous peoples and minorities. Sápmi, the Sámi traditional lands, cross four national borders. Traditional summer and winter pastures sometimes lie on different sides of the borders of the nation-states. In addition to that, there is a border drawn for modern-day Sápmi . Some state that the rights (for reindeer herding and, in some parts, even for fishing and hunting) include not only modern Sápmi but areas that are beyond today's Sápmi that reflect older territories. Today's "borders" originate from the 14th to 16th centuries when land-owning conflicts occurred. The establishment of more stable dwelling places and larger towns originates from the 16th century and was performed for strategic defence and economic reasons, both by peoples from Sámi groups themselves and more southern immigrants. Owning land within the borders or being a member of a siida (Sámi corporation) gives rights. A different law enacted in Sweden in the mid-1990s gave the right to anyone to fish and hunt in the region, something that was met with skepticism and anger amongst the siidas . Court proceedings have been common throughout history, and the aim from the Sámi viewpoint is to reclaim territories used earlier in history. Due to a major defeat in 1996, one siida has introduced a sponsorship "Reindeer Godfather" concept to raise funds for further battles in courts. These "internal conflicts" are usually conflicts between non-Sámi land owners and reindeer owners. Cases question the Sámi ancient rights to reindeer pastures. In 2010, Sweden was criticized for its relations with the Sámi in the Universal Periodic Review conducted by the Working Group of the Human Rights Council. The question whether the fjeld 's territory is owned by the governments (crown land) or by the Sámi population is not answered. From an indigenous perspective, people "belong to the land", the land does not belong to people, but this does not mean that hunters, herders, and fishing people do not know where the borders of their territories are located as well as those of their neighbors. Although the Sámi have considered themselves to be one people throughout history, the idea of Sápmi, a Sámi nation , first gained acceptance among the Sámi in the 1970s, and even later among the majority population. During the 1980s and 1990s, a Sámi flag was created, a Sámi anthem was written, and the date of a national day was established. The Sámi flag was inaugurated during the Sámi Conference in à re , Sweden, on 15 August 1986. It was the result of a competition for which many suggestions were entered. The winning design was submitted by the artist Astrid Båhl from Skibotn , Norway. The motif (shown right) was derived from the shaman's drum and the poem "Päiven Pārne ' " ("Sons of the Sun") by the South Sámi Anders Fjellner describing the Sámi as sons and daughters of the sun. The flag has the Sámi colours, red, green, yellow and blue, and the circle represents the sun (red) and the moon (blue). The Sámi National Day falls on 6 February as this date was when the first Sámi congress was held in 1917 in Trondheim , Norway. This congress was the first time that Norwegian and Swedish Sámi came together across their national borders to work together to find solutions for common problems. The resolution for celebrating on 6 February was passed in 1992 at the 15th Sámi congress in Helsinki. Since 1993, Norway, Sweden and Finland have recognized 6 February as Sámi National Day. " Sámi soga lávlla " ("Song of the Sámi People", lit. ' Song of the Sámi Family ' ) was originally a poem written by Isak Saba that was published in the newspaper Saǥai Muittalægje for the first time on 1 April 1906. In August 1986, it became the Sámi anthem. Arne Sørli set the poem to music, which was then approved at the 15th Sámi Conference in Helsinki in 1992. " Sámi soga lávlla " has been translated into all of the Sámi languages .The Sámi flag was inaugurated during the Sámi Conference in à re , Sweden, on 15 August 1986. It was the result of a competition for which many suggestions were entered. The winning design was submitted by the artist Astrid Båhl from Skibotn , Norway. The motif (shown right) was derived from the shaman's drum and the poem "Päiven Pārne ' " ("Sons of the Sun") by the South Sámi Anders Fjellner describing the Sámi as sons and daughters of the sun. The flag has the Sámi colours, red, green, yellow and blue, and the circle represents the sun (red) and the moon (blue).The Sámi National Day falls on 6 February as this date was when the first Sámi congress was held in 1917 in Trondheim , Norway. This congress was the first time that Norwegian and Swedish Sámi came together across their national borders to work together to find solutions for common problems. The resolution for celebrating on 6 February was passed in 1992 at the 15th Sámi congress in Helsinki. Since 1993, Norway, Sweden and Finland have recognized 6 February as Sámi National Day." Sámi soga lávlla " ("Song of the Sámi People", lit. ' Song of the Sámi Family ' ) was originally a poem written by Isak Saba that was published in the newspaper Saǥai Muittalægje for the first time on 1 April 1906. In August 1986, it became the Sámi anthem. Arne Sørli set the poem to music, which was then approved at the 15th Sámi Conference in Helsinki in 1992. " Sámi soga lávlla " has been translated into all of the Sámi languages .Many Sámi people continued to practice their religion up until the 18th century. Most Sámi today belong to the state-run Lutheran churches of Norway, Sweden and Finland. Some Sámi in Russia belong to the Russian Orthodox Church , and similarly, some Skolt Sámi resettled in Finland are also part of an Eastern Orthodox congregation, with an additional small population in Norway. Indigenous Sámi religion is a type of polytheism . (See Sámi deities .) There is some diversity due to the wide area that is Sápmi , allowing for the evolution of variations in beliefs and practices between tribes. The beliefs are closely connected to the land, animism , and the supernatural . Sámi spirituality is often characterized by pantheism , a strong emphasis on the importance of personal spirituality and its interconnectivity with one's own daily life, and a deep connection between the natural and spiritual "worlds". Among other roles, the Noaidi , or Sámi shaman , enables ritual communication with the supernatural through the use of tools such as drums, Joik , Fadno , chants, sacred objects, and fly agaric . Some practices within the Sámi religion include natural sacred sites such as mountains, springs, land formations, Sieidi , as well as human-made ones such as petroglyphs and labyrinths . Sámi cosmology divides the universe into three worlds. The upper world is related to the South, warmth, life, and the color white. It is also the dwelling of the gods. The middle world is like the Norse Midgard , it is the dwelling of humans and it is associated with the color red. The third world is the underworld and it is associated with the color black, it represents the north, the cold and it is inhabited by otters, loons, and seals and mythical animals. Sámi religion shares some elements with Norse mythology , possibly from early contacts with trading Vikings (or vice versa). They were the last worshippers of Thor, as late as the 18th century according to contemporary ethnographers. Through a mainly French initiative from Joseph Paul Gaimard as part of his La Recherche Expedition , Lars Levi Læstadius began research on Sámi mythology. His work resulted in Fragments of Lappish Mythology , since by his own admission, they contained only a small percentage of what had existed. The fragments were termed Theory of Gods , Theory of Sacrifice , Theory of Prophecy, or short reports about rumorous Sami magic and Sami sagas . Generally, he claims to have filtered out the Norse influence and derived common elements between the South, North, and Eastern Sámi groups. [ citation needed ] The mythology has common elements with other indigenous religions as well—such as those of indigenous peoples in Siberia and North America . The term Sámi religion usually refers to the traditional religion, practiced by most Sámi until approximately the 18th century. Christianity was introduced by Roman Catholic missionaries as early as the 13th century. Increased pressure came after the Protestant Reformation , and rune drums were burned or sent to museums abroad. In this period, many Sámi practiced their traditional religion at home, while going to church on Sunday. Since the Sámi were considered to possess "witchcraft" powers, they were often accused of sorcery during the 17th century and were the subjects of witchcraft trials and burnings. In Norway, a major effort to convert the Sámi was made around 1720, when Thomas von Westen , the "Apostle of the Sámi", burned drums, burned sacred objects, and converted people. Out of the estimated thousands of drums before this period, only about 70 are known to remain today, scattered in museums around Europe. Sacred sites were destroyed, such as sieidi (stones in natural or human-built formations), álda and sáivu (sacred hills), springs, caves and other natural formations where offerings were made. In the far east of the Sámi area, the Russian monk Trifon converted the Sámi in the 16th century. Today, St. George's chapel in Neiden , Norway (1565), testifies to this effort. Around 1840 Swedish Sámi Lutheran pastor and administrator Lars Levi Laestadius initiated among the Sámi a puritanical pietist movement emphasizing complete abstinence from alcohol . This movement is still very dominant in Sámi-speaking areas. Laestadius spoke many languages, and he became fluent and preached in Finnish and Northern Sámi in addition to his native Southern Sámi and Swedish, the language he used for scholarly publications. Two great challenges Laestadius had faced since his early days as a church minister were the indifference of his Sámi parishioners, who had been forced by the Swedish government to convert from their shamanistic religion to Lutheranism, and the misery caused them by alcoholism. The spiritual understanding Laestadius acquired and shared in his new sermons "filled with vivid metaphors from the lives of the Sámi that they could understand, ... about a God who cared about the lives of the people" had a profound positive effect on both problems. One account from a Sámi cultural perspective recalls a new desire among the Sámi to learn to read and a "bustle and energy in the church, with people confessing their sins, crying and praying for forgiveness ... [Alcohol abuse] and the theft of [the Sámis'] reindeer diminished, which had a positive influence on the Sámi's relationships, finances and family life." Today there are a number of Sámi who seek to return to the traditional Pagan values of their ancestors. There are also some Sámi who claim to be noaidi and offer their services through newspaper advertisements, in New Age arrangements, or for tourist groups. While they practice a religion based on that of their ancestors, widespread anti-pagan prejudice has caused these shamans to be generally not viewed as part of an unbroken Sámi religious tradition. [ citation needed ] Traditional Sámi beliefs are composed of three intertwining elements: animism, shamanism, and polytheism. Sámi animism is manifested in the Sámi's belief that all significant natural objects (such as animals, plants, rocks, etc.) possess a soul; and from a polytheistic perspective, traditional Sámi beliefs include a multitude of spirits. Many contemporary practitioners are compared to practitioners of neo-paganism , as a number of neopagan religions likewise combine elements of ancient pagan religions with more recent revisions or innovations, but others feel they are attempting to revive or reconstruct indigenous Sámi religions as found in historic, folkloric sources and oral traditions. In 2012, County Governor of Troms approved Shamanic Association of Tromsø as a new religion. A very different religious idea is represented by the numerous "wise men" and "wise women" found throughout the Sámi area. They often offer to heal the sick through rituals and traditional medicines and may also combine traditional elements, such as older Sámi teachings, with newer monotheistic inventions that Christian missionaries taught their ancestors, such as readings from the Bible.Indigenous Sámi religion is a type of polytheism . (See Sámi deities .) There is some diversity due to the wide area that is Sápmi , allowing for the evolution of variations in beliefs and practices between tribes. The beliefs are closely connected to the land, animism , and the supernatural . Sámi spirituality is often characterized by pantheism , a strong emphasis on the importance of personal spirituality and its interconnectivity with one's own daily life, and a deep connection between the natural and spiritual "worlds". Among other roles, the Noaidi , or Sámi shaman , enables ritual communication with the supernatural through the use of tools such as drums, Joik , Fadno , chants, sacred objects, and fly agaric . Some practices within the Sámi religion include natural sacred sites such as mountains, springs, land formations, Sieidi , as well as human-made ones such as petroglyphs and labyrinths . Sámi cosmology divides the universe into three worlds. The upper world is related to the South, warmth, life, and the color white. It is also the dwelling of the gods. The middle world is like the Norse Midgard , it is the dwelling of humans and it is associated with the color red. The third world is the underworld and it is associated with the color black, it represents the north, the cold and it is inhabited by otters, loons, and seals and mythical animals. Sámi religion shares some elements with Norse mythology , possibly from early contacts with trading Vikings (or vice versa). They were the last worshippers of Thor, as late as the 18th century according to contemporary ethnographers. Through a mainly French initiative from Joseph Paul Gaimard as part of his La Recherche Expedition , Lars Levi Læstadius began research on Sámi mythology. His work resulted in Fragments of Lappish Mythology , since by his own admission, they contained only a small percentage of what had existed. The fragments were termed Theory of Gods , Theory of Sacrifice , Theory of Prophecy, or short reports about rumorous Sami magic and Sami sagas . Generally, he claims to have filtered out the Norse influence and derived common elements between the South, North, and Eastern Sámi groups. [ citation needed ] The mythology has common elements with other indigenous religions as well—such as those of indigenous peoples in Siberia and North America .The term Sámi religion usually refers to the traditional religion, practiced by most Sámi until approximately the 18th century. Christianity was introduced by Roman Catholic missionaries as early as the 13th century. Increased pressure came after the Protestant Reformation , and rune drums were burned or sent to museums abroad. In this period, many Sámi practiced their traditional religion at home, while going to church on Sunday. Since the Sámi were considered to possess "witchcraft" powers, they were often accused of sorcery during the 17th century and were the subjects of witchcraft trials and burnings. In Norway, a major effort to convert the Sámi was made around 1720, when Thomas von Westen , the "Apostle of the Sámi", burned drums, burned sacred objects, and converted people. Out of the estimated thousands of drums before this period, only about 70 are known to remain today, scattered in museums around Europe. Sacred sites were destroyed, such as sieidi (stones in natural or human-built formations), álda and sáivu (sacred hills), springs, caves and other natural formations where offerings were made. In the far east of the Sámi area, the Russian monk Trifon converted the Sámi in the 16th century. Today, St. George's chapel in Neiden , Norway (1565), testifies to this effort.Around 1840 Swedish Sámi Lutheran pastor and administrator Lars Levi Laestadius initiated among the Sámi a puritanical pietist movement emphasizing complete abstinence from alcohol . This movement is still very dominant in Sámi-speaking areas. Laestadius spoke many languages, and he became fluent and preached in Finnish and Northern Sámi in addition to his native Southern Sámi and Swedish, the language he used for scholarly publications. Two great challenges Laestadius had faced since his early days as a church minister were the indifference of his Sámi parishioners, who had been forced by the Swedish government to convert from their shamanistic religion to Lutheranism, and the misery caused them by alcoholism. The spiritual understanding Laestadius acquired and shared in his new sermons "filled with vivid metaphors from the lives of the Sámi that they could understand, ... about a God who cared about the lives of the people" had a profound positive effect on both problems. One account from a Sámi cultural perspective recalls a new desire among the Sámi to learn to read and a "bustle and energy in the church, with people confessing their sins, crying and praying for forgiveness ... [Alcohol abuse] and the theft of [the Sámis'] reindeer diminished, which had a positive influence on the Sámi's relationships, finances and family life." Today there are a number of Sámi who seek to return to the traditional Pagan values of their ancestors. There are also some Sámi who claim to be noaidi and offer their services through newspaper advertisements, in New Age arrangements, or for tourist groups. While they practice a religion based on that of their ancestors, widespread anti-pagan prejudice has caused these shamans to be generally not viewed as part of an unbroken Sámi religious tradition. [ citation needed ] Traditional Sámi beliefs are composed of three intertwining elements: animism, shamanism, and polytheism. Sámi animism is manifested in the Sámi's belief that all significant natural objects (such as animals, plants, rocks, etc.) possess a soul; and from a polytheistic perspective, traditional Sámi beliefs include a multitude of spirits. Many contemporary practitioners are compared to practitioners of neo-paganism , as a number of neopagan religions likewise combine elements of ancient pagan religions with more recent revisions or innovations, but others feel they are attempting to revive or reconstruct indigenous Sámi religions as found in historic, folkloric sources and oral traditions. In 2012, County Governor of Troms approved Shamanic Association of Tromsø as a new religion. A very different religious idea is represented by the numerous "wise men" and "wise women" found throughout the Sámi area. They often offer to heal the sick through rituals and traditional medicines and may also combine traditional elements, such as older Sámi teachings, with newer monotheistic inventions that Christian missionaries taught their ancestors, such as readings from the Bible.Anthropologists have been studying the Sámi people for hundreds of years for their assumed physical and cultural differences from the rest of the Europeans. Recent genetic studies have indicated that the two most frequent maternal lineages of the Sámi people are the haplogroups V ( Neolithic in Europe and not found in Finland 1500 years ago ) and U5b (ancient in Europe). Y-chromosome haplogroup N-VL29 makes up 20%, came from Siberia 3500 years ago. Y-chromosome N-Z1936 makes up similarly about 20%, and likely came from Siberia with the Sámi language, but slightly later than N-VL29. This tallies with archeological evidence suggesting that several different cultural groups made their way to the core area of Sámi from 8000 to 6000 BC, presumably including some of the ancestors of present-day Sámi. The Sámi have been found to be genetically unrelated to people of the Pitted Ware culture . [lower-alpha 3] The Pitted Ware culture are in turn genetically continuous with the original Scandinavian Hunter-Gatherers . [lower-alpha 4] The genetic makeup of Sámi people has been extensively studied for as long as such research has been in existence. Ethnographic photography of the Sámi began with the invention of the camera in the 19th century. This continued on into the 1920s and 1930s, when Sámi were photographed naked and anatomically measured by scientists, with the help of the local police—sometimes at gunpoint—to collect data that would justify their own racial theories. Thus, there is a degree of distrust by some in the Sámi community towards genetic research. Sámi graves were plundered to provide research materials, of which their remains and artifacts from this period from across Sápmi can still be found in various state collections. In the late 19th century, colonial fascination with Arctic peoples led to human beings exhibited in human zoos . Sámi people were exhibited with their traditional lavvu tents, weapons, and sleds, beside a group of reindeer at Tierpark Hagenbeck and other zoos across the globe.The genetic makeup of Sámi people has been extensively studied for as long as such research has been in existence. Ethnographic photography of the Sámi began with the invention of the camera in the 19th century. This continued on into the 1920s and 1930s, when Sámi were photographed naked and anatomically measured by scientists, with the help of the local police—sometimes at gunpoint—to collect data that would justify their own racial theories. Thus, there is a degree of distrust by some in the Sámi community towards genetic research. Sámi graves were plundered to provide research materials, of which their remains and artifacts from this period from across Sápmi can still be found in various state collections. In the late 19th century, colonial fascination with Arctic peoples led to human beings exhibited in human zoos . Sámi people were exhibited with their traditional lavvu tents, weapons, and sleds, beside a group of reindeer at Tierpark Hagenbeck and other zoos across the globe.

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Bubonic plague

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George Pardee

George Cooper Pardee (July 25, 1857 – September 1, 1941) was an American doctor of medicine and politician . As the 21st Governor of California , holding office from January 7, 1903, to January 9, 1907, Pardee was the second native-born Californian to assume the governorship, after Romualdo Pacheco , and the first governor born in California after statehood.Pardee was born on July 25, 1857, in San Francisco, California , the only child of Enoch H. Pardee and Mary Pardee. The Pardee family was well known in the San Francisco Bay Area . His father was a prominent oculist in San Francisco and Oakland . Enoch's stature within the community helped him get elected to the California State Assembly in the early 1870s, and later as the mayor of Oakland for a single term from 1876 to 1878. Raised in the Pardee Home in Oakland, George Pardee closely followed in his father's medical background. He attended the nearby University of California, Berkeley , then studied medicine at the Cooper Medical College in San Francisco. In 1885, Pardee traveled abroad to receive his medical degree at the University of Leipzig in the German Empire . After his return from Germany, Pardee joined his father's medical practice, specializing in eye and ear diseases. Like his father, Enoch, Pardee also developed an early interest in politics. By the early 1890s, Pardee had become an active member of the Republican Party , and was elected to the Oakland Board of Health and the Oakland City Council . In 1893, following a successful election, Pardee became the 29th mayor of Oakland , serving a single two-year term until 1895. During his mayoralship, Pardee began a public battle with the Southern Pacific Railroad's ownership of the Port of Oakland . At one point, Pardee kicked down a piece of the port's fence erected by the Southern Pacific out of anger. During the San Francisco plague of 1900–1904 , Pardee's quick rise in East Bay politics was noticed by the state Republican leadership prior to the 1902 general elections. Deeply embarrassed and financially hurt by the denials of an ongoing bubonic plague outbreak in San Francisco's Chinatown by Governor Henry Gage , Republicans withdrew their support of Gage during the state convention. The party, divided by Railroad Republicans with the backing of the Southern Pacific Railroad and Reform Republicans of the growing Progressive movement , nominated Pardee, due to his municipal and medical background, as a compromise candidate. Despite clashes in the past with their interests, Southern Pacific Republicans believed Pardee the better candidate against the Democratic contender Franklin K. Lane , a San Francisco City Attorney and an ardent anti-Southern Pacific campaigner. In the 1902 general elections, Pardee faced a four-way race between the Democrats' Lane, Socialist Gideon Brower and Prohibitionist Theodore Kanouse . Pardee barely edged over Lane, winning the governorship with a plurality of 0.9%. Less than 3,000 votes separated the two leading candidates.Pardee took office on January 7, 1903. At the start of his term, Pardee did not fully acknowledge the presence of plague in San Francisco. Preceding his inauguration, the Public Health and Marine Hospital Service act was created by Congress on July 1, 1902. This act established that state health officials could initiate a surgeon general call conference, upon request. Due to the uncertainty and fear of the plague, a conference call was requested by eleven states to discuss the plague situation in California. In response, Walter Wyman , Surgeon General, called for a conference to be held on January 19, 1903, at Washington, D.C. Under the Public Health and Marine Hospital Service law, each state had to send one state health board representative to a surgeon general call conference. The problem for California was that the state health board officers, previously headed by former governor, Henry Gage , strongly denied the presence of the plague. In efforts to rectify this dilemma, Surgeon Arthur H. Glennan from the U.S Public Health Service was tasked with working with the new governor, Pardee. With his efforts, Matthew Gardner, former surgeon-in-chief of Southern Pacific Railroad, was selected to represent California at the conference. San Francisco was the heart of trade and commerce. Due to plague rumors, San Francisco commercial circles were alarmed by the advances of the Northwestern Railway and Northern Pacific Railways success. During this time, Northwestern Railway and Northern Pacific Railways wanted to divert commerce towards the western states. A preliminary meeting was held on January 18, 1903, a day before the conference call. Other state health officials that attended were hostile to Gardner, believing that California health officials were interested more in railroad business. Gardner acknowledged the presence of plague and promised to provide statements from Pardee and San Francisco Mayor Eugene Schmitz , promising to undertake a sanitary campaign and eradication. Pardee promised to fulfill all the conditions the officials wanted. But the officials did not take his promise into consideration and voted to change the location troop transport from San Francisco. On the day of the conference call, Wyman discussed inspection results, revealing no detection of plague. But he also did acknowledge it was not fully eradicated. Many health officials were not happy with this answer and proposed two plans. The first plan pertained to the federal support system, which Wyman objected to. The second plan suggested placing embargoes on California borders, where railroads entered, if health officials were not actively participating in plague eradication. This conference concluded the presence of bubonic plague in California and blamed Governor Henry Gage and his state health board for his negligence in acknowledging and eradicating plague. Wyman, after the conference, firmly stated that acknowledging plague would not affect trade. In hopes to avoid a quarantine, Gardner urged Pardee to recognize bubonic plague in San Francisco. Pardee had won the governor election by a narrow margin. He feared that acknowledging the plague would divide the already split Republican Party. Shortly after his inauguration, Pardee and Glennan met privately. He readily supported the U.S. Public Health Service and agreed to remove state inspectors in Chinatown. Pardee also complied to the resolutions established at the conference. But he continued to avoid directly addressing the presence of plague. He stated any disease regardless of plague required sanitary control. Wyman believed Pardee's stance did not reassure the country health officials and urged Glennan to address the issue again with Pardee and Mayor Schmitz. He believed that acknowledging the presence of plague would ease health officials and foreign countries' fear. Pardee continued to elude the topic of plague but continued to work with the government. On the other hand, Schmitz continued to deny plague existence. The unrest caused by the government and San Francisco Health Board lead to Mexico and Australia to ban San Francisco goods. This ban encouraged more cooperation with Seattle and Vancouver. San Francisco businesses established the Mercantile Joint Committee to promote sanitary and preventive measures, in an effort to prove that plague did not exist. The Mercantile Joint Committee were concerned that officially admitting plague would result in a quarantine, leading to decreased trade and commerce. Merchants continued to ignore Wyman, who was still adamant about officially acknowledging plague. Finally, Glennan stated that if there was no official address regarding plague, the U.S Public Health Service would withdraw from San Francisco. This forced the Mercantile Joint Committee to formally admit that there had been ninety three plague cases over the span of 3 years. They also asked for the support from Schmitz and Pardee to officially admit that there was no current risk or danger from plague. Schmitz was the first to sign this document. Pardee, who was resistant to this, eventually signed it. With this in place, Wyman reported that there were no new outbreaks of plague since December 1902 and Chinatown had met satisfactory sanitary conditions to business leaders. This news encouraged Mexico and other foreign countries to lift the embargoes. Under Pardee's orders, new officials were appointed for the State Health Board. His administration was now focused on being transparent and would acknowledge all plague cases. Pardee welcomed health officials to visit California and provide input regarding sanitation and sanitary conditions. On September 8, the first California State, County, and Municipal Sanitary Conference was held in San Francisco. This first meeting was able to create a community where sanitary information and preventative measures could be shared. By the end of 1904, the plague had been brought under control. Nearly 200 deaths were attributed to the outbreak. During his medical studies in the German Empire , Pardee was greatly influenced by Germany's push for higher education and environmental conservation during its rapid industrialization . Throughout his administration, Pardee strongly supported irrigation projects and waterworks throughout the Central Valley with the desire of increasing the state's agricultural output and providing safe drinking water from the Sierra Nevada . Pardee's progressive ideas regarding conservation and distrust of corporate monopolies quickly placed him as an ally of President Theodore Roosevelt . Both the governor and President Roosevelt enjoyed a good working relationship during their respective terms of office on the state and federal levels. On a visit to California in 1903, Pardee was asked by Roosevelt if he would be his running mate as Vice President for the 1904 presidential election . Pardee declined, instead continuing to take an active role in state politics. Both Pardee and Roosevelt remained political allies for the next decade. Since 1901, proposals for a state agricultural school had undergone discussion within the California State Legislature , yet no proposal had gained a serious following. Most agricultural studies in the state during the period were concentrated at UC Berkeley , but due to the climate of Berkeley , most studies remained strictly limited to organic and soil chemistry study and analysis. In 1903, an agricultural bill sponsoring a state agricultural school to give first-hand experience for future farmers passed the legislature. Pardee vetoed the bill, explaining that he was not hostile to the idea of an agricultural school, but wanted a less vague proposal. The Legislature drafted a more detailed bill, the University Farm Bill, in 1905. In it, the bill specified that a future state agricultural school would need a location already irrigated, with provisions for ideal soil and climatic conditions, as well as water and land rights. Pardee agreed, and signed the bill into law. For the next year, an agricultural commission sponsored by Pardee investigated more than fifty sites from Glenn County to Fresno . In 1906, Pardee announced that he decided upon Davisville in Yolo County , located nearly fifteen miles southwest of the state capital of Sacramento . Opened to students in 1908, the School of Agriculture quickly became one of the premier centers of agricultural study in the state. In 1959, the Regents of the University of California granted the school campus autonomy, designating it UC Davis . The state of California's forests also came under Pardee's agenda. Shortly after the beginning of his administration, Pardee, with the help of Gifford Pinchot , ordered a joint state and federal commission to inspect and survey California's forests. In 1905, a State Forestry Act was passed by the legislature and signed by the governor, creating a Board of Forestry to monitor and supervise logging , land usage, and forest fires. The act, along with Pinchot's advocacy, helped influence President Roosevelt to transfer federal forest land over to the U.S. Department of Agriculture , later becoming the National Forest Service . Pardee's own Board of Forestry would later evolve into the California Department of Forestry and Fire Protection . In the early morning hours of April 18, 1906, a magnitude 7.7 to 8.3 earthquake struck along the San Andreas Fault , with an epicenter two miles (three km) from San Francisco , near Mussel Rock in neighboring San Mateo County . While cities as spread as Santa Rosa , San Jose and Palo Alto suffered considerable damage, San Francisco remained hardest hit, with resulting fires destroying much of the central core of the city. As telegraphed reports slowly filtered into the Governor's Office in Sacramento, Pardee mobilized the California Army National Guard to be dispatched to San Francisco, though Pardee was unaware that federal troops of the U.S. Army , under the command Brigadier General Frederick Funston , were already patrolling the streets. Pardee sought to take command of the situation himself, traveling to his native Oakland in the later afternoon to oversee the state response to the disaster. Making his headquarters in Oakland Mayor Frank K. Mott's office, Pardee worked twenty-hour days during the disaster, signing travel permission papers, coordinating state and federal relief funds and trains, and remaining in contact with the outside world through Oakland's undamaged telegraph lines. In addition, Pardee also visited other afflicted cities, such as San Jose and Santa Rosa, to tour and coordinate their own disaster responses. Despite having been heavily praised by the public for his handling of the state bureaucracy during the 1906 disaster , Pardee continued to have a strained relationship with the Southern Pacific Railroad , one that had been ongoing since the 1890s while he was Mayor of Oakland. Pardee's role in the burgeoning Progressive movement which distrusted large corporate monopolies, as well as his efforts to conserve and protect state forests, remained a constant thorn for Southern Pacific executives. A lengthy bitter battle over the Port of Oakland , which Pardee argued on behalf of Oakland that the port was a municipal rather than private corporation, dragged out for much of his governorship. The case was decided upon by the California Supreme Court in 1906, ruling in Oakland's favor. Pardee also encouraged creation of new railroad companies to break the Southern Pacific's monopolies. At the state Republican convention in Santa Cruz to nominate the party's candidate for the governorship in the 1906 general elections, Railroad Republicans led by party machine boss Abe Ruef , sought to strip Pardee of the nomination. Southern Pacific interests within the Republicans believed Pardee as too independent and troublesome. Writing in the San Francisco Chronicle on September 1, 1906, Pardee commented that "[I]t is evident that the Railroad machine and [Abe] Ruef did not want me to be governor again, and as they were in control of the convention, what kick have I coming?" Railroad Republicans, now dominating the Santa Cruz convention due to intense lobbying by Ruef, denied Pardee the nomination. Instead, Republicans and Southern Pacific supporters nominated U.S. House Representative James Gillett , a pro-railroad supporter. Pardee's loss of the nomination sparked anger amongst many Progressive Republican circles, fueling desires for Progressives to reform the political nomination process or to break away from the Republicans altogether. In 1912, a party split occurred with the creation of the Bull Moose Party , led by Theodore Roosevelt and California Governor Hiram Johnson , who himself would lead Progressives to control the legislature and Governor's Office throughout much of the 1910s. In his farewell address to the California State Legislature in January 1907, Pardee demanded that the legislature take up calls for creating a direct primary law.During his medical studies in the German Empire , Pardee was greatly influenced by Germany's push for higher education and environmental conservation during its rapid industrialization . Throughout his administration, Pardee strongly supported irrigation projects and waterworks throughout the Central Valley with the desire of increasing the state's agricultural output and providing safe drinking water from the Sierra Nevada . Pardee's progressive ideas regarding conservation and distrust of corporate monopolies quickly placed him as an ally of President Theodore Roosevelt . Both the governor and President Roosevelt enjoyed a good working relationship during their respective terms of office on the state and federal levels. On a visit to California in 1903, Pardee was asked by Roosevelt if he would be his running mate as Vice President for the 1904 presidential election . Pardee declined, instead continuing to take an active role in state politics. Both Pardee and Roosevelt remained political allies for the next decade. Since 1901, proposals for a state agricultural school had undergone discussion within the California State Legislature , yet no proposal had gained a serious following. Most agricultural studies in the state during the period were concentrated at UC Berkeley , but due to the climate of Berkeley , most studies remained strictly limited to organic and soil chemistry study and analysis. In 1903, an agricultural bill sponsoring a state agricultural school to give first-hand experience for future farmers passed the legislature. Pardee vetoed the bill, explaining that he was not hostile to the idea of an agricultural school, but wanted a less vague proposal. The Legislature drafted a more detailed bill, the University Farm Bill, in 1905. In it, the bill specified that a future state agricultural school would need a location already irrigated, with provisions for ideal soil and climatic conditions, as well as water and land rights. Pardee agreed, and signed the bill into law. For the next year, an agricultural commission sponsored by Pardee investigated more than fifty sites from Glenn County to Fresno . In 1906, Pardee announced that he decided upon Davisville in Yolo County , located nearly fifteen miles southwest of the state capital of Sacramento . Opened to students in 1908, the School of Agriculture quickly became one of the premier centers of agricultural study in the state. In 1959, the Regents of the University of California granted the school campus autonomy, designating it UC Davis . The state of California's forests also came under Pardee's agenda. Shortly after the beginning of his administration, Pardee, with the help of Gifford Pinchot , ordered a joint state and federal commission to inspect and survey California's forests. In 1905, a State Forestry Act was passed by the legislature and signed by the governor, creating a Board of Forestry to monitor and supervise logging , land usage, and forest fires. The act, along with Pinchot's advocacy, helped influence President Roosevelt to transfer federal forest land over to the U.S. Department of Agriculture , later becoming the National Forest Service . Pardee's own Board of Forestry would later evolve into the California Department of Forestry and Fire Protection .In the early morning hours of April 18, 1906, a magnitude 7.7 to 8.3 earthquake struck along the San Andreas Fault , with an epicenter two miles (three km) from San Francisco , near Mussel Rock in neighboring San Mateo County . While cities as spread as Santa Rosa , San Jose and Palo Alto suffered considerable damage, San Francisco remained hardest hit, with resulting fires destroying much of the central core of the city. As telegraphed reports slowly filtered into the Governor's Office in Sacramento, Pardee mobilized the California Army National Guard to be dispatched to San Francisco, though Pardee was unaware that federal troops of the U.S. Army , under the command Brigadier General Frederick Funston , were already patrolling the streets. Pardee sought to take command of the situation himself, traveling to his native Oakland in the later afternoon to oversee the state response to the disaster. Making his headquarters in Oakland Mayor Frank K. Mott's office, Pardee worked twenty-hour days during the disaster, signing travel permission papers, coordinating state and federal relief funds and trains, and remaining in contact with the outside world through Oakland's undamaged telegraph lines. In addition, Pardee also visited other afflicted cities, such as San Jose and Santa Rosa, to tour and coordinate their own disaster responses.Despite having been heavily praised by the public for his handling of the state bureaucracy during the 1906 disaster , Pardee continued to have a strained relationship with the Southern Pacific Railroad , one that had been ongoing since the 1890s while he was Mayor of Oakland. Pardee's role in the burgeoning Progressive movement which distrusted large corporate monopolies, as well as his efforts to conserve and protect state forests, remained a constant thorn for Southern Pacific executives. A lengthy bitter battle over the Port of Oakland , which Pardee argued on behalf of Oakland that the port was a municipal rather than private corporation, dragged out for much of his governorship. The case was decided upon by the California Supreme Court in 1906, ruling in Oakland's favor. Pardee also encouraged creation of new railroad companies to break the Southern Pacific's monopolies. At the state Republican convention in Santa Cruz to nominate the party's candidate for the governorship in the 1906 general elections, Railroad Republicans led by party machine boss Abe Ruef , sought to strip Pardee of the nomination. Southern Pacific interests within the Republicans believed Pardee as too independent and troublesome. Writing in the San Francisco Chronicle on September 1, 1906, Pardee commented that "[I]t is evident that the Railroad machine and [Abe] Ruef did not want me to be governor again, and as they were in control of the convention, what kick have I coming?" Railroad Republicans, now dominating the Santa Cruz convention due to intense lobbying by Ruef, denied Pardee the nomination. Instead, Republicans and Southern Pacific supporters nominated U.S. House Representative James Gillett , a pro-railroad supporter. Pardee's loss of the nomination sparked anger amongst many Progressive Republican circles, fueling desires for Progressives to reform the political nomination process or to break away from the Republicans altogether. In 1912, a party split occurred with the creation of the Bull Moose Party , led by Theodore Roosevelt and California Governor Hiram Johnson , who himself would lead Progressives to control the legislature and Governor's Office throughout much of the 1910s. In his farewell address to the California State Legislature in January 1907, Pardee demanded that the legislature take up calls for creating a direct primary law.Leaving the governorship in 1907, he returned to serve on many national and state boards, including the National Conservation Commission and the California Board of Forestry. Pardee remained publicly active, returning to his native Oakland to become a co-founder of the state Bull Moose Party in 1912. In 1920, he was invited to become Commodore of the Oakland Yacht Club , a position he would enjoy again from 1925 to 1928. In the years following his governorship, Pardee lobbied intensely for a water district specifically for the East Bay . In 1921, the legislature passed the Municipal Utility District Act, and two years later, the East Bay Municipal Utility District (EBMUD) was organized. Pardee would administer EBMUD from 1924 until shortly before his death in 1941. In 1927, Oakland citizens awarded Pardee as a founding commissioner to the Port of Oakland due to his lengthy battle to remove the Southern Pacific monopoly over the waterfront. Pardee died in Oakland on September 1, 1941, at the age of 84.Pardee met his future wife Helen N. Pardee at Oakland High School in the 1870s, graduating together in 1875. Helen was a school teacher, photographer, and art collector. The Pardees had four daughters, Florence, Caroline, Madeline and Helen. Florence Pardee was killed in a car accident in 1910. Caroline Pardee died from the Spanish flu in 1920. Surviving daughters Madeline and Helen would continue to own and live in the family's Pardee Home until Helen Pardee's death in 1981. The Pardee Home opened as a public museum in 1991.Unlike his predecessor Henry Gage and his successor James Gillett , Pardee's governorship has been generally well regarded amongst historians. His efforts of conservation and education have proved to be long standing, such as the creations of bodies that would later become UC Davis and the California Department of Forestry and Fire Protection . Despite their initial support of his nomination in 1902, Pardee's near-constant resistance to the Southern Pacific Railroad has spared his reputation of criticism for being too close to rail monopolies. State historians from the California Secretary of State's office wrote that between Gage, Pardee and Gillett, "only Pardee can be considered an honest earnest administrator." Environmental historian Philip L. Fradkin has cited Pardee as one of the unsung heroes of the 1906 San Francisco earthquake . "Pardee lacked a glamorous frontline role, and he was criticized for not dashing in the flame-licked streets. With a large staff imported from Sacramento , the governor was the expediter of paper; in every great disaster there needs to be at least one such competent bureaucrat." Pardee was also the first governor to reside in the California Governor's Mansion . The mansion would continue to be lived in by the state executive until the governorship of Ronald Reagan . The Pardee Home , located in downtown Oakland, remains a tourist attraction in the center of the city, hosting tours and speaking events. The Pardee Dam and the adjacent Pardee Reservoir along the Mokelumne River are named after the governor. The old Governor's Office within the California State Capitol is refurbished to appear as it did during the time of George Pardee's governorship in 1906.

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Bubonic plague

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Operation PX

Second Sino-Japanese War Operation PX , also known as Operation Cherry Blossoms at Night , was a planned Japanese military attack on civilians in the United States using biological weapons , devised during World War II . The proposal was for Imperial Japanese Navy submarines to launch seaplanes that would deliver weaponized bubonic plague , developed by Unit 731 of the Imperial Japanese Army , to the West Coast of the United States . The operation was abandoned shortly after its planning was finalized in March 1945 due to the strong opposition of General Yoshijirō Umezu , Chief of the Army General Staff .Operation PX was proposed in December 1944 by the Japanese Naval General Staff, led by Vice-Admiral Jisaburō Ozawa . The name for the operation came from the Japanese use of the code name PX for Pestis bacillus -infected fleas. In planning the operation, the navy partnered with Lieutenant-General Shirō Ishii of Unit 731 , who had extensive experience on weaponizing pathogenic bacteria and human vulnerability to biological and chemical warfare. The plan for the attack involved Seiran aircraft launched by submarine aircraft carriers upon the West Coast of the United States—specifically, the cities of San Diego, Los Angeles, and San Francisco. The planes would spread weaponized bubonic plague , cholera , typhus , dengue fever , and other pathogens in a biological terror attack upon the population. The submarine crews would infect themselves and run ashore in a suicide mission. Planning for Operation PX was finalized on March 26, 1945, but shelved shortly thereafter due to the strong opposition of Chief of General Staff Yoshijirō Umezu . Umezu later explained his decision as such: "If bacteriological warfare is conducted, it will grow from the dimension of war between Japan and America to an endless battle of humanity against bacteria. Japan will earn the derision of the world." A final planned use of the biological weapons came just after the surrender of Japan , as Shirō Ishii planned to stage suicide germ attacks against U.S. occupation troops in Japan. This planned attack never took place either, due to opposition from Yoshijirō Umezu and Torashirō Kawabe , who did not want Ishii to die in a suicide attack, and asked him to instead "wait for [the] next opportunity calmly". After the war, Operation PX was first discussed in an interview by former captain Eno Yoshio, who was heavily involved with planning for the attack, in an interview with Sankei on August 14, 1977. According to Yoshio, "This is the first time I have said anything about Operation PX, because it involved the rules of war and international law. The plan was not put into actual operation, but I felt that just the fact that it was formulated would caused [ sic ] international misunderstanding. I never even leaked anything to the staff of the war history archives at the Japanese Defense Agency, and I don't feel comfortable talking about it even now. But at the time, Japan was losing badly, and any means to win would have been all right."

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Bubonic plague

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Second plague pandemic

The second plague pandemic was a major series of epidemics of plague that started with the Black Death , which reached medieval Europe in 1346 and killed up to half of the population of Eurasia in the next four years. It followed the first plague pandemic that began in the 6th century with the Plague of Justinian , but had ended in the 8th century. Although the plague died out in most places, it became endemic and recurred regularly. A series of major epidemics occurred in the late 17th century, and the disease recurred in some places until the late 18th century or the early 19th century. After this, a new strain of the bacterium gave rise to the third plague pandemic , which started in Asia around the mid-19th century. Plague is caused by the bacterium Yersinia pestis , which exists in parasitic fleas of several species in the wild and of rats in human society. In an outbreak, it may kill all of its immediate hosts and thus die out, but it can remain active in other hosts that it does not kill, thereby causing a new outbreak years or decades later.There have been three major outbreaks of plague. The Plague of Justinian in the 6th and 7th centuries is the first known attack on record, and marks the first firmly recorded pattern of plague . From historical descriptions, as much as 40% of the population of Constantinople died from the plague. Modern estimates suggest that half of Europe's population died as a result of this first plague pandemic before it disappeared in the 700s. After 750, plague did not appear again in Europe until the Black Death of the 14th century. The second pandemic's origins are disputed; it originated either in Central Asia or Crimea, and appeared in Crimea by 1347. It may have reduced the world population from an estimated 450 million to 350–375 million by the year 1400. Evidence for Yersinia pestis was found in the teeth of early plague victims in the Tian Shan mountains , now northern Kyrgyzstan , indicating a likely origin of that iteration of the plague. The plague returned at intervals with varying virulence and mortality until the early 19th century. In England, for example, the plague returned between 1360 and 1363, killing 20% of Londoners, and then again in 1369, killing 10–15%. In the 16th century, the plague hit San Cristóbal de La Laguna in the Canary Islands between 1582 and 1583. In the 17th century, there were a series of European "great plague" outbreaks: the Great Plague of Seville between 1647 and 1652, the Great Plague of London between 1665 and 1666, and the Great Plague of Vienna in 1679. The great plague of northern China arose in Shanxi in 1633 and arrived at Beijing in 1641, contributing to the downfall of the Ming Dynasty in 1644. [ citation needed ] In the 18th century, there was the Great Plague of Marseille , which took place between 1720 and 1722; the Great Plague of 1738 , which occurred in Eastern Europe between 1738 and 1740; and the Russian plague of 1770–1772 , which took place in Central Russia and particularly affected Moscow. However, the plague in its virulent form seemed to gradually disappear from Europe, though lingering in Egypt and the Middle East. [ citation needed ] By the early 19th century, the threat of plague had diminished, though it was quickly replaced by the spread of another deadly infectious disease in the first cholera pandemic , beginning in 1817, the first of several cholera pandemics to sweep through Asia and Europe during the 19th and 20th centuries. The third plague pandemic hit China in the 1890s and devastated India. While it was largely contained in the East, it became endemic in the western United States, where sporadic outbreaks of plague continue to occur. Arab historians Ibn Al-Wardi and Almaqrizi believed the Black Death originated in Mongolia , and Chinese records show a huge outbreak in Mongolia in the early 1330s. In recent years, more research has emerged that shows the Black Death most likely originated on the northwestern shores of the Caspian Sea , and may not even have reached India and China, as research on the Delhi Sultanate and the Yuan Dynasty showed no evidence of any serious epidemic in 14th-century India and no specific evidence of plague in 14th-century China. There were large epidemics in China in 1331 and between 1351 and 1354 in the provinces of Hebei , Shanxi , and others, which are considered to have killed between 50% and 90% of the local populations, with numbers running into the tens of millions. However, there is no proof currently that these were caused by plague, though there are indications for the second set of epidemics. Europe was initially protected by a hiatus in the Silk Road . [ citation needed ] Plague was reportedly first introduced to Europe via Genoese traders from their port city of Kaffa in Crimea in 1347. During a protracted siege of the city , between 1345 and 1346, the Mongol Golden Horde army of Jani Beg , whose mainly Tatar troops were suffering from the disease, catapulted infected corpses over the city walls of Kaffa to infect the inhabitants, though it is more likely that infected rats travelling across the siege lines spread the epidemic to the inhabitants. As the disease took hold, Genoese traders fled across the Black Sea to Constantinople , where the disease first arrived in Europe in summer 1347. The epidemic there killed the 13-year-old son of the Byzantine emperor , John VI Kantakouzenos , who wrote a description of the disease modelled on Thucydides ' account of the 5th-century BCE Plague of Athens , but noting the spread of the Black Death by ship between maritime cities. Nicephorus Gregoras also described in writing to Demetrios Kydones the rising death toll, the futility of medicine against it, and the panic of the citizens. It arrived at Genoa and Venice in January 1348, while simultaneously spreading through Asia Minor and into Egypt. The bubonic form was described graphically in Florence in The Decameron and Guy de Chauliac also described the pneumonic form at Avignon . It rapidly spread to France and Spain and, by 1349, was in England. In 1350, it was afflicting Eastern Europe and had reached the centre of Russia by 1351. [ citation needed ] The 14th-century eruption of the Black Death had a drastic effect on Europe's population, irrevocably changing its social structures, and resulted in the widespread persecution of minorities such as Jews , foreigners, beggars, and lepers . The uncertainty of daily survival has been seen as creating a general mood of morbidity , influencing people to "live for the moment", as illustrated by Giovanni Boccaccio in The Decameron (1353). Petrarch , noting the unparalleled and unbelievable extremity of the disease's effects, wrote that "happy posterity, who will not experience such abysmal woe ... will look upon our testimony as a fable". The second pandemic spread throughout Eurasia and the Mediterranean Basin . The plague repeatedly returned to haunt Europe and the Mediterranean Basin throughout the 16th to 17th centuries. The plague ravaged much of the Islamic world . Plague was present in at least one location in the Islamic world virtually every year between 1500 and 1850. According to Jean-Noel Biraben, plague was present somewhere in Europe in every year between 1346 and 1671. According to Ellen Schiferl, between 1400 and 1600, there was a plague epidemic recorded in at least one part of Europe for every year except 1445. In the Byzantine Empire , the 1347 Black Death outbreak in Constantinople lasted a year, but plague recurred ten times before 1400. Plague was repeatedly reintroduced to the city because of its strategic location between the Mediterranean Sea and the Black Sea , and between Europe and Asia, as well as its position as the imperial capital. Constantinople retained its imperial status at the centre of the Ottoman Empire after the Fall of Constantinople to Mehmed the Conqueror in 1453. Approximately 1–2% of the city's population died annually of plague. Especially severe episodes were recorded by the Ottoman historians Mustafa Âlî and Hora Saadettin between 1491 and 1503, with 1491 through 1493 being the most afflicted years. Plague returned in 1511 until 1514 and, after 1520, was endemic in the city until 1529. Plague was endemic in Constantinople again between 1533 and 1549, 1552 and 1567, and for most of the remaining 16th-century. In the 17th century, plague epidemics within Constantinople were noted in the following years: 1603, 1611 to 1613, 1647 to 1649, 1653 to 1656, 1659 to 1688, 1671 to 1680, 1685 to 1695, and 1697 to 1701. [ citation needed ] In the 18th century, there were 64 years in which plague broke out in the capital, and a further 30 plague years which occurred in the first half of the 19th century. Of these later 94 plague epidemics in Constantinople between 1700 and 1850, six of them—occurring in 1705, 1726, 1751, 1778, 1812, and 1836—are estimated to have killed more than 5% of the population, whereas 83 of the epidemics killed 1% or fewer. [ clarification needed ] Plague repeatedly struck the cities of North Africa. Between 1620 and 1621, Algiers lost 30,000–50,000 people to it, with outbreaks returning in 1654 to 1657, 1665, 1691, and 1740 to 1742. Plague remained a major event in Ottoman society until the second quarter of the 19th century. Between 1701 and 1750, 37 large-scale and smaller epidemics were recorded in Constantinople, with a further 31 occurring between 1751 and 1800. The Great Plague of 1738 affected Ottoman territory in the Balkans , lasting until 1740. [ citation needed ] Baghdad suffered severely from visitations of the plague, with outbreaks reducing the population to one-third of its size by 1781. One of the last epidemics to strike the Balkans during the second plague pandemic was Caragea's plague , between 1813 and 1814. Swiss explorer Johann Ludwig Burckhardt witnessed the plague epidemics that ravaged Hejaz and Egypt between 1812 and 1816. He wrote: "In five or six days after my arrival [in Yanbu ] the mortality increased; forty or fifty persons died in a day, which, in a population of five or six thousand, was a terrible mortality." Although regular outbreaks of disease were common for decades prior to 1618, the Thirty Years' War (1618–48) greatly accelerated their spread. Based on local records, military action accounted for less than 3% of civilian deaths; the major causes were starvation (12%) and bubonic plague (64%). The modern consensus is that the population of the Holy Roman Empire declined from 18–20 million in 1600 to 11–13 million in 1650, and did not regain pre-war levels until 1750. The Great Plague of Vienna struck Vienna, the dynastic seat of the Holy Roman Empire, in 1679, killing an estimated 76,000 people. Emperor Leopold I fled the city upon the outbreak, but vowed to erect a Marian column in thanksgiving if the plague would end. Vienna's Plague Column , located on the Graben , was commissioned in 1683 and inaugurated in 1694. [ citation needed ] By 1357, the plague had returned to Venice, and from 1361 to 1363, the rest of Italy experienced the first recurrence of the pandemic. Pisa , Pistoia and Florence in Tuscany were especially badly affected; there pesta secunda , ' second pestilence ' killed a fifth of the population. In the pesta tertia , ' third pestilence ' of 1369 to 1371, 10–15% died. Survivors were aware that the Black Death of 1347–51 was not a unique event and that life was now "far more frightening and precarious than before". The Italian peninsula was struck with an outbreak of plague in 68% of the years between 1348 and 1600. There were 22 outbreaks of plague in Venice between 1361 and 1528. Petrarch , writing to Giovanni Boccaccio in September 1363, lamented that while the Black Death's arrival in Italy in 1348 had been mourned as an unprecedented disaster, "Now we realize that it is only the beginning of our mourning, for since then this evil force, unequalled and unheard of in human annals through the centuries, has never ceased, striking everywhere on all sides, on the left and right, like a skilled warrior." In the Jubilee Year of 1400, announced by Pope Boniface IX , one of the most severe occurrences of plague was exacerbated by the many pilgrims making their way to and from Rome; in the city itself 600–800 died daily. As recorded by the undertakers' records in Florence, at least 10,406 people died; the total death toll was estimated at twice that figure by 15th-century chronicler Giovanni Morelli. Half of the population of Pistoia and its hinterland were killed that year. Another outbreak occurred in Padua in 1405 and claimed 18,000 lives. In the plague epidemic of 1449–52, 30,000 Milanese died in 1451 alone. A particularly deadly plague struck Italy between 1478 and 1482. The territories of the Republic of Venice saw 300,000 dead in the epidemic's eight-year course. Luca Landucci wrote in 1478 that the citizens of Florence "were in a sorry plight. They lived in dread, and no one had any heart to work. The poor creatures could not procure silk or wool ... so that all classes suffered." In addition to plague, Florence was suffering both from excommunication leading to war with the Papal States and from the political strife following the Pazzi conspiracy . In 1479, the plague broke out in Rome; Bartolomeo Platina , the head of the Vatican Library was killed, and Pope Sixtus IV fled the city and was absent for more than a year. Federico da Montefeltro , Duke of Urbino , also died. Following the Sack of Rome in 1527 by Charles V, Holy Roman Emperor , plague broke out in both Rome and Florence. The plague emerged in Rome and killed 30,000 Florentines—a quarter of the city's inhabitants. The Description of the Plague at Florence in the Year 1527 , by Lorenzo di Filippo Strozzi , records this plague in detail; it was copied out by Niccolò Machiavelli with annotations by Strozzi. He wrote: Our pitiful Florence now looks like nothing but a town which has been stormed by infidels and then forsaken. One part of the inhabitants ... have retired to distant country houses, one part is dead, and yet another part is dying. Thus the present is torment, the future menace, so we contend with death and only live in fear and trembling. The clean, fine streets which formerly teemed with rich and noble citizens are now stinking and dirty; crowds of beggars drag themselves through them with anxious groans and only with difficulty and dread can one pass them. Shops and inns are closed, at the factories work has ceased, the law courts are empty, the laws are trampled on. Now one hears of some theft, now of some murder. The squares, the market places on which citizens used frequently to assemble, have now been converted into graves and into the resort of the wicked rabble. ... If by chance relations meet, a brother, a sister, a husband, a wife, they carefully avoid each other. What further words are needed? Fathers and mothers avoid their own children and forsake them. ... A few provision stores are still open, where bread is distributed, but where in the crush plague boils are also spread. Instead of conversation ... one hears now only pitiful, mournful tidings – such a one is dead, such a one is sick, such a one has fled, such a one is interned in his house, such a one is in hospital, such a one has nurses, another is without aid, such like news which by imagination alone would suffice to make Aesculapius sick. Further plague epidemics accompanied the Siege of Florence in 1529; there, religious buildings became hospitals and 600 temporary structures were built to house the infected outside the city walls. After 1530, political strife calmed and warfare in Italy became less frequent. Subsequently, plague outbreaks became more rare, affecting only individual cities or regions, but were particularly severe. In the 43 years between 1533 and 1575, there were 18 epidemics of plague. The especially damaging Italian plague of 1575–78 travelled both north and southwards through the peninsula from either end; the death toll was particularly high. By official reckoning, Milan lost 17,329 to plague in 1576, while Brescia recorded 17,396 killed in a town that did not exceed 46,000 total inhabitants. Venice, meanwhile, saw between a quarter and a third of its population die of plague in the epidemic of 1576–77 with 50,000 deaths. In the first half of the 17th century, a plague claimed some 1.7 million victims in Italy, or about 14% of the population. The Great Plague of Milan (1629–31) was possibly the most disastrous of the century: the city of Milan lost half its population of about 100,000, while Venice was as afflicted as in its severe 1553–56 outbreak. The Italian Plague of 1656–57 was the last major catastrophic plague in Italy, with the Naples Plague the most severe. In 1656, the plague killed about half of Naples 's 300,000 inhabitants. Messina saw the last epidemic in Italy, in 1742–44. The final recorded incidence of plague in Italy was in 1815–16, when plague broke out in Noja, a town near Bari . Over 60% of Norway's population died from 1348 to 1350. The last plague outbreak ravaged Oslo in 1654. In Russia, the disease hit somewhere once every five or six years from 1350 to 1490. In 1654, the Russian plague killed about 700,000 inhabitants. In 1709–13, a plague epidemic followed the Great Northern War (1700–1721), between Sweden and the Tsardom of Russia and its allies, killing about 100,000 in Sweden and 300,000 in Prussia . The plague killed two-thirds of the inhabitants of Helsinki , and claimed a third of Stockholm 's population. This was the last plague in Scandinavia, but the Russian plague of 1770–1772 killed up to 100,000 people in Moscow . The 1560s European wave of the plague first hit Lithuania and Russian Pskov in 1564-1565 but didn't progress further east until 1566, when it ravaged in Muscovian lands already suffering from the Livonian War and the Oprichnina . It made a pause until hitting even harder in two waves in 1569-1570 and 1571-1572, which, combined with concurrent famine, may have killed between a third and a quarter of Russian population. The Great Plague of 1738 was a pandemic of plague lasting 1738–40 and affecting areas in the modern nations of Romania , Hungary , Ukraine , Serbia , Croatia , and Austria . The Russian plague epidemic of 1770-1772 killed as many as 100,000 people in Moscow alone, with thousands more dying in the surrounding countryside. In 1466, perhaps 40,000 people died of plague in Paris. During the 16th and 17th centuries, plague visited Paris nearly once every three years on average. According to historian Geoffrey Parker , " France alone lost almost a million people to plague in the epidemic of 1628–31." Western Europe's last major epidemic occurred in 1720 in Marseilles . Plague epidemics ravaged London in the 1563 London plague , in 1593, 1603, 1625, 1636, and 1665, reducing its population by 10 to 30% during those years. The 1665–66 Great Plague of London was the final major epidemic of the pandemic, with the last death of plague in the walled City of London recorded fourteen years later in 1679. [ citation needed ] Over 10% of Amsterdam 's population died in 1623–25, and again in 1635–36, 1655, and 1664. More than 1.25 million deaths resulted from the extreme incidence of plague in 17th-century Spain . The plague of 1649 probably reduced the population of Seville by half. Malta suffered from a number of plague outbreaks during the second pandemic between the mid-14th and early 19th centuries. The most severe outbreak was the epidemic of 1675–1676 , which killed around 11,300 people, followed by the epidemic of 1813–1814 and that of 1592–1593 , which killed around 4,500 and 3,000 people respectively. The 1582 Tenerife plague epidemic (also 1582 San Cristóbal de La Laguna plague epidemic) was an outbreak of bubonic plague that occurred between 1582 and 1583 on the island of Tenerife , Spain. It is currently believed to have caused between 5,000 and 9,000 deaths on an island with fewer than 20,000 inhabitants at that time (approximately 25-45% of the island's population). In the Byzantine Empire , the 1347 Black Death outbreak in Constantinople lasted a year, but plague recurred ten times before 1400. Plague was repeatedly reintroduced to the city because of its strategic location between the Mediterranean Sea and the Black Sea , and between Europe and Asia, as well as its position as the imperial capital. Constantinople retained its imperial status at the centre of the Ottoman Empire after the Fall of Constantinople to Mehmed the Conqueror in 1453. Approximately 1–2% of the city's population died annually of plague. Especially severe episodes were recorded by the Ottoman historians Mustafa Âlî and Hora Saadettin between 1491 and 1503, with 1491 through 1493 being the most afflicted years. Plague returned in 1511 until 1514 and, after 1520, was endemic in the city until 1529. Plague was endemic in Constantinople again between 1533 and 1549, 1552 and 1567, and for most of the remaining 16th-century. In the 17th century, plague epidemics within Constantinople were noted in the following years: 1603, 1611 to 1613, 1647 to 1649, 1653 to 1656, 1659 to 1688, 1671 to 1680, 1685 to 1695, and 1697 to 1701. [ citation needed ] In the 18th century, there were 64 years in which plague broke out in the capital, and a further 30 plague years which occurred in the first half of the 19th century. Of these later 94 plague epidemics in Constantinople between 1700 and 1850, six of them—occurring in 1705, 1726, 1751, 1778, 1812, and 1836—are estimated to have killed more than 5% of the population, whereas 83 of the epidemics killed 1% or fewer. [ clarification needed ] Plague repeatedly struck the cities of North Africa. Between 1620 and 1621, Algiers lost 30,000–50,000 people to it, with outbreaks returning in 1654 to 1657, 1665, 1691, and 1740 to 1742. Plague remained a major event in Ottoman society until the second quarter of the 19th century. Between 1701 and 1750, 37 large-scale and smaller epidemics were recorded in Constantinople, with a further 31 occurring between 1751 and 1800. The Great Plague of 1738 affected Ottoman territory in the Balkans , lasting until 1740. [ citation needed ] Baghdad suffered severely from visitations of the plague, with outbreaks reducing the population to one-third of its size by 1781. One of the last epidemics to strike the Balkans during the second plague pandemic was Caragea's plague , between 1813 and 1814. Swiss explorer Johann Ludwig Burckhardt witnessed the plague epidemics that ravaged Hejaz and Egypt between 1812 and 1816. He wrote: "In five or six days after my arrival [in Yanbu ] the mortality increased; forty or fifty persons died in a day, which, in a population of five or six thousand, was a terrible mortality." Although regular outbreaks of disease were common for decades prior to 1618, the Thirty Years' War (1618–48) greatly accelerated their spread. Based on local records, military action accounted for less than 3% of civilian deaths; the major causes were starvation (12%) and bubonic plague (64%). The modern consensus is that the population of the Holy Roman Empire declined from 18–20 million in 1600 to 11–13 million in 1650, and did not regain pre-war levels until 1750. The Great Plague of Vienna struck Vienna, the dynastic seat of the Holy Roman Empire, in 1679, killing an estimated 76,000 people. Emperor Leopold I fled the city upon the outbreak, but vowed to erect a Marian column in thanksgiving if the plague would end. Vienna's Plague Column , located on the Graben , was commissioned in 1683 and inaugurated in 1694. [ citation needed ]By 1357, the plague had returned to Venice, and from 1361 to 1363, the rest of Italy experienced the first recurrence of the pandemic. Pisa , Pistoia and Florence in Tuscany were especially badly affected; there pesta secunda , ' second pestilence ' killed a fifth of the population. In the pesta tertia , ' third pestilence ' of 1369 to 1371, 10–15% died. Survivors were aware that the Black Death of 1347–51 was not a unique event and that life was now "far more frightening and precarious than before". The Italian peninsula was struck with an outbreak of plague in 68% of the years between 1348 and 1600. There were 22 outbreaks of plague in Venice between 1361 and 1528. Petrarch , writing to Giovanni Boccaccio in September 1363, lamented that while the Black Death's arrival in Italy in 1348 had been mourned as an unprecedented disaster, "Now we realize that it is only the beginning of our mourning, for since then this evil force, unequalled and unheard of in human annals through the centuries, has never ceased, striking everywhere on all sides, on the left and right, like a skilled warrior." In the Jubilee Year of 1400, announced by Pope Boniface IX , one of the most severe occurrences of plague was exacerbated by the many pilgrims making their way to and from Rome; in the city itself 600–800 died daily. As recorded by the undertakers' records in Florence, at least 10,406 people died; the total death toll was estimated at twice that figure by 15th-century chronicler Giovanni Morelli. Half of the population of Pistoia and its hinterland were killed that year. Another outbreak occurred in Padua in 1405 and claimed 18,000 lives. In the plague epidemic of 1449–52, 30,000 Milanese died in 1451 alone. A particularly deadly plague struck Italy between 1478 and 1482. The territories of the Republic of Venice saw 300,000 dead in the epidemic's eight-year course. Luca Landucci wrote in 1478 that the citizens of Florence "were in a sorry plight. They lived in dread, and no one had any heart to work. The poor creatures could not procure silk or wool ... so that all classes suffered." In addition to plague, Florence was suffering both from excommunication leading to war with the Papal States and from the political strife following the Pazzi conspiracy . In 1479, the plague broke out in Rome; Bartolomeo Platina , the head of the Vatican Library was killed, and Pope Sixtus IV fled the city and was absent for more than a year. Federico da Montefeltro , Duke of Urbino , also died. Following the Sack of Rome in 1527 by Charles V, Holy Roman Emperor , plague broke out in both Rome and Florence. The plague emerged in Rome and killed 30,000 Florentines—a quarter of the city's inhabitants. The Description of the Plague at Florence in the Year 1527 , by Lorenzo di Filippo Strozzi , records this plague in detail; it was copied out by Niccolò Machiavelli with annotations by Strozzi. He wrote: Our pitiful Florence now looks like nothing but a town which has been stormed by infidels and then forsaken. One part of the inhabitants ... have retired to distant country houses, one part is dead, and yet another part is dying. Thus the present is torment, the future menace, so we contend with death and only live in fear and trembling. The clean, fine streets which formerly teemed with rich and noble citizens are now stinking and dirty; crowds of beggars drag themselves through them with anxious groans and only with difficulty and dread can one pass them. Shops and inns are closed, at the factories work has ceased, the law courts are empty, the laws are trampled on. Now one hears of some theft, now of some murder. The squares, the market places on which citizens used frequently to assemble, have now been converted into graves and into the resort of the wicked rabble. ... If by chance relations meet, a brother, a sister, a husband, a wife, they carefully avoid each other. What further words are needed? Fathers and mothers avoid their own children and forsake them. ... A few provision stores are still open, where bread is distributed, but where in the crush plague boils are also spread. Instead of conversation ... one hears now only pitiful, mournful tidings – such a one is dead, such a one is sick, such a one has fled, such a one is interned in his house, such a one is in hospital, such a one has nurses, another is without aid, such like news which by imagination alone would suffice to make Aesculapius sick. Further plague epidemics accompanied the Siege of Florence in 1529; there, religious buildings became hospitals and 600 temporary structures were built to house the infected outside the city walls. After 1530, political strife calmed and warfare in Italy became less frequent. Subsequently, plague outbreaks became more rare, affecting only individual cities or regions, but were particularly severe. In the 43 years between 1533 and 1575, there were 18 epidemics of plague. The especially damaging Italian plague of 1575–78 travelled both north and southwards through the peninsula from either end; the death toll was particularly high. By official reckoning, Milan lost 17,329 to plague in 1576, while Brescia recorded 17,396 killed in a town that did not exceed 46,000 total inhabitants. Venice, meanwhile, saw between a quarter and a third of its population die of plague in the epidemic of 1576–77 with 50,000 deaths. In the first half of the 17th century, a plague claimed some 1.7 million victims in Italy, or about 14% of the population. The Great Plague of Milan (1629–31) was possibly the most disastrous of the century: the city of Milan lost half its population of about 100,000, while Venice was as afflicted as in its severe 1553–56 outbreak. The Italian Plague of 1656–57 was the last major catastrophic plague in Italy, with the Naples Plague the most severe. In 1656, the plague killed about half of Naples 's 300,000 inhabitants. Messina saw the last epidemic in Italy, in 1742–44. The final recorded incidence of plague in Italy was in 1815–16, when plague broke out in Noja, a town near Bari . Over 60% of Norway's population died from 1348 to 1350. The last plague outbreak ravaged Oslo in 1654. In Russia, the disease hit somewhere once every five or six years from 1350 to 1490. In 1654, the Russian plague killed about 700,000 inhabitants. In 1709–13, a plague epidemic followed the Great Northern War (1700–1721), between Sweden and the Tsardom of Russia and its allies, killing about 100,000 in Sweden and 300,000 in Prussia . The plague killed two-thirds of the inhabitants of Helsinki , and claimed a third of Stockholm 's population. This was the last plague in Scandinavia, but the Russian plague of 1770–1772 killed up to 100,000 people in Moscow . The 1560s European wave of the plague first hit Lithuania and Russian Pskov in 1564-1565 but didn't progress further east until 1566, when it ravaged in Muscovian lands already suffering from the Livonian War and the Oprichnina . It made a pause until hitting even harder in two waves in 1569-1570 and 1571-1572, which, combined with concurrent famine, may have killed between a third and a quarter of Russian population. The Great Plague of 1738 was a pandemic of plague lasting 1738–40 and affecting areas in the modern nations of Romania , Hungary , Ukraine , Serbia , Croatia , and Austria . The Russian plague epidemic of 1770-1772 killed as many as 100,000 people in Moscow alone, with thousands more dying in the surrounding countryside. In 1466, perhaps 40,000 people died of plague in Paris. During the 16th and 17th centuries, plague visited Paris nearly once every three years on average. According to historian Geoffrey Parker , " France alone lost almost a million people to plague in the epidemic of 1628–31." Western Europe's last major epidemic occurred in 1720 in Marseilles . Plague epidemics ravaged London in the 1563 London plague , in 1593, 1603, 1625, 1636, and 1665, reducing its population by 10 to 30% during those years. The 1665–66 Great Plague of London was the final major epidemic of the pandemic, with the last death of plague in the walled City of London recorded fourteen years later in 1679. [ citation needed ]Over 10% of Amsterdam 's population died in 1623–25, and again in 1635–36, 1655, and 1664. More than 1.25 million deaths resulted from the extreme incidence of plague in 17th-century Spain . The plague of 1649 probably reduced the population of Seville by half. Malta suffered from a number of plague outbreaks during the second pandemic between the mid-14th and early 19th centuries. The most severe outbreak was the epidemic of 1675–1676 , which killed around 11,300 people, followed by the epidemic of 1813–1814 and that of 1592–1593 , which killed around 4,500 and 3,000 people respectively. The 1582 Tenerife plague epidemic (also 1582 San Cristóbal de La Laguna plague epidemic) was an outbreak of bubonic plague that occurred between 1582 and 1583 on the island of Tenerife , Spain. It is currently believed to have caused between 5,000 and 9,000 deaths on an island with fewer than 20,000 inhabitants at that time (approximately 25-45% of the island's population). The 18th- and 19th-century outbreaks, though severe, marked the retreat of the pandemic from most of Europe (18th century), northern Africa, and the Near East (19th century). The pandemic died out progressively across Europe. One documented case was in 17th-century London, where the first proper demographer , John Graunt , failed by just five years to see the last recorded death from plague, which happened in 1679, 14 years after the Great Plague of London . The reasons it died out totally are not well understood. It is tempting to think that the Great Fire of London the next year destroyed the hiding places of the rats in the roofs. There was not a single recorded plague death "within the walls" after 1666. However, by this time, the city had spread well beyond the walls, which contained most of the fire, and most plague cases happened beyond the limits of the fire. Likely more significant was the fact that all buildings after the fire were constructed of brick rather than wood and other flammable materials. [ citation needed ] This pattern was broadly followed after major epidemics in northern Italy (1631), southern and eastern Spain (1652), southern Italy and Genoa (1657), and Paris (1668). Appleby considers six possible explanations: People developed immunity. Improvements in nutrition made people more resistant. Improvements in housing, urban sanitation and personal cleanliness reduced the number of rats and rat fleas. The dominant rat species changed. (The brown rat did not arrive in London until 1727.) Quarantine methods improved in the 17th century. Some rats developed immunity, so fleas never left them in droves to humans; non-resistant rats were eliminated and this broke the cycle. Synder suggests that the replacement of the Black rat ( Rattus rattus ), which thrived among people and was frequently kept as a pet, by the more aggressive and prolific Norway or brown rat ( Rattus norvegicus ) was a major factor. The Brown rat, which arrived as an invasive species from the East, is skittish and avoids human contact, and its aggressive and asocial behaviour made it less attractive to humans. As the Brown rat violently drove out the Black rat in country after country, becoming the dominant species in that ecological niche, rat-to-human contact declined, as did the opportunities for plague to pass from rat fleas to humans. One of the major demarcations for hot spots in the third plague pandemic was the places where the Black rat had yet to be replaced, such as Bombay (now Mumbai) in India. [ citation needed ] It has been suggested that evolutionary processes may have favoured less virulent strains of the pathogen Yersinia pestis . In all probability, almost all of these factors had some effect in bringing about the end of the pandemic, though the main cause may never be conclusively determined. The disappearance happened rather later in the Nordic and eastern European countries, but there was a similar halt after major epidemics. [ citation needed ]

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Bubonic plague

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Great Plague of 1738

The Great Plague of 1738 was an outbreak of the bubonic plague between 1738 and 1740 that affected areas of the Habsburg Empire , now in the modern nations of Romania , Hungary , Ukraine , Serbia , Croatia , Slovakia , Czechia , and Austria . Although no exact figure is available, the epidemic likely killed over 50,000 people. [ citation needed ] In February 1738, the plague hit the Banat region, having been spread there by the Imperial Army . According to the 1740 Hungarian Diet, the Great Plague claimed 36,000 lives. Southeastern Transylvania may have been the hardest area hit. Over the following eight years, the plague killed a sixth of the population of Timișoara . Timișoara's St. Mary and St. John of Nepomuk Monument is dedicated to the plague's victims. The plague would return to hit the city again in 1762–1763. Other cities in the region were also stricken. Between October 1737 and April 1738, 111 deaths were reported in Zărneşti , and 70 in Codlea . More than 10% of the population of Cluj-Napoca was reported to have been killed by the pandemic. The disease's spread extended to the Adriatic . It made its way to the island of Brač in modern-day Croatia.

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Bubonic plague

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Siege of Caffa

Over 15,000 killed The Siege of Caffa was a siege of the Genoese port town of Caffa by a large Crimean Tatar army under the Golden Horde , led by their Khan Jani Beg , which is known largely for its role in spreading a pandemic. The Mongol army allegedly threw the bodies of Mongol warriors who had died of plague over the walls of the besieged city, which is considered one of the earliest examples of biological warfare . In Gabriel de Mussis ' writings, the Black Death was alleged to have reached Europe from the Crimea as the result of biological warfare during the siege. Caffa was established by Genoese traders in 1266 by a purchase agreement with the Khan of the Golden Horde . Relations between the Genoese and the Mongol Golden Horde were strained. The khan of the Golden Horde , Toqta , was piqued at the Italian slave trade in Turkic slaves who were sold as soldiers to the Mamluk Sultanate . He arrested the Italian residents of Sarai (the Mongol capital), and besieged Caffa, which the Genoese resisted for a year, but in 1308 set fire to their city and abandoned it. Relations between the Italians and the Golden Horde remained tense until Toqta 's death in 1312. Toqtai's successor, Özbeg Khan , mended relations with the Geneose , which allowed Caffa to become a thriving city once again by the 1340s. However, the ascension of Özbeg Khan 's son Jani Beg to the throne changed the political scene once more. The conversion of the Golden Horde Khans to Islam , led to them prosecuting Christians .The Mongols under Jani Beg besieged Caffa in 1343 and the Venetian territory of Tana , the cause of which was a brawl between Italians and Muslims in Tana . The siege of Caffa lasted until February 1344, when it was lifted after an Italian relief force killed 15,000 Mongol troops and destroyed their siege machines. Jani Beg renewed the siege in 1345, and cut off any supplies to the city, leading to miserable conditions within Caffa. However, a serious epidemic of bubonic plague devastated his forces, giving hope to the Italians, and he was forced to lift the siege in 1347. Before retreating though, in a final act of sabotage, Jani Beg used catapults to launch the plague -infested corpses of his dead soldiers over the fortified walls of Caffa. The Italians quickly dumped these bodies back into the sea, but the damage was done. To escape the plague epidemic, four Genoese ships, considered safe from the disease, sailed out from Caffa. These ships are believed to have brought the plague deep into Europe . The siege and despair of the city's citizens as the disease spread is vividly described by the Italian notary Gabriel de Mussis . The Italians blockaded Mongol ports, forcing Jani Beg to negotiate for peace, and they were allowed to reestablish their colony in Tana in 1347.

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Bubonic plague

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1772–1773 Persian Plague

The Persian plague epidemic of 1772–1773 , also simply known as the Persian Plague , was a massive outbreak of plague , more specifically Bubonic plague , in the Persian Empire , which claimed around 2 million lives in total. It was one of the most devastating Plague epidemics in recorded human history. The outbreak resulted in the introduction of several quarantine measures for the first time in the Persian Gulf regions. The epidemic is believed to have started in Baghdad in the winter of 1772. It then spread to other parts of the Persian-controlled lands. By 1773, the epidemic reached Basra , where it proved to be especially devastating, claiming more than 250,000 lives there alone. The Plague then quickly spread further southwards along the Persian Gulf, eventually reaching Bahrain . Eastwards, the epidemic extended as far as Bombay in India (modern-day Mumbai ). At the peak of the outbreak, a thousand deaths were recorded on a daily basis all throughout the Persian Empire. The outbreak was contained when imposed quarantine measures among the Persian Gulf populations started to show a positive effect by the end of 1773. [ citation needed ]

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Bubonic plague

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Theories of the Black Death

Theories of the Black Death are a variety of explanations that have been advanced to explain the nature and transmission of the Black Death (1347–51). A number of epidemiologists from the 1980s to the 2000s challenged the traditional view that the Black Death was caused by plague based on the type and spread of the disease. The confirmation in 2010 and 2011 that Yersinia pestis DNA was associated with a large number of plague sites has led researchers to conclude that "Finally, plague is plague." Several possible causes have been advanced for the Black Death; the most prevalent is the bubonic plague theory. Efficient transmission of Yersinia pestis is generally thought to occur only through the bites of fleas whose mid guts become obstructed by replicating Y. pestis several days after feeding on an infected host. This blockage results in starvation and aggressive feeding behaviour by fleas that repeatedly attempt to clear their blockage by regurgitation , resulting in thousands of plague bacteria being flushed into the feeding site, infecting the host. However, modelling of epizootic plague observed in prairie dogs , suggests that occasional reservoirs of infection such as an infectious carcass, rather than "blocked fleas" are a better explanation for the observed epizootic behaviour of the disease in nature. One hypothesis about the epidemiology —the appearance, spread, and especially disappearance—of plague from Europe is that the flea-bearing rodent reservoir of disease was eventually succeeded by another species. The black rat ( Rattus rattus ) was originally introduced from Asia to Europe by trade, but was subsequently displaced and succeeded throughout Europe by the bigger brown rat ( Rattus norvegicus ). The brown rat was not as prone to transmit the germ-bearing fleas to humans in large die-offs due to a different rat ecology. The dynamic complexities of rat ecology, herd immunity in that reservoir, interaction with human ecology, secondary transmission routes between humans with or without fleas, human herd immunity, and changes in each might explain the eruption, dissemination, and re-eruptions of plague that continued for centuries until its unexplained disappearance. The plague comes in three forms and it brought an array of signs and symptoms to those infected. The classic sign of bubonic plague was the appearance of buboes in the groin, the neck, and armpits, which oozed pus and bled. Most victims died within four to seven days after infection. The septicaemic plague is a form of "blood poisoning", and pneumonic plague is an airborne plague that attacks the lungs before the rest of the body. The bubonic plague was the most commonly seen form during the Black Death. The bubonic form of the plague has a mortality rate of thirty to seventy-five percent and symptoms include fever of 38–41 ° C (101–105 °F ), headaches , painful aching joints, nausea and vomiting , and a general feeling of malaise . The second most common form is the pneumonic plague and has symptoms that include fever, cough, and blood-tinged sputum . As the disease progressed, sputum became free flowing and bright red and death occurred within 2 days. The pneumonic form of the plague has a high mortality rate at ninety to ninety-five percent. Septicemic plague is the least common of the three forms, with a mortality rate close to one hundred percent. Symptoms include high fevers and purple skin patches ( purpura due to DIC ). Both pneumonic and septicemic plague can be caused by flea bites when the lymph nodes are overwhelmed. In this case they are referred to as secondary forms of the disease. David Herlihy identifies from the records another potential sign of the plague: freckle-like spots and rashes. Sources from Viterbo, Italy refer to "the signs which are vulgarly called lenticulae ", a word which bears resemblance to the Italian word for freckles, lentiggini . These are not the swellings of buboes, but rather "darkish points or pustules which covered large areas of the body". The uncharacteristically rapid spread of the plague could be due to respiratory droplet transmission, and low levels of immunity in the European population at that period. Historical examples of pandemics of other diseases in populations without previous exposure, such as smallpox and tuberculosis transmitted by aerosol amongst Native Americans , show that the first instance of an epidemic spreads faster and is far more virulent than later instances among the descendants of survivors, for whom natural selection has produced characteristics that are protective against the disease. [ citation needed ] Historians who believe that the Black Death was indeed caused by bubonic plague have put forth several theories questioning the traditional identification of Rattus sp. and their associated fleas as plague's primary vector . A 2012 report from the University of Bergen acknowledges that Y. pestis could have been the cause of the pandemic, but states that the epidemiology of the disease is different, most importantly the rapid spread and the lack of rats in Scandinavia and other parts of Northern Europe . R. rattus was present in Scandinavian cities and ports at the time of the Black Death but was not found in small, inland villages. Based on archaeological evidence from digs all over Norway , the black rat population was present in sea ports but remained static in the cold climate and would only have been sustained if ships continually brought black rats and that the rats would be unlikely to venture across open ground to remote villages. It argues that while healthy black rats are rarely seen, rats suffering from bubonic plague behave differently from healthy rats; where accounts from warmer climates mention rats falling from roofs and walls and piling high in the streets, Samuel Pepys , who described trifling observations and events of the London plague of 1665 in great detail, makes no mention of sick or dead rats, nor does Absalon Pederssøn in his diary, which contains detailed descriptions of a plague epidemic in Bergen in 1565. Ultimately, Hufthammer and Walløe offer the possibility of human fleas and lice in place of rats. University of Oslo researchers concluded that Y. pestis was likely carried over the Silk Road via fleas on giant gerbils from Central Asia during intermittent warm spells. Michael McCormick, a historian supporting bubonic plague as the Black Death, explains how archaeological research has confirmed that the black or "ship" rat ( Rattus rattus) was already present in Roman and medieval Europe . Also, the DNA of Y. pestis has been identified in the teeth of the human victims, the same DNA which has been widely believed to have come from the infected rodents. Pneumonic expression of Y. pestis can be transmitted by human-to-human contact, but McCormick states that this does not spread as easily as previous historians have imagined. According to him, the rat is the only plausible agent of transmission that could have led to such a wide and quick spread of the plague. This is because of rats' proclivity to associate with humans and the ability of their blood to withstand very large concentrations of the bacillus . When rats died, their fleas (which were infected with bacterial blood) found new hosts in the form of humans and animals. The Black Death tapered off in the eighteenth century, and according to McCormick, a rat-based theory of transmission could explain why this occurred. The plague(s) had killed a large portion of the human host population of Europe and dwindling cities meant that more people were isolated, and so geography and demography did not allow rats to have as much contact with Europeans. Greatly curtailed communication and transportation systems due to the drastic decline in human population also hindered the replenishment of devastated rat colonies. [ clarification needed ]The plague comes in three forms and it brought an array of signs and symptoms to those infected. The classic sign of bubonic plague was the appearance of buboes in the groin, the neck, and armpits, which oozed pus and bled. Most victims died within four to seven days after infection. The septicaemic plague is a form of "blood poisoning", and pneumonic plague is an airborne plague that attacks the lungs before the rest of the body. The bubonic plague was the most commonly seen form during the Black Death. The bubonic form of the plague has a mortality rate of thirty to seventy-five percent and symptoms include fever of 38–41 ° C (101–105 °F ), headaches , painful aching joints, nausea and vomiting , and a general feeling of malaise . The second most common form is the pneumonic plague and has symptoms that include fever, cough, and blood-tinged sputum . As the disease progressed, sputum became free flowing and bright red and death occurred within 2 days. The pneumonic form of the plague has a high mortality rate at ninety to ninety-five percent. Septicemic plague is the least common of the three forms, with a mortality rate close to one hundred percent. Symptoms include high fevers and purple skin patches ( purpura due to DIC ). Both pneumonic and septicemic plague can be caused by flea bites when the lymph nodes are overwhelmed. In this case they are referred to as secondary forms of the disease. David Herlihy identifies from the records another potential sign of the plague: freckle-like spots and rashes. Sources from Viterbo, Italy refer to "the signs which are vulgarly called lenticulae ", a word which bears resemblance to the Italian word for freckles, lentiggini . These are not the swellings of buboes, but rather "darkish points or pustules which covered large areas of the body". The uncharacteristically rapid spread of the plague could be due to respiratory droplet transmission, and low levels of immunity in the European population at that period. Historical examples of pandemics of other diseases in populations without previous exposure, such as smallpox and tuberculosis transmitted by aerosol amongst Native Americans , show that the first instance of an epidemic spreads faster and is far more virulent than later instances among the descendants of survivors, for whom natural selection has produced characteristics that are protective against the disease. [ citation needed ]Historians who believe that the Black Death was indeed caused by bubonic plague have put forth several theories questioning the traditional identification of Rattus sp. and their associated fleas as plague's primary vector . A 2012 report from the University of Bergen acknowledges that Y. pestis could have been the cause of the pandemic, but states that the epidemiology of the disease is different, most importantly the rapid spread and the lack of rats in Scandinavia and other parts of Northern Europe . R. rattus was present in Scandinavian cities and ports at the time of the Black Death but was not found in small, inland villages. Based on archaeological evidence from digs all over Norway , the black rat population was present in sea ports but remained static in the cold climate and would only have been sustained if ships continually brought black rats and that the rats would be unlikely to venture across open ground to remote villages. It argues that while healthy black rats are rarely seen, rats suffering from bubonic plague behave differently from healthy rats; where accounts from warmer climates mention rats falling from roofs and walls and piling high in the streets, Samuel Pepys , who described trifling observations and events of the London plague of 1665 in great detail, makes no mention of sick or dead rats, nor does Absalon Pederssøn in his diary, which contains detailed descriptions of a plague epidemic in Bergen in 1565. Ultimately, Hufthammer and Walløe offer the possibility of human fleas and lice in place of rats. University of Oslo researchers concluded that Y. pestis was likely carried over the Silk Road via fleas on giant gerbils from Central Asia during intermittent warm spells. Michael McCormick, a historian supporting bubonic plague as the Black Death, explains how archaeological research has confirmed that the black or "ship" rat ( Rattus rattus) was already present in Roman and medieval Europe . Also, the DNA of Y. pestis has been identified in the teeth of the human victims, the same DNA which has been widely believed to have come from the infected rodents. Pneumonic expression of Y. pestis can be transmitted by human-to-human contact, but McCormick states that this does not spread as easily as previous historians have imagined. According to him, the rat is the only plausible agent of transmission that could have led to such a wide and quick spread of the plague. This is because of rats' proclivity to associate with humans and the ability of their blood to withstand very large concentrations of the bacillus . When rats died, their fleas (which were infected with bacterial blood) found new hosts in the form of humans and animals. The Black Death tapered off in the eighteenth century, and according to McCormick, a rat-based theory of transmission could explain why this occurred. The plague(s) had killed a large portion of the human host population of Europe and dwindling cities meant that more people were isolated, and so geography and demography did not allow rats to have as much contact with Europeans. Greatly curtailed communication and transportation systems due to the drastic decline in human population also hindered the replenishment of devastated rat colonies. [ clarification needed ]Although Y. pestis as the causative agent of plague was still widely accepted during this period, scientific and historical investigations in the late 20th century through publication of conclusive evidence in 2011 led some researchers to doubt the long-held belief that the Black Death was an epidemic of bubonic plague. The arguments for an alternate causative agent were based on differences in mortality levels, disease diffusion rates, rat distribution, flea reproduction and climate, and distribution of human population. In 1984, Graham Twigg published The Black Death: A Biological Reappraisal , where he argued that the climate and ecology of Europe and particularly England made it nearly impossible for rats and fleas to have transmitted bubonic plague. Combining information on the biology of Rattus rattus , Rattus norvegicus , and the common fleas Xenopsylla cheopis and Pulex irritans with modern studies of plague epidemiology, particularly in India, where the R. rattus is a native species and conditions are nearly ideal for plague to be spread, Twigg concluded that it would have been nearly impossible for Yersinia pestis to have been the causative agent of the plague, let alone its explosive spread across Europe. Twigg also showed that the common alternate theory of entirely pneumonic spread does not hold up. He proposed, based on a reexamination of the evidence and symptoms, that the Black Death may actually have been an epidemic of pulmonary anthrax caused by Bacillus anthracis . In 2002, Samuel K. Cohn published the controversial article, "The Black Death: End of the Paradigm". Cohn argued that the medieval and modern plagues were two distinct diseases differing in their symptoms, signs, and epidemiologies. Cohn's argument that medieval plague was not rat-based is supported by his claims that the modern and medieval plagues occurred in different seasons (a claim supported in a 2009 article by Mark Welford and Brian Bossak ), had unparalleled cycles of recurrence, and varied in the manner in which immunity was acquired. The modern plague reaches its peak in seasons with high humidity and a temperature of between 50 °F (10 °C) and 78 °F (26 °C) , as rats' fleas thrive in this climate. In comparison, the Black Death is recorded as occurring in periods during which rats' fleas could not have survived, i.e. hot Mediterranean summers above 78 °F (26 °C) . In terms of recurrence, the Black Death on average did not resurface in an area for between five and fifteen years after it had occurred. In contrast, modern plagues often recur in a given area yearly for an average of eight to forty years. Last, Cohn presented evidence displaying that individuals gained immunity to the Black Death, unlike the modern plague, during the fourteenth century. He stated that in 1348, two-thirds of those suffering from plague died, in comparison to one-twentieth by 1382. Statistics display that immunity to the modern plague has not been acquired in modern times. In the Encyclopedia of Population, Cohn pointed to five major weaknesses in the bubonic plague theory: Cohn also pointed out that while the identification of the disease as having buboes relies on accounts of Boccaccio and others, they described buboes, abscesses , rashes and carbuncles occurring all over the body, the neck or behind the ears. In contrast, the modern disease rarely has more than one bubo, most commonly in the groin, and is not characterised by abscesses, rashes and carbuncles. This difference, he argued, ties in with the fact that fleas caused the modern plague and not the Black Death. Since flea bites do not usually reach beyond a person's ankles, in the modern period the groin was the nearest lymph node that could be infected. As the neck and the armpit were often infected during the medieval plague, it appears less likely that these infections were caused by fleas on rats. In 2001, Susan Scott and Christopher Duncan, respectively a demographer and zoologist from Liverpool University , proposed the theory that the Black Death might have been caused by an Ebola -like virus , not a bacterium. Their rationale was that this plague spread much faster and the incubation period was much longer than other confirmed Y. pestis –caused plagues. A longer period of incubation will allow carriers of the infection to travel farther and infect more people than a shorter one. When the primary vector is humans, as opposed to birds, this is of great importance. Epidemiological studies suggest the disease was transferred between humans (which happens rarely with Yersinia pestis and very rarely for Bacillus anthracis ), and some genes that determine immunity to Ebola-like viruses are much more widespread in Europe than in other parts of the world. Their research and findings are thoroughly documented in Biology of Plagues . More recently the researchers have published computer modeling demonstrating how the Black Death has made around 10% of Europeans resistant to HIV. In a similar vein, historian Norman Cantor , in In the Wake of the Plague: The Black Death and the World It Made (2001), suggested the Black Death might have been a combination of pandemics including a form of anthrax , a cattle murrain . He cited reported disease symptoms not in keeping with the known effects of either bubonic or pneumonic plague, the discovery of anthrax spores in a plague pit in Scotland, and the fact that meat from infected cattle was known to have been sold in many rural English areas prior to the onset of the plague. The means of infection varied widely, with infection in the absence of living or recently dead humans in Sicily (which speaks against most viruses). Also, diseases with similar symptoms were generally not distinguished between in that period (see murrain above), at least not in the Christian world; Chinese and Muslim medical records can be expected to yield better information which however only pertains to the specific disease(s) which affected these areas. Cutaneous anthrax infection in humans shows up as a boil-like skin lesion that eventually forms an ulcer with a black center ( eschar ), often beginning as an irritating and itchy skin lesion or blister that is dark and usually concentrated as a black dot. Cutaneous infections generally form within the site of spore penetration between two and five days after exposure. Without treatment about 20% of cutaneous skin infection cases progress to toxemia and death. Respiratory infection in humans initially presents with cold or flu-like symptoms for several days, followed by severe (and often fatal) respiratory collapse. Historical mortality was 92%. Gastrointestinal infection in humans is most often caused by eating anthrax-infected meat and is characterized by serious gastrointestinal difficulty, vomiting of blood, severe diarrhea, acute inflammation of the intestinal tract, and loss of appetite. After the bacteria invades the bowel system, it spreads through the bloodstream throughout the body, making more toxins on the way. The arguments for an alternate causative agent were based on differences in mortality levels, disease diffusion rates, rat distribution, flea reproduction and climate, and distribution of human population. In 1984, Graham Twigg published The Black Death: A Biological Reappraisal , where he argued that the climate and ecology of Europe and particularly England made it nearly impossible for rats and fleas to have transmitted bubonic plague. Combining information on the biology of Rattus rattus , Rattus norvegicus , and the common fleas Xenopsylla cheopis and Pulex irritans with modern studies of plague epidemiology, particularly in India, where the R. rattus is a native species and conditions are nearly ideal for plague to be spread, Twigg concluded that it would have been nearly impossible for Yersinia pestis to have been the causative agent of the plague, let alone its explosive spread across Europe. Twigg also showed that the common alternate theory of entirely pneumonic spread does not hold up. He proposed, based on a reexamination of the evidence and symptoms, that the Black Death may actually have been an epidemic of pulmonary anthrax caused by Bacillus anthracis . In 2002, Samuel K. Cohn published the controversial article, "The Black Death: End of the Paradigm". Cohn argued that the medieval and modern plagues were two distinct diseases differing in their symptoms, signs, and epidemiologies. Cohn's argument that medieval plague was not rat-based is supported by his claims that the modern and medieval plagues occurred in different seasons (a claim supported in a 2009 article by Mark Welford and Brian Bossak ), had unparalleled cycles of recurrence, and varied in the manner in which immunity was acquired. The modern plague reaches its peak in seasons with high humidity and a temperature of between 50 °F (10 °C) and 78 °F (26 °C) , as rats' fleas thrive in this climate. In comparison, the Black Death is recorded as occurring in periods during which rats' fleas could not have survived, i.e. hot Mediterranean summers above 78 °F (26 °C) . In terms of recurrence, the Black Death on average did not resurface in an area for between five and fifteen years after it had occurred. In contrast, modern plagues often recur in a given area yearly for an average of eight to forty years. Last, Cohn presented evidence displaying that individuals gained immunity to the Black Death, unlike the modern plague, during the fourteenth century. He stated that in 1348, two-thirds of those suffering from plague died, in comparison to one-twentieth by 1382. Statistics display that immunity to the modern plague has not been acquired in modern times. In the Encyclopedia of Population, Cohn pointed to five major weaknesses in the bubonic plague theory: Cohn also pointed out that while the identification of the disease as having buboes relies on accounts of Boccaccio and others, they described buboes, abscesses , rashes and carbuncles occurring all over the body, the neck or behind the ears. In contrast, the modern disease rarely has more than one bubo, most commonly in the groin, and is not characterised by abscesses, rashes and carbuncles. This difference, he argued, ties in with the fact that fleas caused the modern plague and not the Black Death. Since flea bites do not usually reach beyond a person's ankles, in the modern period the groin was the nearest lymph node that could be infected. As the neck and the armpit were often infected during the medieval plague, it appears less likely that these infections were caused by fleas on rats. In 2001, Susan Scott and Christopher Duncan, respectively a demographer and zoologist from Liverpool University , proposed the theory that the Black Death might have been caused by an Ebola -like virus , not a bacterium. Their rationale was that this plague spread much faster and the incubation period was much longer than other confirmed Y. pestis –caused plagues. A longer period of incubation will allow carriers of the infection to travel farther and infect more people than a shorter one. When the primary vector is humans, as opposed to birds, this is of great importance. Epidemiological studies suggest the disease was transferred between humans (which happens rarely with Yersinia pestis and very rarely for Bacillus anthracis ), and some genes that determine immunity to Ebola-like viruses are much more widespread in Europe than in other parts of the world. Their research and findings are thoroughly documented in Biology of Plagues . More recently the researchers have published computer modeling demonstrating how the Black Death has made around 10% of Europeans resistant to HIV.In a similar vein, historian Norman Cantor , in In the Wake of the Plague: The Black Death and the World It Made (2001), suggested the Black Death might have been a combination of pandemics including a form of anthrax , a cattle murrain . He cited reported disease symptoms not in keeping with the known effects of either bubonic or pneumonic plague, the discovery of anthrax spores in a plague pit in Scotland, and the fact that meat from infected cattle was known to have been sold in many rural English areas prior to the onset of the plague. The means of infection varied widely, with infection in the absence of living or recently dead humans in Sicily (which speaks against most viruses). Also, diseases with similar symptoms were generally not distinguished between in that period (see murrain above), at least not in the Christian world; Chinese and Muslim medical records can be expected to yield better information which however only pertains to the specific disease(s) which affected these areas. Cutaneous anthrax infection in humans shows up as a boil-like skin lesion that eventually forms an ulcer with a black center ( eschar ), often beginning as an irritating and itchy skin lesion or blister that is dark and usually concentrated as a black dot. Cutaneous infections generally form within the site of spore penetration between two and five days after exposure. Without treatment about 20% of cutaneous skin infection cases progress to toxemia and death. Respiratory infection in humans initially presents with cold or flu-like symptoms for several days, followed by severe (and often fatal) respiratory collapse. Historical mortality was 92%. Gastrointestinal infection in humans is most often caused by eating anthrax-infected meat and is characterized by serious gastrointestinal difficulty, vomiting of blood, severe diarrhea, acute inflammation of the intestinal tract, and loss of appetite. After the bacteria invades the bowel system, it spreads through the bloodstream throughout the body, making more toxins on the way. Recently, however, more evidence has appeared that the Black Death was caused by Y. pestis . In 2000, Didier Raoult and others reported finding Y. pestis DNA by performing a "suicide PCR " on tooth pulp tissue from a fourteenth-century plague cemetery in Montpellier . Drancourt and Raoult reported similar findings in a 2007 study. However, other researchers argued the study was flawed and cited contrary evidence. In 2003, Susan Scott of the University of Liverpool argued that there was no conclusive reason to believe the Montpellier teeth were from Black Death victims. Also in 2003, a team led by Alan Cooper from Oxford University tested 121 teeth from sixty-six skeletons found in 14th century mass graves, including well-documented Black Death plague pits in East Smithfield and Spitalfields . Their results showed no genetic evidence for Y. pestis , and Cooper concluded that though in 2003 "[w]e cannot rule out Yersinia as the cause of the Black Death ... right now there is no molecular evidence for it." Other researchers argued that those burial sites where Y. pestis could not be found had nothing to do with the Black Death in the first place. In October 2010 the journal PLoS Pathogens published a paper by Haensch et al. (2010), a multinational team that investigated the role of Yersinia pestis in the Black Death. The paper detailed the results of new surveys that combined ancient DNA analyses and protein-specific detection which were used to find DNA and protein signatures specific for Y. pestis in human skeletons from widely distributed mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. The authors concluded that this research, together with prior analyses from the south of France and Germany Significantly, the study also identified two previously unknown but related clades (genetic branches) of the Y. pestis genome that were associated with distinct medieval mass graves. These were found to be ancestral to modern isolates of the modern Y. pestis strains Orientalis and Medievalis, suggesting that these variant strains (which are now presumed to be extinct) may have entered Europe in two distinct waves. The presence of Y. pestis during the Black Death and its phylogenetic placement was definitely established in 2011 with the publication of a Y. pestis genome using new amplification techniques used on DNA extracts from teeth from over 100 samples from the East Smithfield burial site in London. Surveys of plague pit remains in France and England indicate that the first variant entered western Europe through the port of Marseilles around November 1347 and spread through France over the next two years, eventually reaching England in the spring of 1349, where it spread through the country in three successive epidemics. However, surveys of plague pit remains from the Netherlands town of Bergen op Zoom showed that the Y. pestis genotype responsible for the pandemic that spread through the Low Countries from 1350 differed from that found in Britain and France, implying that Bergen op Zoom (and possibly other parts of the southern Netherlands) was not directly infected from England or France in AD 1349, suggesting that a second wave of plague infection, distinct from those in Britain and France, may have been carried to the Low Countries from Norway, the Hanseatic cities, or another site.

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Bubonic plague

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Patron saints of ailments, illness, and dangers

Saints have often been prevailed upon in requests for intercessory prayers to protect against or help combatting a variety of dangers, illnesses, and ailments. This is a list of saints and such ills traditionally associated with them. In shorthand, they are called the patron saints of (people guarding against or grappling with) these various troubles.

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Bubonic plague

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Henry T. Gage

Henry Tifft Gage (December 25, 1852 – August 28, 1924) was an American lawyer, politician and diplomat. A Republican , Gage was elected to a single term as the 20th governor of California from 1899 to 1903. Gage was also the U.S. Minister to Portugal for several months in 1910.Gage was born on Christmas Day , 1852 in Geneva, New York . Relocating with his family to East Saginaw, Michigan , he spent his teenage years in Michigan , studying law with his lawyer father. In 1873 at the age of 21, Gage was admitted to the Michigan Bar, working for his father's law practice in East Saginaw for over a year. Over a year later, Gage relocated to California , settling in Los Angeles . Between 1874 and 1877, Gage was a successful sheep dealer, selling sheep to various farms around Los Angeles County . In 1877, Gage returned to law, opening his own practice. Largely successful in court, his practice quickly began to attract a number of prominent corporate clients in Southern California , including the Southern Pacific Railroad , who would enjoy a decades-long relationship with Gage. Three years later, Gage married Francesca V. Rains, a great-granddaughter of a Californio family. The Gages settled in Bell Gardens at his wife's family home. Running as a Republican , Gage was elected as Los Angeles City Attorney in 1881, beginning a slow rise within party ranks. At the 1888 Republican National Convention in Chicago , Gage was chosen as a delegate-at-large during the proceedings. In a speech to the convention, Gage seconded the motion to nominate Levi P. Morton as the party's nomination for the vice presidency . In 1891, President Benjamin Harrison appointed Gage as a federal prosecutor to prosecute the crew of the Chilean steamer Itata due to the Itata Incident . The U.S. federal government charged the crew with knowingly assisting an illegal arms purchase. Its cargo had consisted of weapons purchased for National Congressional insurgent forces fighting in the 1891 Chilean Civil War against President José Manuel Balmaceda . Upon review of the federal government's case, Gage dropped all charges against Itata's crew, claiming that the government had mistaken the arms purchase as illegal. By 1898, Gage had become a prominent corporate lawyer within Los Angeles business circles, as well as a successful owner of real estate, particularly the Red Rover gold mine in Acton in the Santa Clarita Valley . At the state Republican convention that year, Gage was chosen in the first round of voting as the party's nominee for the governorship. His nomination was largely orchestrated by the Southern Pacific Railroad , who had worked with Gage since the 1870s, and saw him as supportive of their interests. In the 1898 California gubernatorial election , Gage defeated his Democratic rival, House Representative James G. Maguire by 6.7%. Other minor candidates in the election included Job Harriman of the Socialist Labor Party of America and Prohibitionist J. E. McComas , a former State Senator .Gage was inaugurated as the 20th Governor of California on January 4, 1899. In his inauguration speech, Gage spoke at length about foreign policy, viewing with favor the recent results of the Spanish–American War and their effect on California's economy . "The peaceful acquisition of the Hawaiian Islands , extending our empire beyond our Pacific shore, should be followed as a political necessity by the annexation of the Philippines ," Gage stated. "The center of commerce must move westward. California , favorably situated, will, among other advantages, reap the harvest of trade with these new territories, developing our many varied and growing resources, creating a western merchant marine for the carriage of our imports and exports, and luring to our markets the nations of the world." In one of his first acts, Gage's administration reopened the State Printing Office, which had been closed down by Governor James Budd to cut governmental expenditures. From early on in his administration, Gage was highly partisan, mostly because of frequent accusations from Reform Republicans and Democrats alike who accused Gage as being a pawn for the Southern Pacific . When a newspaper published a political cartoon portraying railroad tycoon Collis Potter Huntington leading the governor around on a leash, Gage was so incensed by the accusation that he ramrodded a censorship bill through the California State Legislature , restricting the press whenever editorial content involved politics or politicians. On January 3, 1900, Gage held a legislative session to discuss ways to improve San Francisco's port in attempt to increase trading with Asia. He also wanted to bring back the State Quarantine Service which had recently been removed. The federal Marine Hospital Service on Angel Island was responsible for the inspection of all incoming ships and preventing all foreign diseases from coming into California. Reintroduction of the State Quarantine Service would provide Gage with more oversight and ability to minimize threats of quarantine. However, the session was adjourned before any action upon the request could take place. From 1900 onwards, Gage's administration was often rocky. That year, the ship Australia laid anchor in the Port of San Francisco , unknowingly bringing to the city rats carrying the Third Pandemic of the bubonic plague . The disease soon made home in the cramped ghetto quarters of the city's Chinatown . Rumors of the plague's presence abounded in the city, quickly gaining the notice of authorities from the federal Marine Hospital Service , including the Marine Hospital Service's head in San Francisco, Joseph J. Kinyoun . Allied with powerful railroad and city business interests, Gage publicly denied the existence of any pestilence outbreak in the city, fearing that any word of the plague's presence would deeply damage the city and state's economy. Supportive newspapers, such as the San Francisco Call , San Francisco Chronicle and the San Francisco Bulletin , echoed Gage's denials, beginning what was to become an intense defamation campaign against Joseph Kinyoun, director of the San Francisco Quarantine Station. In response to the state's refuting of the plague's existence, U.S. Surgeon General Walter Wyman recommended to federal Treasury Secretary Lyman J. Gage to intervene. Secretary Gage agreed, creating a three-man medical commission to medically investigate the city. The commission conclusively discovered that bubonic plague was present. Like Kinyoun, the Treasury commission's findings were again immediately denounced by Governor Gage. Gage believed the federal government's growing presence in the matter was a gross intrusion of what he recognized as a state concern. In his retaliation, Gage denied the federal commission any use of the University of California, Berkeley 's laboratories to further study the outbreak. The Bulletin would also attack the federal commission, branding it as a "youthful and inexperienced trio". The clash between Gage and federal authorities intensified. Surgeon General Wyman instructed Kinyoun to place Chinatown under quarantine , as well as blocking all East Asians from entering state borders. Upon hearing Kinyoun's announcement, Gage sent telegrams and spread the word to California's elected officials, party leaders, and even delegates of the National Convention. He encouraged them to speak with the President about cancelling the quarantine and removing Kinyoun from his duties. This event along with the help of San Francisco newspapers sparked the campaign to remove and discredit Kinyoun. Chinese residents, supported by Gage and local businesses, fought the quarantine through numerous federal court battles, claiming the Marine Hospital Service was violating their rights under the Fourteenth Amendment , and in the process, launched lawsuits against Kinyoun. In these court proceedings, residents insisted Gage was correct in his denials of the plague outbreak. The courts initially agreed that Chinatown residents were correct in that the quarantine violated their civil rights, yet most of these lawsuits were eventually thrown out of court on later dates. Between 1901 and 1902, the plague outbreak continued to worsen. On January 8, 1901, Gage pushed to allow the state health board members to delegate the local health units in attempt to monitor and control cases regarding the plague. In a 1901 address to both houses of the California State Legislature , Gage accused federal authorities, particularly Kinyoun, of injecting bubonic plague into cadavers . In response to what he said to be massive scaremongering by the Marine Hospital Service, Gage pushed a censorship bill through the Legislature to gag any media reports of plague infection. The legislation failed, yet laws to gag reports amongst the medical community succeeded in passage and were signed into law by the governor. In addition, $100,000 was allocated to a public campaign led by Gage to deny the plague's existence. Privately, however, Gage sent a special commission to Washington , consisting of Southern Pacific , newspaper and shipping lawyers to negotiate a settlement with the Marine Hospital Service, whereby the federal government would remove Kinyoun from San Francisco with the promise that the state would secretly cooperate with the Marine Hospital Service in stamping out the plague outbreak. Secret cooperations included preventive measures such as inspection, isolation and disinfection. Gage and Mayor Phelan provided funding to inspect and disinfect Chinatown of any signs of the plague. To the public, however, this was marketed as a cleanup campaign that was renovating and getting rid of the town's filth. Despite the secret agreement allowing for Kinyoun's removal, Gage went back on his promise of assisting federal authorities and continued to obstruct their efforts for study and quarantine. A report issued by the State Board of Health on September 16, 1901, bolstered Gage's claims, denying the plague's outbreak. As Gage fought his growing battle with the federal government, labor agitation was starting to spill over along the San Francisco waterfront. In the July 1901, members of the International Brotherhood of Teamsters went on strike , protesting against recent orders to haul luggage for a non- unionized cargo company. The Teamsters strike was quickly joined by sympathizing sailors , stevedores and fireman belonging to the City Front Federation. Between 10,000 and 16,000 men joined the strike. Employers grew quickly frustrated with the strikers, asking for San Francisco Mayor James D. Phelan to request Gage in ordering in the state militia to crush the strike. Phelan refused, though violence between strikers and officers of the San Francisco Police Department began to break out in September. Gage became increasingly concerned that violence along San Francisco's waterfront was spilling out of the city's control. On one instance, in order to reassure himself that violence was not increasing, Gage disguised himself as a striker and walked amongst the stevedores to observe conditions personally. In October, Gage negotiated settlement with employers and the Teamsters, though the terms of the settlement were never made publicly known. Gage was the first California governor to negotiate an end to a labor strike. Gage's troubles over the bubonic plague continued to worsen. Despite San Francisco-based newspapers continual denials, contradicting reports from the Sacramento Bee and the Associated Press on the plague's spread had made the outbreak become publicly known throughout the United States . The state governments of Colorado , Texas and Louisiana passed quarantines of California, arguing that since the state had refused to admit a health crisis within its borders, states receiving rail or shipping cargo from California ports of call had the duty to protect themselves. Threats of a national quarantine grew. As the 1902 elections approached, Southern Pacific supporters increasingly saw Gage, a man who had represented their interests since his days as a Los Angeles -based lawyer, as an embarrassment to state Republicans . This harmed Gage whose allies were mostly business interests. However, instead of putting allegations of the outbreak to rest, conflicting studies and reports from federal officials and the media continued to contradict Gage's assertions. In turn, the powerful shipping and rail companies within the state and throughout the country faced quarantine and economic boycotts from other states. At the state Republican convention that year, the Railroad Republican faction refused Gage renomination for the governorship. In his place, former Mayor of Oakland George Pardee , a German-trained medical physician, received the nomination. Pardee's nomination was largely a compromise between the Railroad and the growing progressive -minded Reform factions of the party. In his final address to the California State Legislature in early January 1903, Gage continued to publicly deny the outbreak, blaming the federal government, in particular Joseph Kinyoun, the Marine Hospital Service and the San Francisco Board of Health, for damaging the state's economy. In my first biennial message, January 7, 1901, I referred, at some length, to the subject of certain false and exaggerated reports concerning the alleged existence of bubonic plague in San Francisco, which, through the interest, ignorance, or recklessness of a few persons, were indiscriminately published in the year 1900, and thereafter intermittently continued. The falsity of the reports has been frequently proved, but, unfortunately, through the ill-designed efforts and action of Dr. J. J. Kinyoun , assuming to represent the United States Marine Hospital Service at San Francisco, and of the members of the San Francisco Board of Health , much damage nevertheless accrued to the various commercial, industrial, and other productive interests of the State, injuring alike the laborer, merchant, farmer, and fruit-grower.On January 3, 1900, Gage held a legislative session to discuss ways to improve San Francisco's port in attempt to increase trading with Asia. He also wanted to bring back the State Quarantine Service which had recently been removed. The federal Marine Hospital Service on Angel Island was responsible for the inspection of all incoming ships and preventing all foreign diseases from coming into California. Reintroduction of the State Quarantine Service would provide Gage with more oversight and ability to minimize threats of quarantine. However, the session was adjourned before any action upon the request could take place. From 1900 onwards, Gage's administration was often rocky. That year, the ship Australia laid anchor in the Port of San Francisco , unknowingly bringing to the city rats carrying the Third Pandemic of the bubonic plague . The disease soon made home in the cramped ghetto quarters of the city's Chinatown . Rumors of the plague's presence abounded in the city, quickly gaining the notice of authorities from the federal Marine Hospital Service , including the Marine Hospital Service's head in San Francisco, Joseph J. Kinyoun . Allied with powerful railroad and city business interests, Gage publicly denied the existence of any pestilence outbreak in the city, fearing that any word of the plague's presence would deeply damage the city and state's economy. Supportive newspapers, such as the San Francisco Call , San Francisco Chronicle and the San Francisco Bulletin , echoed Gage's denials, beginning what was to become an intense defamation campaign against Joseph Kinyoun, director of the San Francisco Quarantine Station. In response to the state's refuting of the plague's existence, U.S. Surgeon General Walter Wyman recommended to federal Treasury Secretary Lyman J. Gage to intervene. Secretary Gage agreed, creating a three-man medical commission to medically investigate the city. The commission conclusively discovered that bubonic plague was present. Like Kinyoun, the Treasury commission's findings were again immediately denounced by Governor Gage. Gage believed the federal government's growing presence in the matter was a gross intrusion of what he recognized as a state concern. In his retaliation, Gage denied the federal commission any use of the University of California, Berkeley 's laboratories to further study the outbreak. The Bulletin would also attack the federal commission, branding it as a "youthful and inexperienced trio". The clash between Gage and federal authorities intensified. Surgeon General Wyman instructed Kinyoun to place Chinatown under quarantine , as well as blocking all East Asians from entering state borders. Upon hearing Kinyoun's announcement, Gage sent telegrams and spread the word to California's elected officials, party leaders, and even delegates of the National Convention. He encouraged them to speak with the President about cancelling the quarantine and removing Kinyoun from his duties. This event along with the help of San Francisco newspapers sparked the campaign to remove and discredit Kinyoun. Chinese residents, supported by Gage and local businesses, fought the quarantine through numerous federal court battles, claiming the Marine Hospital Service was violating their rights under the Fourteenth Amendment , and in the process, launched lawsuits against Kinyoun. In these court proceedings, residents insisted Gage was correct in his denials of the plague outbreak. The courts initially agreed that Chinatown residents were correct in that the quarantine violated their civil rights, yet most of these lawsuits were eventually thrown out of court on later dates. Between 1901 and 1902, the plague outbreak continued to worsen. On January 8, 1901, Gage pushed to allow the state health board members to delegate the local health units in attempt to monitor and control cases regarding the plague. In a 1901 address to both houses of the California State Legislature , Gage accused federal authorities, particularly Kinyoun, of injecting bubonic plague into cadavers . In response to what he said to be massive scaremongering by the Marine Hospital Service, Gage pushed a censorship bill through the Legislature to gag any media reports of plague infection. The legislation failed, yet laws to gag reports amongst the medical community succeeded in passage and were signed into law by the governor. In addition, $100,000 was allocated to a public campaign led by Gage to deny the plague's existence. Privately, however, Gage sent a special commission to Washington , consisting of Southern Pacific , newspaper and shipping lawyers to negotiate a settlement with the Marine Hospital Service, whereby the federal government would remove Kinyoun from San Francisco with the promise that the state would secretly cooperate with the Marine Hospital Service in stamping out the plague outbreak. Secret cooperations included preventive measures such as inspection, isolation and disinfection. Gage and Mayor Phelan provided funding to inspect and disinfect Chinatown of any signs of the plague. To the public, however, this was marketed as a cleanup campaign that was renovating and getting rid of the town's filth. Despite the secret agreement allowing for Kinyoun's removal, Gage went back on his promise of assisting federal authorities and continued to obstruct their efforts for study and quarantine. A report issued by the State Board of Health on September 16, 1901, bolstered Gage's claims, denying the plague's outbreak. As Gage fought his growing battle with the federal government, labor agitation was starting to spill over along the San Francisco waterfront. In the July 1901, members of the International Brotherhood of Teamsters went on strike , protesting against recent orders to haul luggage for a non- unionized cargo company. The Teamsters strike was quickly joined by sympathizing sailors , stevedores and fireman belonging to the City Front Federation. Between 10,000 and 16,000 men joined the strike. Employers grew quickly frustrated with the strikers, asking for San Francisco Mayor James D. Phelan to request Gage in ordering in the state militia to crush the strike. Phelan refused, though violence between strikers and officers of the San Francisco Police Department began to break out in September. Gage became increasingly concerned that violence along San Francisco's waterfront was spilling out of the city's control. On one instance, in order to reassure himself that violence was not increasing, Gage disguised himself as a striker and walked amongst the stevedores to observe conditions personally. In October, Gage negotiated settlement with employers and the Teamsters, though the terms of the settlement were never made publicly known. Gage was the first California governor to negotiate an end to a labor strike.Gage's troubles over the bubonic plague continued to worsen. Despite San Francisco-based newspapers continual denials, contradicting reports from the Sacramento Bee and the Associated Press on the plague's spread had made the outbreak become publicly known throughout the United States . The state governments of Colorado , Texas and Louisiana passed quarantines of California, arguing that since the state had refused to admit a health crisis within its borders, states receiving rail or shipping cargo from California ports of call had the duty to protect themselves. Threats of a national quarantine grew. As the 1902 elections approached, Southern Pacific supporters increasingly saw Gage, a man who had represented their interests since his days as a Los Angeles -based lawyer, as an embarrassment to state Republicans . This harmed Gage whose allies were mostly business interests. However, instead of putting allegations of the outbreak to rest, conflicting studies and reports from federal officials and the media continued to contradict Gage's assertions. In turn, the powerful shipping and rail companies within the state and throughout the country faced quarantine and economic boycotts from other states. At the state Republican convention that year, the Railroad Republican faction refused Gage renomination for the governorship. In his place, former Mayor of Oakland George Pardee , a German-trained medical physician, received the nomination. Pardee's nomination was largely a compromise between the Railroad and the growing progressive -minded Reform factions of the party. In his final address to the California State Legislature in early January 1903, Gage continued to publicly deny the outbreak, blaming the federal government, in particular Joseph Kinyoun, the Marine Hospital Service and the San Francisco Board of Health, for damaging the state's economy. In my first biennial message, January 7, 1901, I referred, at some length, to the subject of certain false and exaggerated reports concerning the alleged existence of bubonic plague in San Francisco, which, through the interest, ignorance, or recklessness of a few persons, were indiscriminately published in the year 1900, and thereafter intermittently continued. The falsity of the reports has been frequently proved, but, unfortunately, through the ill-designed efforts and action of Dr. J. J. Kinyoun , assuming to represent the United States Marine Hospital Service at San Francisco, and of the members of the San Francisco Board of Health , much damage nevertheless accrued to the various commercial, industrial, and other productive interests of the State, injuring alike the laborer, merchant, farmer, and fruit-grower.After leaving Sacramento , Gage returned to Los Angeles to resume his law practice. In 1909, President William Howard Taft appointed Gage as U.S. Minister to Portugal . Gage served in Lisbon for a little more than five months until November 1910. Political instability in Portugal, due to the Revolution of 1910 that deposed King Manuel II , as well as his wife's deteriorating health, forced Gage to submit his resignation to the U.S. Department of State and President Taft. He returned to California shortly afterwards. Gage died in Los Angeles on August 28, 1924, at the age of 71.Despite his administration being characterized by historians as both rocky and incompetent, a lasting legacy of Gage's tenure of office was his signing off on the establishment of the California Polytechnic State University in 1901. In 1902, Gage appointed Ulysses S. Webb as California Attorney General . Webb became one of the most successful, longest-serving attorneys general in the history of California. Gage Avenue in Los Angeles was named after him on October 28, 1929. Henry T. Gage Middle School , also located on Gage Avenue, is named after the governor. The Gage Mansion located in Bell Gardens is now the oldest remaining home in Los Angeles County and is a registered California State Historical Site. Henry Gage Mansion is a California Historic Landmark (No. 984) given the title on May 26, 1989.

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Bubonic plague

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Eyam

Eyam Eyam ( / ˈ iː m / ) is an English village and civil parish in the Derbyshire Dales that lies within the Peak District National Park . There is evidence of early occupation by Ancient Britons on the surrounding moors and lead was mined in the area by the Romans . A settlement was founded on the present site by Anglo-Saxons , when mining was continued and other industries later developed. However, Eyam's main claim to fame is the story of how the village chose to go into isolation so as to prevent infection spreading after bubonic plague was discovered there in 1665. In the later 20th century, the village's sources of livelihood largely disappeared. The local economy now relies on the tourist trade, with Eyam being promoted as "the plague village". Although the story has been kept alive by a growing number of literary works since the early 19th century, its truth has been questioned.Eyam has its own Parish Council with a wide range of powers at community level. At district level, Eyam has representation on Derbyshire Dales District Council and this, in turn, is represented on Derbyshire County Council . At parliamentary level, the village lies within the constituency of Derbyshire Dales .Lead mining seems to have had a continuous history in the Eyam district since at least the Roman era and there is evidence of habitation from earlier. Stone circles and earth barrows on the moors above the present village have largely been destroyed, although some remain and more are recorded. The most notable site is the Wet Withens stone circle on Eyam Moor . Coins bearing the names of many emperors provide evidence of Roman lead-mining locally. However, the village's name derives from Old English and is first recorded in the Domesday Book as Aium . It is a dative form of the noun ēġ ('an island') and probably refers to a patch of cultivable land amidst the moors, or else to the settlement's situation between two brooks. In the churchyard is an Anglo-Saxon cross in Mercian style dated to the 8th century, moved there from its original location beside a moorland cart track. Grade I listed and a Scheduled Monument , it is covered in complex carvings and is almost complete, but for a missing section of the shaft. The present parish church of St. Lawrence dates from the 14th century, but evidence of an earlier church there can be found in the Saxon font, a Norman window at the west end of the north aisle, and Norman pillars that are thought to rest on Saxon foundations. There have been alterations since the Middle Ages, including a large sundial dated 1775 mounted on a wall outside. Some of the rectors at the church have had contentious histories, none less than the fanatically Royalist Sherland Adams who, it was accused, "gave tythe of lead ore to the King against the Parliament", and as a consequence was removed from the living and imprisoned. The lead mining tithe was due to the rectors by ancient custom. They received one penny for every 'dish' of ore and twopence farthing for every load of hillock -stuff. Owing to the working of a newly discovered rich vein during the 18th century, the Eyam living was a valuable one. Mining continued into the 19th century, after which better sources were discovered and a change-over was made to the working and treatment of fluorspar as a slagging agent in smelting . The last to close was the Ladywash Mine, which was operative between 1948 and 1979. Within a 3-mile radius of the village there are 439 known mines (some running beneath the village itself), drained by 49 drainage levels ('soughs'). According to the 1841 Census for Eyam, there were 954 inhabitants living in the parish, chiefly employed in agriculture, lead mining, and cotton and silk weaving. By the 1881 Census , most men either worked as lead miners or in the manufacture of boots and shoes, a trade that only ended in the 1960s. The transition from industrial village to tourist-based economy is underlined by Roger Ridgeway's statement that, at the beginning of the 20th century, "a hundred horses and carts would have been seen taking fluorspar to Grindleford and Hassop stations. Until recently, up to a dozen coach loads of visiting children arrived each day in the village," and as of the 2011 Census the population has remained largely unchanged at 969. The history of the plague in the village began in 1665 when a flea -infested bundle of cloth arrived from London for Alexander Hadfield, the local tailor. Within a week his assistant George Viccars, noticing the bundle was damp, had opened it up. Before long he was dead and more began dying in the household soon after. As the disease spread, the villagers turned for leadership to their rector , the Reverend William Mompesson , and the ejected Puritan minister Thomas Stanley . They introduced a number of precautions to slow the spread of the illness from May 1666. The measures included the arrangement that families were to bury their own dead and relocation of church services to the natural amphitheatre of Cucklett Delph, allowing villagers to separate themselves and so reducing the risk of infection. Perhaps the best-known decision was to quarantine the entire village to prevent further spread of the disease. Merchants from surrounding villages sent supplies that they would leave on marked rocks; the villagers then made holes there which they would fill with vinegar to disinfect the money left as payment. The plague ran its course over 14 months and one account states that it killed at least 260 villagers, with only 83 surviving out of a population of 350. That figure has been challenged, with alternative figures of 430 survivors from a population of around 800 being given. The church in Eyam has a record of 273 individuals who were victims of the plague. Survival among those affected appeared random, as many who remained alive had close contact with those who died but never caught the disease. For example, Elizabeth Hancock was uninfected despite burying six children and her husband in eight days. The graves are known as the Riley graves after the farm where they lived. The unofficial village gravedigger , Marshall Howe, also survived, despite handling many infected bodies. Plague Sunday has been celebrated in the village since the plague's bicentenary in 1866. Originally held in mid-August, it now takes place in Cucklett Delph on the last Sunday in August, coinciding with the (much older) Wakes Week and well dressing ceremonies. Plague Sunday has been celebrated in the village since the plague's bicentenary in 1866. Originally held in mid-August, it now takes place in Cucklett Delph on the last Sunday in August, coinciding with the (much older) Wakes Week and well dressing ceremonies. Today Eyam has many plague-related places of interest. One is the Boundary Stone in the fields between Eyam and Stoney Middleton in which money, usually soaked in vinegar, which was believed to kill the infection, was placed in exchange for food and medicine. It is just one of several 'plague stones' marking the boundary that should not be crossed by either inhabitant or outsider. Another site is the isolated enclosure of the Riley graves mentioned above, now under the guardianship of the National Trust . A reminder of the village's industrial past remains in the name of its only pub, the Miner's Arms. Built in 1630, before the plague, it was originally called The Kings Arms. Opposite the church is the Mechanics' Institute , originally established in 1824, although the present building with its pillared portico dates from 1859 and was enlarged in 1894. At one time, it held a library paid for by subscription, which then contained 766 volumes. The premises now double as the village club. Up the main street is the Jacobean -styled Eyam Hall , built just after the plague. It was leased and managed by the National Trust for five years until December 2017 but is now run by the owners (the Wright Family). The green opposite has an ancient set of village stocks reputedly used to punish the locals for minor crimes. Catherine Mompesson's tabletop grave is in the churchyard and has a wreath laid on it every Plague Sunday. This is in remembrance of her constancy in staying by her husband, rather than moving away with the rest of her family, and dying in the very last days of the plague. The church's burial register also records "Anna the traveller, who according to her own account, was 136 years of age" and was interred on 30 December 1663. A more recent arrival there is the cricketer Harry Bagshaw , who played for Derbyshire and then acted as a respected umpire after retiring. At the apex of his headstone is a hand with a finger pointing upwards. Underneath the lettering a set of stumps is carved with a bat, and the bails flying off where a ball has just hit the wicket. Respect for its heritage has not always been a priority in Eyam. In his Peak Scenery (1824), Ebenezer Rhodes charges that by the start of the 19th century many former gravestones of plague victims had been pulled up to floor houses and barns and that ploughing was allowed to encroach on the Riley Graves; that the lime trees planted on either side of Mrs Mompesson's grave had been cut down for timber; that the missing piece from the shaft of the Saxon Cross had been broken up for domestic use; and that in general the profit of the living was put before respect for the dead. Two brooks flow through the village, the Jumber Brook and Hollow Brook. Eyam Museum was opened in 1994 and, besides its focus on the plague, includes exhibits on the village's local history in general. Among the art exhibits there are painted copies from different eras of a print (taken from a drawing by Francis Chantrey ) in Ebenezer Rhodes ' Peak Scenery (1818). These depict the sweep of the road by the 'plague cottages' where the first victims died, with the church tower beyond. The local amateur John Platt painted in naive style and is represented by depictions of the Riley Graves (1871) and the old windmill (1874). Since the area is scenically beautiful it has attracted many artists, among whom one of the most notable was the Sheffield artist Harry Epworth Allen . The picturesque is subordinated in his paintings of Eyam so as to interpret his subject as a living community within a worked landscape. His "Road above Eyam" (1936), now in the Laing Art Gallery , is travelled by people going about their daily business, for example, and his "Burning Limestone" in Newport Museum and Art Gallery acknowledges the two centuries and more of industrialisation by which the local inhabitants earned their living among harsh conditions. "The village of Eyam," its historian begins his account, "has been long characterized throughout the Peak of Derbyshire, as the birthplace of genius – the seat of the Muses – the Athens of the Peak". During the 18th century the place was notable for having no fewer than four poets associated with it. Reverend Peter Cunningham , curate there between 1775 and 1790, published two sermons during that time as well as several poems of a political nature. In addition, William Wood's account speaks of "numberless stones in the burial place that contain the offerings of his muse". The rector for whom Cunningham deputised much of the time, Thomas Seward , published infrequently, but at least one poem written during his tenure at Eyam deals with personal matters. His "Ode on a Lady's Illness after the Death of her Child", dated 14 April 1748, concerns the death in infancy of his daughter Jenny. Seward also encouraged one of his surviving daughters, Anna Seward , to write poetry, but only after she moved with her father to Lichfield . A pioneer of Romanticism , Seward could not hide from herself the fact that the wild natural rocks she admired were daily being blasted for utilitarian purposes and the "perpetual consumption of the ever burning lime kilns", while the view was hidden behind the smoke from the smelting works. Following a visit to her birthplace in 1788, she wrote a poem about it filled with nostalgia. She celebrated this lost domain of happiness once more in "Epistle to Mr. Newton, the Derbyshire Minstrel, on receiving his description in verse of an autumnal scene near Eyam, September 1791". No copy of the poem by William Newton now exists. The author was a labouring-class protégé from nearby, originally discovered by Cunningham and introduced to Miss Seward in 1783. The poet Richard Furness belongs to the early 19th century and was known as 'the Poet of Eyam' after his birthplace, but the bulk of his poetry too was written after he had left the district. Among the several references to the village there are his "Lines written in sight of the rectory", which praises both Anna Seward and her father. William Wood, the author of The History and Antiquities of Eyam , was a village resident. At the head of his first chapter is an excerpt from a poem that links the place with the story of the plague. Simply initialled W. W., the inference to be drawn is that it had earlier appeared in Wood's collection The genius of the Peak and other poems (1837). A later visitor from across the Peak District was Thomas Matthew Freeman, who included a blank verse meditation "On Eyam" and its plague history in his collection Spare minutes of a country parson . At the start of the following century Sarah Longsdon O'Ferrall was living at Eyam Rectory and published The Lamp of St Helen and other poems in 1912. This contained hymns sung on special occasions in Eyam and some verse referring to plague sites. Prose writers also came to live in the area. The village of Milton that figures in some of Robert Murray Gilchrist 's fiction is in fact based upon Eyam. His The Peakland Faggot (1897) consists of short stories, each focusing on a particular character in the village. This was followed by two other series, Nicholas and Mary and Other Milton Folk (1899) and Natives of Milton (1902). Eyam was also featured under its own name in Joseph Hatton 's novel The Dagger and the Cross (1897). Set in the former Bradshaw Hall in the year before the plague arrives, it includes local characters who had key roles during the spread of the disease, such as George Vicars and William and Catherine Mompesson. Eyam Museum was opened in 1994 and, besides its focus on the plague, includes exhibits on the village's local history in general. Among the art exhibits there are painted copies from different eras of a print (taken from a drawing by Francis Chantrey ) in Ebenezer Rhodes ' Peak Scenery (1818). These depict the sweep of the road by the 'plague cottages' where the first victims died, with the church tower beyond. The local amateur John Platt painted in naive style and is represented by depictions of the Riley Graves (1871) and the old windmill (1874). Since the area is scenically beautiful it has attracted many artists, among whom one of the most notable was the Sheffield artist Harry Epworth Allen . The picturesque is subordinated in his paintings of Eyam so as to interpret his subject as a living community within a worked landscape. His "Road above Eyam" (1936), now in the Laing Art Gallery , is travelled by people going about their daily business, for example, and his "Burning Limestone" in Newport Museum and Art Gallery acknowledges the two centuries and more of industrialisation by which the local inhabitants earned their living among harsh conditions. "The village of Eyam," its historian begins his account, "has been long characterized throughout the Peak of Derbyshire, as the birthplace of genius – the seat of the Muses – the Athens of the Peak". During the 18th century the place was notable for having no fewer than four poets associated with it. Reverend Peter Cunningham , curate there between 1775 and 1790, published two sermons during that time as well as several poems of a political nature. In addition, William Wood's account speaks of "numberless stones in the burial place that contain the offerings of his muse". The rector for whom Cunningham deputised much of the time, Thomas Seward , published infrequently, but at least one poem written during his tenure at Eyam deals with personal matters. His "Ode on a Lady's Illness after the Death of her Child", dated 14 April 1748, concerns the death in infancy of his daughter Jenny. Seward also encouraged one of his surviving daughters, Anna Seward , to write poetry, but only after she moved with her father to Lichfield . A pioneer of Romanticism , Seward could not hide from herself the fact that the wild natural rocks she admired were daily being blasted for utilitarian purposes and the "perpetual consumption of the ever burning lime kilns", while the view was hidden behind the smoke from the smelting works. Following a visit to her birthplace in 1788, she wrote a poem about it filled with nostalgia. She celebrated this lost domain of happiness once more in "Epistle to Mr. Newton, the Derbyshire Minstrel, on receiving his description in verse of an autumnal scene near Eyam, September 1791". No copy of the poem by William Newton now exists. The author was a labouring-class protégé from nearby, originally discovered by Cunningham and introduced to Miss Seward in 1783. The poet Richard Furness belongs to the early 19th century and was known as 'the Poet of Eyam' after his birthplace, but the bulk of his poetry too was written after he had left the district. Among the several references to the village there are his "Lines written in sight of the rectory", which praises both Anna Seward and her father. William Wood, the author of The History and Antiquities of Eyam , was a village resident. At the head of his first chapter is an excerpt from a poem that links the place with the story of the plague. Simply initialled W. W., the inference to be drawn is that it had earlier appeared in Wood's collection The genius of the Peak and other poems (1837). A later visitor from across the Peak District was Thomas Matthew Freeman, who included a blank verse meditation "On Eyam" and its plague history in his collection Spare minutes of a country parson . At the start of the following century Sarah Longsdon O'Ferrall was living at Eyam Rectory and published The Lamp of St Helen and other poems in 1912. This contained hymns sung on special occasions in Eyam and some verse referring to plague sites. Prose writers also came to live in the area. The village of Milton that figures in some of Robert Murray Gilchrist 's fiction is in fact based upon Eyam. His The Peakland Faggot (1897) consists of short stories, each focusing on a particular character in the village. This was followed by two other series, Nicholas and Mary and Other Milton Folk (1899) and Natives of Milton (1902). Eyam was also featured under its own name in Joseph Hatton 's novel The Dagger and the Cross (1897). Set in the former Bradshaw Hall in the year before the plague arrives, it includes local characters who had key roles during the spread of the disease, such as George Vicars and William and Catherine Mompesson. Some have questioned the details of the story of Eyam's response to the plague and the wisdom of the actors in it. The reviewer of the poem The Tale of Eyam in the British Medical Journal of 30 November 1889 comments on its poetic phraseology: "The author speaks of the pestilence and 'its hellborn brood'; and again of firebolts from 'heaven's reeking nostrils.' Such phraseology, says the unknown author, "aptly exemplifies the mental attitude of men who lived in the infancy of modern science, when in the plague they saw the angry stroke of offended Deity, and recognised the 'scourge' of God in what we know to be only the scourge of filth.' Shortly afterwards, writing in his A History of Epidemics in Britain (Cambridge University Press, 1891), Charles Creighton , while affirming the account of what happened, questioned the wisdom of the actions taken at the revival of the epidemic in 1666 as mistaken, though well-meaning. Instead, "the villagers of Eyam were sacrificed...to an idea, and to an idea which we may now say was not scientifically sound," suggesting that they should have fled elsewhere as long as they didn't gather together or take "tainted" articles with them. A 2005 study of Eyam's story as history claims it is no more than a literary construct fabricated long after the actual events. Contemporary reporting was rare and often the result of political or religious bias. From the dawn of the 19th century, the romanticised and sentimental accounts of events at Eyam were "largely produced by poets, writers and local historians – not doctors", : 22 as is apparent from the dissenting opinions quoted above. The 1886 bicentenary commemoration, repeated annually for close on a century and a half, is claimed by the author to be the beginning of "an overtly invented tradition" which has spawned a heritage industry to profit the village in the face its declining prosperity and population, and provided instead "a plague tourism infrastructure". : 27–31 By contrast, the 2000 study led by Dr. Steve O'Brien suggested that a human gene mutation, CCR5-Delta 32, known to give immunity from HIV, may have helped the survivors at Eyam: "the timing is right, the numbers are right..." and their descendants had a higher than average percentage of the mutation. In addition the 2016 study by Drs. Didelot and Whittles acknowledged that Eyam was "important because it gives us fantastic data for the plague." They found that human-to-human transmission was far greater than previously thought and that the village's isolation did indeed help to stop the spread of the plague. The "Eyam Hypothesis" is a medical theory named after the village's contribution to containing the spread of the plague through self-isolation. It has been proposed in the recent discussion over whether observed isolationary behaviour in sickness among vertebrates is the result of evolution or of altruism and still awaits validation. The "Eyam Hypothesis" is a medical theory named after the village's contribution to containing the spread of the plague through self-isolation. It has been proposed in the recent discussion over whether observed isolationary behaviour in sickness among vertebrates is the result of evolution or of altruism and still awaits validation.

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Bubonic plague

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The Plague Dogs (novel)

The Plague Dogs is a novel by English author Richard Adams , first published in 1977 by Allen Lane . The book centres around the friendship of two dogs that escape an animal testing facility and are subsequently pursued by both the government and the media . As in Adams' debut novel, Watership Down (1972), the animal characters in The Plague Dogs are anthropomorphised . The Plague Dogs features location maps drawn by Alfred Wainwright , a fellwalker and author. The conclusion of the book involves two real-life characters, Adams' long-time friend Ronald Lockley , and the world-famous naturalist Sir Peter Scott . Having seen a manuscript, both men readily agreed to be identified with the characters and opinions that Adams had attributed to them, as is shown in Adams' preface to the book. In 1982, The Plague Dogs was adapted into an animated feature film of the same name .This book tells of the escape of two dogs, Rowf and Snitter, from a government research station in the Lake District in England, where they had been horribly mistreated. They live on their own with help from a red fox , or "tod", who speaks to them in a Geordie dialect. After the starving dogs attack some sheep on the fells, they are reported as ferocious man-eating monsters by an opportunistic journalist. A great dog hunt follows, which is later intensified with the fear that the dogs could be carriers of a dangerous bioweapon , such as the bubonic plague .Adams stated in the book's introduction that "There is no such place in the Lake District as Animal Research (Scientific and Experimental). In reality, no single testing or experimental station would cover so wide a range of work as Animal Research. However, every 'experiment' described is one which has actually been carried out on animals somewhere." The actual location of "ARSE" (an acronym for Animal Research, Scientific and Experimental, and British slang for buttocks ) was based on the remote hill farm of Lawson Park , now run as an artist residence by the contemporary art organisation Grizedale Arts .Digby Driver: A newspaper reporter for the fictional London Orator . He is an amoral, self-centred man, writing wildly sensationalist articles with only the sketchiest grounding in fact and using blackmail to extort background information about bio-weapon research at ARSE. The media hysteria he creates causes panic among the local populace and eventually moves the government to deploy the army to exterminate the dogs. He redeems himself when he receives a letter from Snitter's hospitalized master and brings him from the hospital to the centre of the action in the nick of time to meet the boat returning the dogs to land and assert his legal claim as Snitter's owner, thus saving the dogs from summary execution by the waiting soldiers. Dr. Boycott: A senior researcher at ARSE who was in charge of the experimental programme which involved Rowf. He is callous and unfeeling, with no sympathy for either the animals in his experiments or his subordinate, Stephen Powell. His inept handling of the situation arising from the dogs' escape serves both to antagonize the local farmers, who are losing sheep to the dogs, and to provide grist to Digby Driver's mill despite his efforts to do the opposite. Harry Tyson: The odd-job man at ARSE, in charge of feeding and cleaning the animals and general care-taking duties. It is his neglecting to close Rowf's cage properly that allows the dogs to escape, but he successfully conceals his mistake by sabotaging the catch of the cage before anyone notices the missing animals. The Under Secretary: Harbottle's senior civil servant who was responsible for having ARSE set up in Lawson Park. When he and Harbottle prepare to have the dogs shot after they were rescued from sea, the warden of the Drigg Nature Reserve and Digby Driver confront them and force them to leave as Rowf chases them away. Kiff: Rowf and Snitter's former friend who was mentioned several times throughout the book. It is stated that he had black and white fur and was a friend of Rowf and Snitter. Unfortunately, he was taken away by the scientists and was sentenced to death by cumulative electrocution.Like its predecessor Watership Down , Martin Rosen directed and adapted The Plague Dogs into an animated feature film , which was released in 1982. Unlike the book, there is the implication that the Tod might still be alive in the film; a hunter who found him says he and the others "caught" a fox, this could imply the Tod is merely playing dead. In contrast to the ending in all published editions of the book—which describes the dogs being rescued from the sea, cleared of carrying the plague, and united with Snitter's lost master—the film ends the way Adams first envisioned (before being prevailed upon by his editor and others who read his original manuscript), with the dogs swimming out to sea, hoping to find what Snitter calls "The Isle of Dog" in the novel (though Rowf grimly speculates that it's probably the Isle of Man ). After swimming for a while, Snitter eventually comes to the conclusion that he imagined the island. As he is about to give up and drown, Rowf claims to directly see the island and they struggle on. It then ends with them disappearing into the mist, supposedly heading to the island. In the film's credits an island can be seen in the distance, seemingly confirming that it is real.

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Bubonic plague

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1994 plague in India

The 1994 plague in India was an outbreak of bubonic and pneumonic plague in south-central and western India from 26 August to 18 October 1994. 693 suspected cases and 56 deaths were reported from the five affected Indian states as well as the Union Territory of Delhi . These cases were from Maharashtra (488 cases), Gujarat (77 cases), Karnataka (46 cases), Uttar Pradesh (10 cases), Madhya Pradesh (4 cases) and New Delhi (68 cases). There are no reports of cases being exported to other countries. A committee under chairmanship of Professor Vulimiri Ramalingaswami was formed by the Government of India to investigate the plague episode. In 1995, the committee submitted the report "The Plague Epidemic of 1994" to the government of India. The report concluded that the disease was plague, but did not identify the origin. Other sources identify the ultimate cause as the 1993 Latur earthquake , which caused a large number of homes to be abandoned with food grains inside. This destabilised the population of domestic and wild rats (in which the plague is endemic ), allowing transmission of the plague from wild rats to domestic rats to people. The World Health Organization collected reports of excessive rat deaths in Malma in the Beed district of Maharashtra on 5 August 1994, followed by complaints of fleas. After three weeks, WHO received reports of suspected bubonic plague in Malma, followed by other villages and districts. Flooding in Surat, which had open sewers, put the bodies of many dead rats on the street, which residents probably came into contact with. The Ganesh Chaturthi festival created crowds in the city shortly thereafter, promoting the spread of pneumonic plague , which was declared on 21 September. By the end of the outbreak, an estimated 78% of confirmed cases were in the slums of Surat. In the first week of August 1994, health officials reported unusually large numbers of deaths of domestic rats in Surat city of Gujarat state. On 21 September 1994, the Deputy Municipal Commissioner of Health (DMCH) for Surat city received a report that a patient had died seemingly due to pneumonic plague . The DMCH of Surat alerted medical officers in the area where the patient had died. Later that day, a worried caller informed DMCH about 10 deaths in Ved Road residential area and around 50 seriously ill patients admitted to the hospital. News of the plague spread through Surat city through the night of 21 September 1994. Ill-prepared, medical shops quickly exhausted stocks of tetracycline . This led to panic with people fleeing hospitals fearing infection from other sick patients. This triggered one of the biggest post- partition migration of people in India with around 300,000 people leaving Surat city in 2 days, for fear of illness or of being quarantined.Initial questions about whether it was an epidemic of plague arose because the Indian health authorities were unable to culture Yersinia pestis , but this could have been due to lack of sophisticated laboratory equipment. Yet there are several lines of evidence strongly suggesting that it was a plague epidemic: blood tests for Yersinia were positive, a number of individuals showed antibodies against Yersinia and the clinical symptoms displayed by the affected were all consistent with the disease being plague. About 6,000 cases of fever were misidentified as plague, adding to panic and confusion. Villagers in Rajasthan reportedly tried to exterminate rats, which might have led to more cases as fleas would have had to abandon rat hosts for humans. Tourism was negatively affected, flights to India were cancelled, and some planes from India were fumigated at airports. Many flights from India to the nearby Gulf region were suspended. Some countries also put a hold on the imports from India. Paramilitary forces set up checkpoints to deal with people fleeing Surat. Panic buying and government-ordered closures spread to Mumbai and Delhi. Economic damage in Surat was estimated at ₹ 816 crore (₹8.160 billion). The city implemented massive infrastructure improvements, tearing down slums, covering sewers, constructing public pay toilets, and implementing fines for littering. It also improved its plans for emergency travel advisories, and fired some corrupt officials and disciplined ineffective city workers, including street sweepers.

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Bubonic plague

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Flea

Ceratophyllomorpha Hystrichopsyllomorpha Pulicomorpha Pygiopsyllomorpha Aphaniptera Flea , the common name for the order Siphonaptera , includes 2,500 species of small flightless insects that live as external parasites of mammals and birds . Fleas live by ingesting the blood of their hosts. Adult fleas grow to about 3 millimetres ( 1 ⁄ 8 inch) long, are usually brown, and have bodies that are "flattened" sideways or narrow, enabling them to move through their hosts' fur or feathers. They lack wings; their hind legs are extremely well adapted for jumping. Their claws keep them from being dislodged, and their mouthparts are adapted for piercing skin and sucking blood . They can leap 50 times their body length, a feat second only to jumps made by another group of insects, the superfamily of froghoppers . Flea larvae are worm-like, with no limbs; they have chewing mouthparts and feed on organic debris left on their hosts' skin. Genetic evidence indicates that fleas are a specialised lineage of parasitic scorpionflies (Mecoptera) sensu lato , most closely related to the family Nannochoristidae . The earliest known fleas lived in the Middle Jurassic ; modern-looking forms appeared in the Cenozoic . Fleas probably originated on mammals first and expanded their reach to birds. Each species of flea specializes, more or less, on one species of host: many species of flea never breed on any other host; some are less selective. Some families of fleas are exclusive to a single host group; for example, the Malacopsyllidae are found only on armadillos , the Ischnopsyllidae only on bats , and the Chimaeropsyllidae only on elephant shrews . The oriental rat flea, Xenopsylla cheopis , is a vector of Yersinia pestis , the bacterium that causes bubonic plague . The disease was spread to humans by rodents, such as the black rat , which were bitten by infected fleas. Major outbreaks included the Plague of Justinian , about 540, and the Black Death , about 1350, each of which killed a sizeable fraction of the world's people. Fleas appear in human culture in such diverse forms as flea circuses ; poems, such as John Donne 's erotic " The Flea "; works of music, such as those by Modest Mussorgsky ; and a film by Charlie Chaplin .Fleas are wingless insects, 1.5 to 3.3 millimetres ( 1 ⁄ 16 to 1 ⁄ 8 inch) long, that are agile, usually dark colored (for example, the reddish-brown of the cat flea ), with a proboscis , or stylet, adapted to feeding by piercing the skin and sucking their host's blood through their epipharynx. Flea legs end in strong claws that are adapted to grasp a host. Unlike other insects, fleas do not possess compound eyes but instead only have simple eyespots with a single biconvex lens; some species lack eyes altogether. Their bodies are laterally compressed, permitting easy movement through the hairs or feathers on the host's body. The flea body is covered with hard plates called sclerites. These sclerites are covered with many hairs and short spines directed backward, which also assist its movements on the host. The tough body is able to withstand great pressure, likely an adaptation to survive attempts to eliminate them by scratching. Fleas lay tiny, white, oval eggs. The larvae are small and pale, have bristles covering their worm-like bodies, lack eyes, and have mouth parts adapted to chewing. The larvae feed on organic matter, especially the feces of mature fleas, which contain dried blood. Adults feed only on fresh blood. Their legs are long, the hind pair well adapted for jumping; a flea can jump vertically up to 18 cm (7 in) and horizontally up to 33 cm (13 in) , making the flea one of the best jumpers of all known animals (relative to body size), second only to the froghopper . A flea can jump 60 times its length in height and 110 times its length in distance (vertically up to 7 inches and horizontally 13 inches). That's equivalent to a 1.8 m (6 ft) adult human jumping 360 ft vertically and 660 ft horizontally. Rarely do fleas jump from dog to dog. Most flea infestations come from newly developed fleas from the pet's environment. The flea jump is so rapid and forceful that it exceeds the capabilities of muscle, and instead of relying on direct muscle power, fleas store muscle energy in a pad of the elastic protein named resilin before releasing it rapidly (like a human using a bow and arrow). Immediately before the jump, muscles contract and deform the resilin pad, slowly storing energy which can then be released extremely rapidly to power leg extension for propulsion. To prevent premature release of energy or motions of the leg, the flea employs a "catch mechanism". Early in the jump, the tendon of the primary jumping muscle passes slightly behind the coxa-trochanter joint, generating a torque which holds the joint closed with the leg close to the body. To trigger jumping, another muscle pulls the tendon forward until it passes the joint axis, generating the opposite torque to extend the leg and power the jump by release of stored energy. The actual take off has been shown by high-speed video to be from the tibiae and tarsi rather than from the trochantera (knees). Their legs are long, the hind pair well adapted for jumping; a flea can jump vertically up to 18 cm (7 in) and horizontally up to 33 cm (13 in) , making the flea one of the best jumpers of all known animals (relative to body size), second only to the froghopper . A flea can jump 60 times its length in height and 110 times its length in distance (vertically up to 7 inches and horizontally 13 inches). That's equivalent to a 1.8 m (6 ft) adult human jumping 360 ft vertically and 660 ft horizontally. Rarely do fleas jump from dog to dog. Most flea infestations come from newly developed fleas from the pet's environment. The flea jump is so rapid and forceful that it exceeds the capabilities of muscle, and instead of relying on direct muscle power, fleas store muscle energy in a pad of the elastic protein named resilin before releasing it rapidly (like a human using a bow and arrow). Immediately before the jump, muscles contract and deform the resilin pad, slowly storing energy which can then be released extremely rapidly to power leg extension for propulsion. To prevent premature release of energy or motions of the leg, the flea employs a "catch mechanism". Early in the jump, the tendon of the primary jumping muscle passes slightly behind the coxa-trochanter joint, generating a torque which holds the joint closed with the leg close to the body. To trigger jumping, another muscle pulls the tendon forward until it passes the joint axis, generating the opposite torque to extend the leg and power the jump by release of stored energy. The actual take off has been shown by high-speed video to be from the tibiae and tarsi rather than from the trochantera (knees). Fleas are holometabolous insects, going through the four lifecycle stages of egg , larva , pupa , and imago (adult). In most species, neither female nor male fleas are fully mature when they first emerge but must feed on blood before they become capable of reproduction. The first blood meal triggers the maturation of the ovaries in females and the dissolution of the testicular plug in males, and copulation soon follows. Some species breed all year round while others synchronise their activities with their hosts' life cycles or with local environmental factors and climatic conditions. Flea populations consist of roughly 50% eggs, 35% larvae, 10% pupae, and 5% adults. The number of eggs laid depends on species, with batch sizes ranging from two to several dozen. The total number of eggs produced in a female's lifetime (fecundity) varies from around one hundred to several thousand. In some species, the flea lives in the host's nest or burrow and the eggs are deposited on the substrate, but in others, the eggs are laid on the host itself and can easily fall off onto the ground. Because of this, areas where the host rests and sleeps become one of the primary habitats of eggs and developing larvae. The eggs take around two days to two weeks to hatch. Flea larvae emerge from the eggs to feed on any available organic material such as dead insects, faeces, conspecific eggs, and vegetable matter. In laboratory studies, some dietary diversity seems necessary for proper larval development. Blood-only diets allow only 12% of larvae to mature, whereas blood and yeast or dog chow diets allow almost all larvae to mature. Another study also showed that 90% of larvae matured into adults when the diet included nonviable eggs. They are blind and avoid sunlight, keeping to dark, humid places such as sand or soil, cracks and crevices, under carpets and in bedding. The entire larval stage lasts between four and 18 days. Given an adequate supply of food, larvae pupate and weave silken cocoons after three larval stages. Within the cocoon, the larva molts for a final time and undergoes metamorphosis into the adult form. This can take just four days, but may take much longer under adverse conditions, and there follows a variable-length stage during which the pre-emergent adult awaits a suitable opportunity to emerge. Trigger factors for emergence include vibrations (including sound), heat (in warm-blooded hosts), and increased levels of carbon dioxide , all of which may indicate the presence of a suitable host. Large numbers of pre-emergent fleas may be present in otherwise flea-free environments, and the introduction of a suitable host may trigger a mass emergence. Once the flea reaches adulthood, its primary goal is to find blood and then to reproduce. Female fleas can lay 5000 or more eggs over their life, permitting rapid increase in numbers. Generally speaking, an adult flea only lives for 2 or 3 months. Without a host to provide a blood meal, a flea's life can be as short as a few days. Under ideal conditions of temperature, food supply, and humidity, adult fleas can live for up to a year and a half. Completely developed adult fleas can live for several months without eating, so long as they do not emerge from their puparia . Optimum temperatures for the flea's life cycle are 21 °C to 30 °C (70 °F to 85 °F) and optimum humidity is 70%. Adult female rabbit fleas, Spilopsyllus cuniculi , can detect the changing levels of cortisol and corticosterone hormones in the rabbit's blood that indicate it is getting close to giving birth. This triggers sexual maturity in the fleas and they start producing eggs. As soon as the baby rabbits are born, the fleas make their way down to them and once on board they start feeding, mating, and laying eggs. After 12 days, the adult fleas make their way back to the mother. They complete this mini-migration every time she gives birth. The number of eggs laid depends on species, with batch sizes ranging from two to several dozen. The total number of eggs produced in a female's lifetime (fecundity) varies from around one hundred to several thousand. In some species, the flea lives in the host's nest or burrow and the eggs are deposited on the substrate, but in others, the eggs are laid on the host itself and can easily fall off onto the ground. Because of this, areas where the host rests and sleeps become one of the primary habitats of eggs and developing larvae. The eggs take around two days to two weeks to hatch. Flea larvae emerge from the eggs to feed on any available organic material such as dead insects, faeces, conspecific eggs, and vegetable matter. In laboratory studies, some dietary diversity seems necessary for proper larval development. Blood-only diets allow only 12% of larvae to mature, whereas blood and yeast or dog chow diets allow almost all larvae to mature. Another study also showed that 90% of larvae matured into adults when the diet included nonviable eggs. They are blind and avoid sunlight, keeping to dark, humid places such as sand or soil, cracks and crevices, under carpets and in bedding. The entire larval stage lasts between four and 18 days. Given an adequate supply of food, larvae pupate and weave silken cocoons after three larval stages. Within the cocoon, the larva molts for a final time and undergoes metamorphosis into the adult form. This can take just four days, but may take much longer under adverse conditions, and there follows a variable-length stage during which the pre-emergent adult awaits a suitable opportunity to emerge. Trigger factors for emergence include vibrations (including sound), heat (in warm-blooded hosts), and increased levels of carbon dioxide , all of which may indicate the presence of a suitable host. Large numbers of pre-emergent fleas may be present in otherwise flea-free environments, and the introduction of a suitable host may trigger a mass emergence. Once the flea reaches adulthood, its primary goal is to find blood and then to reproduce. Female fleas can lay 5000 or more eggs over their life, permitting rapid increase in numbers. Generally speaking, an adult flea only lives for 2 or 3 months. Without a host to provide a blood meal, a flea's life can be as short as a few days. Under ideal conditions of temperature, food supply, and humidity, adult fleas can live for up to a year and a half. Completely developed adult fleas can live for several months without eating, so long as they do not emerge from their puparia . Optimum temperatures for the flea's life cycle are 21 °C to 30 °C (70 °F to 85 °F) and optimum humidity is 70%. Adult female rabbit fleas, Spilopsyllus cuniculi , can detect the changing levels of cortisol and corticosterone hormones in the rabbit's blood that indicate it is getting close to giving birth. This triggers sexual maturity in the fleas and they start producing eggs. As soon as the baby rabbits are born, the fleas make their way down to them and once on board they start feeding, mating, and laying eggs. After 12 days, the adult fleas make their way back to the mother. They complete this mini-migration every time she gives birth. Between 1735 and 1758, the Swedish naturalist Carl Linnaeus first classified insects, doing so on the basis of their wing structure. One of the seven orders into which he divided them was "Aptera", meaning wingless, a group in which as well as fleas, he included spiders , woodlice and myriapods . It wasn't until 1810 that the French zoologist Pierre André Latreille reclassified the insects on the basis of their mouthparts as well as their wings, splitting Aptera into Thysanura (silverfish), Anoplura (sucking lice) and Siphonaptera (fleas), at the same time separating off the arachnids and crustaceans into their own subphyla. The group's name, Siphonaptera, is zoological Latin from the Greek siphon (a tube) and aptera (wingless). It was historically unclear whether the Siphonaptera are sister to the Mecoptera (scorpionflies and allies), or are inside that clade, making "Mecoptera" paraphyletic. The earlier suggestion that the Siphonaptera are sister to the Boreidae (snow scorpionflies) is not supported. A 2020 genetic study recovered Siphonaptera within Mecoptera, with strong support, as the sister group to Nannochoristidae , a small, relictual group of mecopterans native to the Southern Hemisphere. Fleas and nannochoristids share several similarities with each other that are not shared with other mecopterans, including similar mouthparts as well as a similar sperm pump organisation. Relationships of Siphonaptera per Tihelka et al. 2020. Diptera (true flies) Boreidae (snow scorpionflies, 30 spp.) Nannochoristidae (southern scorpionflies, 8 spp.) Siphonaptera (fleas, 2500 spp.) Pistillifera (scorpionflies, hangingflies, 400 spp .) Fleas likely descended from scorpionflies , insects that are predators or scavengers. Fossils of large, wingless stem-group fleas with siphonate (sucking) mouthparts from the Middle Jurassic to Early Cretaceous have been found in northeastern China and Russia, belonging to the families Saurophthiridae and Pseudopulicidae , as well as Tarwinia from the Early Cretaceous of Australia. Most flea families formed after the end of the Cretaceous (in the Paleogene and onwards). Modern fleas probably arose in the southern continental area of Gondwana , and migrated rapidly northwards from there. They most likely evolved with mammal hosts, only later moving to birds . Siphonaptera is a relatively small order of insects: members of the order undergo complete metamorphosis and are secondarily wingless (their ancestors had wings which modern forms have lost). In 2005, Medvedev listed 2005 species in 242 genera, and despite subsequent descriptions of new species, bringing the total up to around 2500 species, this is the most complete database available. The order is divided into four infraorders and eighteen families. Some families are exclusive to a single host group; these include the Malacopsyllidae ( armadillos ), Ischnopsyllidae ( bats ) and Chimaeropsyllidae ( elephant shrews ). Many of the known species are little studied. Some 600 species (a quarter of the total) are known from single records. Over 94% of species are associated with mammalian hosts, and only about 3% of species can be considered to be specific parasites of birds . The fleas on birds are thought to have originated from mammalian fleas; at least sixteen separate groups of fleas switched to avian hosts during the evolutionary history of the Siphonaptera. Occurrences of fleas on reptiles is accidental, and fleas have been known to feed on the hemolymph (bloodlike body fluid) of ticks . Flea phylogeny was long neglected, the discovery of homologies with the parts of other insects being made difficult by their extreme specialization. Whiting and colleagues prepared a detailed molecular phylogeny in 2008, with the basic structure shown in the cladogram. The Hectopsyllidae , including the harmful chigoe flea or jigger , is sister to the rest of the Siphonaptera. Hectopsyllidae (inc. jigger ) Pygiopsyllomorpha Macropsyllidae , Coptopsyllidae Neotyphloceratini , Ctenophthalmini , Doratopsyllinae Stephanocircidae clade inc. Rhopalopsyllidae , Ctenophthalmidae , Hystrichopsyllidae Chimaeropsyllidae Pulicidae (inc. the cat flea , vector of bubonic plague ) Ceratophyllomorpha (inc. the Ceratophyllidae , such as the widespread moorhen flea )Between 1735 and 1758, the Swedish naturalist Carl Linnaeus first classified insects, doing so on the basis of their wing structure. One of the seven orders into which he divided them was "Aptera", meaning wingless, a group in which as well as fleas, he included spiders , woodlice and myriapods . It wasn't until 1810 that the French zoologist Pierre André Latreille reclassified the insects on the basis of their mouthparts as well as their wings, splitting Aptera into Thysanura (silverfish), Anoplura (sucking lice) and Siphonaptera (fleas), at the same time separating off the arachnids and crustaceans into their own subphyla. The group's name, Siphonaptera, is zoological Latin from the Greek siphon (a tube) and aptera (wingless). It was historically unclear whether the Siphonaptera are sister to the Mecoptera (scorpionflies and allies), or are inside that clade, making "Mecoptera" paraphyletic. The earlier suggestion that the Siphonaptera are sister to the Boreidae (snow scorpionflies) is not supported. A 2020 genetic study recovered Siphonaptera within Mecoptera, with strong support, as the sister group to Nannochoristidae , a small, relictual group of mecopterans native to the Southern Hemisphere. Fleas and nannochoristids share several similarities with each other that are not shared with other mecopterans, including similar mouthparts as well as a similar sperm pump organisation. Relationships of Siphonaptera per Tihelka et al. 2020. Diptera (true flies) Boreidae (snow scorpionflies, 30 spp.) Nannochoristidae (southern scorpionflies, 8 spp.) Siphonaptera (fleas, 2500 spp.) Pistillifera (scorpionflies, hangingflies, 400 spp .)Fleas likely descended from scorpionflies , insects that are predators or scavengers. Fossils of large, wingless stem-group fleas with siphonate (sucking) mouthparts from the Middle Jurassic to Early Cretaceous have been found in northeastern China and Russia, belonging to the families Saurophthiridae and Pseudopulicidae , as well as Tarwinia from the Early Cretaceous of Australia. Most flea families formed after the end of the Cretaceous (in the Paleogene and onwards). Modern fleas probably arose in the southern continental area of Gondwana , and migrated rapidly northwards from there. They most likely evolved with mammal hosts, only later moving to birds . Siphonaptera is a relatively small order of insects: members of the order undergo complete metamorphosis and are secondarily wingless (their ancestors had wings which modern forms have lost). In 2005, Medvedev listed 2005 species in 242 genera, and despite subsequent descriptions of new species, bringing the total up to around 2500 species, this is the most complete database available. The order is divided into four infraorders and eighteen families. Some families are exclusive to a single host group; these include the Malacopsyllidae ( armadillos ), Ischnopsyllidae ( bats ) and Chimaeropsyllidae ( elephant shrews ). Many of the known species are little studied. Some 600 species (a quarter of the total) are known from single records. Over 94% of species are associated with mammalian hosts, and only about 3% of species can be considered to be specific parasites of birds . The fleas on birds are thought to have originated from mammalian fleas; at least sixteen separate groups of fleas switched to avian hosts during the evolutionary history of the Siphonaptera. Occurrences of fleas on reptiles is accidental, and fleas have been known to feed on the hemolymph (bloodlike body fluid) of ticks . Flea phylogeny was long neglected, the discovery of homologies with the parts of other insects being made difficult by their extreme specialization. Whiting and colleagues prepared a detailed molecular phylogeny in 2008, with the basic structure shown in the cladogram. The Hectopsyllidae , including the harmful chigoe flea or jigger , is sister to the rest of the Siphonaptera. Hectopsyllidae (inc. jigger ) Pygiopsyllomorpha Macropsyllidae , Coptopsyllidae Neotyphloceratini , Ctenophthalmini , Doratopsyllinae Stephanocircidae clade inc. Rhopalopsyllidae , Ctenophthalmidae , Hystrichopsyllidae Chimaeropsyllidae Pulicidae (inc. the cat flea , vector of bubonic plague ) Ceratophyllomorpha (inc. the Ceratophyllidae , such as the widespread moorhen flea )As of 2023 [ update ] , there are 21 recognized families within the order Siphonaptera, 3 of which are extinct. In addition, some researchers have suggested that the subfamily Stenoponiinae should be elevated to its own family ( Stenoponiidae ). Fleas feed on a wide variety of warm-blooded vertebrates including dogs, cats, rabbits, squirrels, ferrets, rats, mice, birds, and sometimes humans. Fleas normally specialise in one host species or group of species, but can often feed but not reproduce on other species. Ceratophyllus gallinae affects poultry as well as wild birds. As well as the degree of relatedness of a potential host to the flea's original host, it has been shown that avian fleas that exploit a range of hosts, only parasitise species with low immune responses. In general, host specificity decreases as the size of the host species decreases. Another factor is the opportunities available to the flea to change host species; this is smaller in colonially nesting birds, where the flea may never encounter another species, than it is in solitary nesting birds. A large, long-lived host provides a stable environment that favours host-specific parasites. Although there are species named dog fleas ( Ctenocephalides canis Curtis, 1826) and cat fleas ( Ctenocephalides felis ), fleas are not always strictly species-specific. A study in Virginia examined 244 fleas from 29 dogs: all were cat fleas. Dog fleas had not been found in Virginia in more than 70 years, and may not even occur in the US, so a flea found on a dog is likely a cat flea ( Ctenocephalides felis ). One theory of human hairlessness is that the loss of hair helped humans to reduce their burden of fleas and other ectoparasites. In many species, fleas are principally a nuisance to their hosts, causing an itching sensation which in turn causes the host to try to remove the pest by biting, pecking or scratching. Fleas are not simply a source of annoyance, however. Flea bites cause a slightly raised, swollen, irritating nodule to form on the epidermis at the site of each bite, with a single puncture point at the centre, like a mosquito bite. : 126 This can lead to an eczematous itchy skin disease called flea allergy dermatitis , which is common in many host species, including dogs and cats. The bites often appear in clusters or lines of two bites, and can remain itchy and inflamed for up to several weeks afterwards. Fleas can lead to secondary hair loss as a result of frequent scratching and biting by the animal. They can also cause anemia in extreme cases. : 126 Fleas are vectors for viral , bacterial and rickettsial diseases of humans and other animals, as well as of protozoan and helminth parasites. Bacterial diseases carried by fleas include murine or endemic typhus : 124 and bubonic plague . Fleas can transmit Rickettsia typhi , Rickettsia felis , Bartonella henselae , and the myxomatosis virus. : 73 They can carry Hymenolepiasis tapeworms and Trypanosome protozoans. : 74 The chigoe flea or jigger ( Tunga penetrans ) causes the disease tungiasis , a major public health problem around the world. Fleas that specialize as parasites on specific mammals may use other mammals as hosts; thus, humans may be bitten by cat and dog fleas. In many species, fleas are principally a nuisance to their hosts, causing an itching sensation which in turn causes the host to try to remove the pest by biting, pecking or scratching. Fleas are not simply a source of annoyance, however. Flea bites cause a slightly raised, swollen, irritating nodule to form on the epidermis at the site of each bite, with a single puncture point at the centre, like a mosquito bite. : 126 This can lead to an eczematous itchy skin disease called flea allergy dermatitis , which is common in many host species, including dogs and cats. The bites often appear in clusters or lines of two bites, and can remain itchy and inflamed for up to several weeks afterwards. Fleas can lead to secondary hair loss as a result of frequent scratching and biting by the animal. They can also cause anemia in extreme cases. : 126Fleas are vectors for viral , bacterial and rickettsial diseases of humans and other animals, as well as of protozoan and helminth parasites. Bacterial diseases carried by fleas include murine or endemic typhus : 124 and bubonic plague . Fleas can transmit Rickettsia typhi , Rickettsia felis , Bartonella henselae , and the myxomatosis virus. : 73 They can carry Hymenolepiasis tapeworms and Trypanosome protozoans. : 74 The chigoe flea or jigger ( Tunga penetrans ) causes the disease tungiasis , a major public health problem around the world. Fleas that specialize as parasites on specific mammals may use other mammals as hosts; thus, humans may be bitten by cat and dog fleas. Fleas have appeared in poetry, literature, music and art; these include Robert Hooke 's drawing of a flea under the microscope in his pioneering book Micrographia published in 1665, poems by Donne and Jonathan Swift , works of music by Giorgio Federico Ghedini and Modest Mussorgsky , a play by Georges Feydeau , a film by Charlie Chaplin , and paintings by artists such as Giuseppe Crespi , Giovanni Battista Piazzetta , and Georges de La Tour . John Donne's erotic metaphysical poem " The Flea ", published in 1633 after his death, uses the conceit of a flea, which has sucked blood from the male speaker and his female lover, as an extended metaphor for their sexual relationship. The speaker tries to convince a lady to sleep with him, arguing that if the mingling of their blood in the flea is innocent, then sex would be also. The comic poem Siphonaptera was written in 1915 by the mathematician Augustus De Morgan , It describes an infinite chain of parasitism made of ever larger and ever smaller fleas. Flea circuses provided entertainment to nineteenth century audiences. These circuses, extremely popular in Europe from 1830 onwards, featured fleas dressed as humans or towing miniature carts, chariots , rollers or cannon . These devices were originally made by watchmakers or jewellers to show off their skill at miniaturization. A ringmaster called a "professor" accompanied their performance with a rapid circus patter. Oriental rat fleas , Xenopsylla cheopis , can carry the coccobacillus Yersinia pestis . The infected fleas feed on rodent vectors of this bacterium, such as the black rat , Rattus rattus , and then infect human populations with the plague , as has happened repeatedly from ancient times, as in the Plague of Justinian in 541–542. Outbreaks killed up to 200 million people across Europe between 1346 and 1671. The Black Death pandemic between 1346 and 1353 likely killed over a third of the population of Europe. Because fleas carry plague, they have seen service as a biological weapon . During World War II , the Japanese army dropped fleas infested with Y. pestis in China. The bubonic and septicaemic plagues are the most probable form of the plague that would spread as a result of a bioterrorism attack that used fleas as a vector. The banker Charles Rothschild devoted much of his time to entomology , creating a large collection of fleas now in the Rothschild Collection at the Natural History Museum, London . He discovered and named the plague vector flea, Xenopsylla cheopis , also known as the oriental rat flea, in 1903. Using what was probably the world's most complete collection of fleas of about 260,000 specimens (representing some 73% of the 2,587 species and subspecies so far described), he described around 500 species and subspecies of Siphonaptera. He was followed in this interest by his daughter Miriam Rothschild , who helped to catalogue his enormous collection of the insects in seven volumes. Fleas have a significant economic impact. In America alone, approximately $2.8 billion is spent annually on flea-related veterinary bills and another $1.6 billion annually for flea treatment with pet groomers. Four billion dollars is spent annually for prescription flea treatment and $348 million for flea pest control. Fleas have appeared in poetry, literature, music and art; these include Robert Hooke 's drawing of a flea under the microscope in his pioneering book Micrographia published in 1665, poems by Donne and Jonathan Swift , works of music by Giorgio Federico Ghedini and Modest Mussorgsky , a play by Georges Feydeau , a film by Charlie Chaplin , and paintings by artists such as Giuseppe Crespi , Giovanni Battista Piazzetta , and Georges de La Tour . John Donne's erotic metaphysical poem " The Flea ", published in 1633 after his death, uses the conceit of a flea, which has sucked blood from the male speaker and his female lover, as an extended metaphor for their sexual relationship. The speaker tries to convince a lady to sleep with him, arguing that if the mingling of their blood in the flea is innocent, then sex would be also. The comic poem Siphonaptera was written in 1915 by the mathematician Augustus De Morgan , It describes an infinite chain of parasitism made of ever larger and ever smaller fleas. Flea circuses provided entertainment to nineteenth century audiences. These circuses, extremely popular in Europe from 1830 onwards, featured fleas dressed as humans or towing miniature carts, chariots , rollers or cannon . These devices were originally made by watchmakers or jewellers to show off their skill at miniaturization. A ringmaster called a "professor" accompanied their performance with a rapid circus patter. Oriental rat fleas , Xenopsylla cheopis , can carry the coccobacillus Yersinia pestis . The infected fleas feed on rodent vectors of this bacterium, such as the black rat , Rattus rattus , and then infect human populations with the plague , as has happened repeatedly from ancient times, as in the Plague of Justinian in 541–542. Outbreaks killed up to 200 million people across Europe between 1346 and 1671. The Black Death pandemic between 1346 and 1353 likely killed over a third of the population of Europe. Because fleas carry plague, they have seen service as a biological weapon . During World War II , the Japanese army dropped fleas infested with Y. pestis in China. The bubonic and septicaemic plagues are the most probable form of the plague that would spread as a result of a bioterrorism attack that used fleas as a vector. The banker Charles Rothschild devoted much of his time to entomology , creating a large collection of fleas now in the Rothschild Collection at the Natural History Museum, London . He discovered and named the plague vector flea, Xenopsylla cheopis , also known as the oriental rat flea, in 1903. Using what was probably the world's most complete collection of fleas of about 260,000 specimens (representing some 73% of the 2,587 species and subspecies so far described), he described around 500 species and subspecies of Siphonaptera. He was followed in this interest by his daughter Miriam Rothschild , who helped to catalogue his enormous collection of the insects in seven volumes. Fleas have a significant economic impact. In America alone, approximately $2.8 billion is spent annually on flea-related veterinary bills and another $1.6 billion annually for flea treatment with pet groomers. Four billion dollars is spent annually for prescription flea treatment and $348 million for flea pest control.

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Bubonic plague

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Pax Mongolica

The Pax Mongolica (Latin for "Mongol Peace"), less often known as Pax Tatarica ("Tatar Peace"), is a historiographical term modeled after the original phrase Pax Romana which describes the stabilizing effects of the conquests of the Mongol Empire on the social, cultural and economic life of the inhabitants of the vast Eurasian territory that the Mongols conquered in the 13th and 14th centuries. The term is used to describe the eased communication and commerce the unified administration helped to create and the period of relative peace that followed the Mongols' vast and violent conquests . The conquests of Genghis Khan (r. 1206–1227) and his successors , spanning from Southeast Asia to Eastern Europe , effectively connected the Eastern world with the Western world . The Silk Road , connecting trade centres across Asia and Europe , came under the sole rule of the Mongol Empire. It was commonly said that "a maiden bearing a nugget of gold on her head could wander safely throughout the realm". Despite the political fragmentation of the Mongol Empire into four khanates ( Yuan dynasty , Golden Horde , Chagatai Khanate and Ilkhanate ), nearly a century of conquest and civil war was followed by relative stability in the early 14th century. The end of the Pax Mongolica was marked by the disintegration of the khanates and the outbreak of the Black Death in Asia which spread along trade routes to much of the world in the mid-14th century. During this time, Mongol elements including the 'Phags-pa script made numerous appearances in Western art .Pax Mongolica followed the wake of conquests by the Mongol Empire beginning with Genghis Khan in the early 13th century. In the process of conquering the various tribes in the region, Genghis Khan revolutionised the way Mongolian tribal society was structured. After each new victory, more and more people were incorporated under Genghis Khan's rule, thus diversifying the societal balance of the tribe. In 1203, Genghis Khan, in an effort to strengthen his army, ordered a reform that reorganised his army's structure while breaking down the traditional clan- and kindred-based divisions that had previously fragmented the society and military. He arranged his army into arbans (inter-ethnic groups of ten), and the members of an arban were commanded to be loyal to one another regardless of ethnic origin. Ten arbans made a zuun , or a company; ten zuuns made a myangan , or a battalion; and ten myangans formed a tumen , or an army of 10,000. This decimal system organisation of Genghis Khan's strong military would prove very effective in conquering, by persuasion or force, the many tribes of the central Asian steppe, but it would also strengthen Mongol society as a whole. By 1206 Genghis Khan's military expansion had unified the tribes of Mongolia, and in the same year he was elected and acclaimed as the leader of Mongolia . The new Mongol empire quickly moved to annex more territory. The first Mongol conquests were campaigns against the Western Xia . In 1209 the Mongols conquered the Western Xia. Between 1213 and 1214 the Mongols conquered the Jin Empire , and by 1214 the Mongols had captured most of the land north of the Yellow River . In 1221 Mongol generals Jebe and Subodei began their expedition around the Caspian Sea and into Kievan Rus '; Genghis Khan defeated Turkic Jalal ad-Din Mingburnu at the Battle of Indus ; the Khwarezmian Empire were defeated that same year. In 1235 the Mongols successfully invaded Korea . Two years later in 1237 Batu Khan and Subodei began their conquest of Rus' ; they invaded Poland and Hungary in 1241. In 1252 the Mongols began their invasion of Song China ; they would seize the capital of Hangzhou in 1276. In 1258 Hulagu Khan captured Baghdad . Each new victory gave the Mongols the chance to incorporate new people, especially foreign engineers and labourers , into their society. Each new conquest also acquired new trade routes and the opportunity to control taxation and tribute . Thus, through territorial expansion, the Mongol Nation not only became an empire, but also became more technologically and economically advanced. At its height, the Mongolian empire stretched from Busan in the east to Budapest in the west, from Lithuania in the north to Vietnam in the south. This meant that an extremely large part of the continent was united under one political authority. As a result, the trade routes used by merchants became safe for travel, resulting in an overall growth and expansion of trade from China in the east to Britain in the west. Thus, the Pax Mongolica greatly influenced many civilizations in Eurasia during the 13th and 14th centuries. Under the Mongols new technologies and commodities were exchanged across the Old World , particularly Eurasia. Thomas T. Allsen noted many personnel exchanges occurred during the Mongol period. There were many significant developments in economy (especially trade and public finance), military , medicine , agriculture , cuisine , astronomy , printing , geography , and historiography , which were not limited to Eurasia but also included North Africa . Before the Mongols' rise, the Old World system consisted of isolated imperial systems. The new Mongol empire amalgamated the once isolated civilizations into a new continental system, and re-established the Silk Road as a dominant method of transportation. The unification of Eurasia under the Mongols greatly diminished the number of competing tribute gatherers throughout the trade network and assured greater safety and security in travel. During the Pax Mongolica , European merchants like Marco Polo made their way from Europe to China on the well-maintained and well travelled roads that linked Anatolia to China. On the Silk Road caravans with Chinese silk ; pepper , ginger , cinnamon , and nutmeg came to the West from the Spice Islands via the transcontinental trade routes. Eastern diets were introduced to Europeans as well. Indian muslins, cottons, pearls, and precious stones were sold in Europe, as well as weapons, carpets, and leather goods from Iran . Gunpowder was also introduced to Europe from China. In the opposite direction, Europeans sent silver, fine cloth, horses, linen, and other goods to the near and far East. Increasing trade and commerce meant that the respective nations and societies increased their exposure to new goods and markets, thus increasing the GDP of each nation or society that was involved in the trade system. Μany of the cities participating in the 13th century world trade system grew rapidly in size. Along with land trade routes, a Maritime Silk Road contributed to the flow of goods and establishment of a Pax Mongolica . This Maritime Silk Road started with short coastal routes in Southern China. As technology and navigation progressed these routes developed into a high-seas route into the Indian Ocean. Eventually these routes further developed encompassing the Arabian Sea , Persian Gulf , Red Sea , and the sea off East Africa. Along with tangible goods, people, techniques, information, and ideas moved lucidly across the Eurasian landmass for the first time. For example, John of Montecorvino , archbishop of Beijing founded Roman Catholic missions in India and China and also translated the New Testament into the Mongolian language. Long-distance trade brought new methods of doing business from the far East to Europe; bills of exchange , deposit banking, and insurance were introduced to Europe during the Pax Mongolica . Bills of exchange made it significantly easier to travel long distances because a traveller would not be burdened by the weight of metal coins. Islamic methods of mathematics , astronomy , and science made their way to Africa , East Asia and Europe during the Pax Mongolica . Methods of paper-making and printing made their way from China to Europe. Rudimentary banking systems were established, and money changing and credit extension were common, resulting in large amounts of merchant wealth. Mongolia's central geographical position on the Asian continent was an important reason why it was able to play such a large role in the trade system. The Mongol army was easily able to assert strong rule [ specify ] throughout most of the empire . The military ensured that supply lines and trade routes flowed smoothly; permanent garrisons were established along trade routes to protect the travelers on these routes. Complex local systems of taxation and extortion that were prevalent before Mongol rule were abolished to ensure the smooth flow of merchants and trade through the empire. A system of weights-and-measures was also standardised. To make the voyage on the trade routes less harrowing, the Mongols went as far as to plant trees along the roads to shade the merchants and travelers in the summer months; stone pillars were used to mark the roads where trees could not grow. The Mongols sought alliances with other nations and societies to ensure the flow of trade through the empire. The Mongol army was also used to reshape and streamline the flow of trade through the continent by destroying cities on the less-important or more inaccessible routes. The Mongol military was mostly made up of cavalrymen. This allowed the military to move swiftly and easily over large distances. The Mongols developed the concepts of liability in relation to investments and loans in Mongol–ortoq partnerships, promoting trade and investment to facilitate the commercial integration of the Mongol Empire. In Mongol times, the contractual features of a Mongol- ortoq partnership closely resembled that of qirad and commenda arrangements, however, Mongol investors used metal coins, paper money, gold and silver ingots and tradable goods for partnership investments and primarily financed money-lending and trade activities. Moreover, Mongol elites formed trade partnerships with merchants from Central and Western Asia and Europe, including Chinese and Marco Polo 's family. The code of Mongol law, known as the Yassa ("Great Law"), decreed strict rules and punishments in many areas of the Mongolian Empire's society, especially those areas concerning trade and commerce. The Yassa helped suppress the traditional causes of tribal feuding and war, thus helping to ensure a peaceful trading and traveling environment. Theft and animal rustling were outlawed, and the Mongol Empire under Genghis Khan even established a massive lost-and-found system. Harsh penalties including a retribution of nine times the original value of stolen goods helped deter theft on Mongol roads. The Yassa also decreed complete religious freedom, ensuring that Buddhists , Muslims , Christians , etc., were all allowed to travel freely throughout the empire; religious leaders were also exempted from taxation, as were doctors, lawyers, undertakers , teachers, and scholars. The Yassa did allow for flexibility and it usually adapted, absorbed, or built upon legal systems in remote parts of the empire, thus maintaining a level of openness to various societies and ensuring peace and stability. In order to ensure Mongol law was enforced, a hierarchy of legal administration was developed. This was headed by the Secretarial Council "chung-shu-sheng" (中書省) of the central government which oversaw 10 provincial governments known as "hsing-sheng" (行省). The Xingsheng was further split into smaller districts which handled legal cases. A police commissioner known as "hsien wei" (縣委) was entrusted with law enforcement and had the authority to arrest suspects. This method of federalising the empire made it easier and more efficient for laws to be administered throughout the continent. The Mongols established the Yam ( Mongolian : Өртөө , Örtöö , checkpoint ), the first system of communication that connected the Far East and the West. Relay stations were set up every 25–30 miles or an average day's journey on horse. These stations were introduced by Ögedei Khan in 1234 and supplied fresh horses and fodder . His brothers Chagatai Khan and Tolui and his nephew Batu Khan further extended this network. The Mongol army administered the Yam . The Yam stretched across Mongol territory from Eastern Europe to the Pacific Ocean. The routes were well organised, funded, maintained, and administered by the Mongols. This highly sophisticated system of communication and travel made it relatively easy to send important messages and travel long distances in relatively short amounts of time. As a result of the relatively lucid communication and ease of movement, the Mongols were able to govern their vast empire effectively, thereby ensuring political and economic stability. Before the Mongols' rise, the Old World system consisted of isolated imperial systems. The new Mongol empire amalgamated the once isolated civilizations into a new continental system, and re-established the Silk Road as a dominant method of transportation. The unification of Eurasia under the Mongols greatly diminished the number of competing tribute gatherers throughout the trade network and assured greater safety and security in travel. During the Pax Mongolica , European merchants like Marco Polo made their way from Europe to China on the well-maintained and well travelled roads that linked Anatolia to China. On the Silk Road caravans with Chinese silk ; pepper , ginger , cinnamon , and nutmeg came to the West from the Spice Islands via the transcontinental trade routes. Eastern diets were introduced to Europeans as well. Indian muslins, cottons, pearls, and precious stones were sold in Europe, as well as weapons, carpets, and leather goods from Iran . Gunpowder was also introduced to Europe from China. In the opposite direction, Europeans sent silver, fine cloth, horses, linen, and other goods to the near and far East. Increasing trade and commerce meant that the respective nations and societies increased their exposure to new goods and markets, thus increasing the GDP of each nation or society that was involved in the trade system. Μany of the cities participating in the 13th century world trade system grew rapidly in size. Along with land trade routes, a Maritime Silk Road contributed to the flow of goods and establishment of a Pax Mongolica . This Maritime Silk Road started with short coastal routes in Southern China. As technology and navigation progressed these routes developed into a high-seas route into the Indian Ocean. Eventually these routes further developed encompassing the Arabian Sea , Persian Gulf , Red Sea , and the sea off East Africa. Along with tangible goods, people, techniques, information, and ideas moved lucidly across the Eurasian landmass for the first time. For example, John of Montecorvino , archbishop of Beijing founded Roman Catholic missions in India and China and also translated the New Testament into the Mongolian language. Long-distance trade brought new methods of doing business from the far East to Europe; bills of exchange , deposit banking, and insurance were introduced to Europe during the Pax Mongolica . Bills of exchange made it significantly easier to travel long distances because a traveller would not be burdened by the weight of metal coins. Islamic methods of mathematics , astronomy , and science made their way to Africa , East Asia and Europe during the Pax Mongolica . Methods of paper-making and printing made their way from China to Europe. Rudimentary banking systems were established, and money changing and credit extension were common, resulting in large amounts of merchant wealth. Mongolia's central geographical position on the Asian continent was an important reason why it was able to play such a large role in the trade system. The Mongol army was easily able to assert strong rule [ specify ] throughout most of the empire . The military ensured that supply lines and trade routes flowed smoothly; permanent garrisons were established along trade routes to protect the travelers on these routes. Complex local systems of taxation and extortion that were prevalent before Mongol rule were abolished to ensure the smooth flow of merchants and trade through the empire. A system of weights-and-measures was also standardised. To make the voyage on the trade routes less harrowing, the Mongols went as far as to plant trees along the roads to shade the merchants and travelers in the summer months; stone pillars were used to mark the roads where trees could not grow. The Mongols sought alliances with other nations and societies to ensure the flow of trade through the empire. The Mongol army was also used to reshape and streamline the flow of trade through the continent by destroying cities on the less-important or more inaccessible routes. The Mongol military was mostly made up of cavalrymen. This allowed the military to move swiftly and easily over large distances. The Mongols developed the concepts of liability in relation to investments and loans in Mongol–ortoq partnerships, promoting trade and investment to facilitate the commercial integration of the Mongol Empire. In Mongol times, the contractual features of a Mongol- ortoq partnership closely resembled that of qirad and commenda arrangements, however, Mongol investors used metal coins, paper money, gold and silver ingots and tradable goods for partnership investments and primarily financed money-lending and trade activities. Moreover, Mongol elites formed trade partnerships with merchants from Central and Western Asia and Europe, including Chinese and Marco Polo 's family. The code of Mongol law, known as the Yassa ("Great Law"), decreed strict rules and punishments in many areas of the Mongolian Empire's society, especially those areas concerning trade and commerce. The Yassa helped suppress the traditional causes of tribal feuding and war, thus helping to ensure a peaceful trading and traveling environment. Theft and animal rustling were outlawed, and the Mongol Empire under Genghis Khan even established a massive lost-and-found system. Harsh penalties including a retribution of nine times the original value of stolen goods helped deter theft on Mongol roads. The Yassa also decreed complete religious freedom, ensuring that Buddhists , Muslims , Christians , etc., were all allowed to travel freely throughout the empire; religious leaders were also exempted from taxation, as were doctors, lawyers, undertakers , teachers, and scholars. The Yassa did allow for flexibility and it usually adapted, absorbed, or built upon legal systems in remote parts of the empire, thus maintaining a level of openness to various societies and ensuring peace and stability. In order to ensure Mongol law was enforced, a hierarchy of legal administration was developed. This was headed by the Secretarial Council "chung-shu-sheng" (中書省) of the central government which oversaw 10 provincial governments known as "hsing-sheng" (行省). The Xingsheng was further split into smaller districts which handled legal cases. A police commissioner known as "hsien wei" (縣委) was entrusted with law enforcement and had the authority to arrest suspects. This method of federalising the empire made it easier and more efficient for laws to be administered throughout the continent. The Mongols established the Yam ( Mongolian : Өртөө , Örtöö , checkpoint ), the first system of communication that connected the Far East and the West. Relay stations were set up every 25–30 miles or an average day's journey on horse. These stations were introduced by Ögedei Khan in 1234 and supplied fresh horses and fodder . His brothers Chagatai Khan and Tolui and his nephew Batu Khan further extended this network. The Mongol army administered the Yam . The Yam stretched across Mongol territory from Eastern Europe to the Pacific Ocean. The routes were well organised, funded, maintained, and administered by the Mongols. This highly sophisticated system of communication and travel made it relatively easy to send important messages and travel long distances in relatively short amounts of time. As a result of the relatively lucid communication and ease of movement, the Mongols were able to govern their vast empire effectively, thereby ensuring political and economic stability. The decline of Pax Mongolica was a result of a number of factors: incompetent and rivaling leaders, corruption, revolts, decadence , factional struggles, assassinations, external attacks, and disease. The decline of the Pax Mongolica resulted in a decline of eased trade between East and West. The Mongol Empire, near the time of its decline, consisted of many different territories. Each territory was defined as a " khanate ". Due to the isolation [ specify ] of the Mongolian world, many rulers in the 14th century started to focus on their own khanates. Religious intolerance was one particular factor in the decline of the Pax Mongolica . In Rus ', the Mongols (known as the Golden Horde ), gradually lost power and territory due to intolerance specifically geared towards different religions. The Rus' Mongols converted to Islam and joined the Egyptian Mamluks for political reasons. At one point in the war [ specify ] , the Golden Horde even fought the Persian Mongols . The eastern part of the Golden Horde, White Horde , had friendly relations with the Ilkhanate and the Great Khan. The decentralisation occurred because communication was so difficult due to the collapsing trade system and the rivalry between Mongol princes. Eventually, the Persian Mongol leader Ghazan converted to Islam in 1295. This contributed to the growing power of Nawruz ; a Muslim Oirat general. In China, descendants of Kublai Khan claimed the Mongols weakened their power by becoming "too Chinese". This led to Yuan emperors separating themselves from their subjects in order to stress their Mongol identity and to reject their Chinese culture. Kublai Khan once promoted Chinese culture and the importance of its practice but under the Yuan emperors this was prohibited. As the Chinese culture was changing, intolerance became more common. Some Chinese thought that the Mongols were planning to kill Chinese children and perform sexual rituals [ specify ] on them. As a result many Chinese became xenophobic towards the Mongols. This xenophobia led Chinese rulers to expel the Mongols from China and form the Ming dynasty . The segregation and fragmentation of the respective khanates in the Mongol Empire were not the only factors in contributing to the decline of the Pax Mongolica . The outbreak of bubonic plague , or Black Death , also played a devastating role in the decline of the Pax Mongolica . Because the Mongol Empire bridged once isolated regions, it made it easy for the Black Death to spread rapidly. Historian William H. McNeill has noted that the plague was transferred from ground rodents living in southern Chinese and Burmese Himalayan foothills to Mongol soldiers when they invaded the area in 1252. In 1331 the plague was noted in China, and from East Asia it was carried west along the trade routes by merchants and Mongol soldiers who were able to so freely and quickly travel across the continent during the Pax Mongolica . Plague-infected fleas hitched rides in the manes of horses , on the hair of camels , or on black rats that nestled in cargoes or in saddlebags . The Black Death is estimated to have killed one-third of China's population and 25-50% of Europe's population. Demographically weakened, the Mongols were not able to exert their rule over remote domains in their empire, which began to revolt once the plague broke out. These revolts disrupted the production of goods and flow of trade, which ended the Pax Mongolica . Over the next 300 years, China became increasingly isolationist and inward-looking. [ citation needed ] China prohibited foreigners, foreign trade, and languages other than Chinese. [ citation needed ] Confucianism and Taoism were reinstated as the national religions, and the Chinese experienced cultural stagnation. During the early years of the Ming dynasty , despite the voyages of Zheng He , trade with the rest of the world overall declined. This is attributed to wars, epidemics and widespread disruptions rather than "symbolic policy change". Economic difficulties also contributed to the decline as an important world trade player. The Black Death quickly spread to the rest of the world trade system, and the long-distance trading that was common and applauded during the Pax Mongolica almost entirely stopped.The Mongol Empire, near the time of its decline, consisted of many different territories. Each territory was defined as a " khanate ". Due to the isolation [ specify ] of the Mongolian world, many rulers in the 14th century started to focus on their own khanates. Religious intolerance was one particular factor in the decline of the Pax Mongolica . In Rus ', the Mongols (known as the Golden Horde ), gradually lost power and territory due to intolerance specifically geared towards different religions. The Rus' Mongols converted to Islam and joined the Egyptian Mamluks for political reasons. At one point in the war [ specify ] , the Golden Horde even fought the Persian Mongols . The eastern part of the Golden Horde, White Horde , had friendly relations with the Ilkhanate and the Great Khan. The decentralisation occurred because communication was so difficult due to the collapsing trade system and the rivalry between Mongol princes. Eventually, the Persian Mongol leader Ghazan converted to Islam in 1295. This contributed to the growing power of Nawruz ; a Muslim Oirat general. In China, descendants of Kublai Khan claimed the Mongols weakened their power by becoming "too Chinese". This led to Yuan emperors separating themselves from their subjects in order to stress their Mongol identity and to reject their Chinese culture. Kublai Khan once promoted Chinese culture and the importance of its practice but under the Yuan emperors this was prohibited. As the Chinese culture was changing, intolerance became more common. Some Chinese thought that the Mongols were planning to kill Chinese children and perform sexual rituals [ specify ] on them. As a result many Chinese became xenophobic towards the Mongols. This xenophobia led Chinese rulers to expel the Mongols from China and form the Ming dynasty . The segregation and fragmentation of the respective khanates in the Mongol Empire were not the only factors in contributing to the decline of the Pax Mongolica . The outbreak of bubonic plague , or Black Death , also played a devastating role in the decline of the Pax Mongolica . Because the Mongol Empire bridged once isolated regions, it made it easy for the Black Death to spread rapidly. Historian William H. McNeill has noted that the plague was transferred from ground rodents living in southern Chinese and Burmese Himalayan foothills to Mongol soldiers when they invaded the area in 1252. In 1331 the plague was noted in China, and from East Asia it was carried west along the trade routes by merchants and Mongol soldiers who were able to so freely and quickly travel across the continent during the Pax Mongolica . Plague-infected fleas hitched rides in the manes of horses , on the hair of camels , or on black rats that nestled in cargoes or in saddlebags . The Black Death is estimated to have killed one-third of China's population and 25-50% of Europe's population. Demographically weakened, the Mongols were not able to exert their rule over remote domains in their empire, which began to revolt once the plague broke out. These revolts disrupted the production of goods and flow of trade, which ended the Pax Mongolica . Over the next 300 years, China became increasingly isolationist and inward-looking. [ citation needed ] China prohibited foreigners, foreign trade, and languages other than Chinese. [ citation needed ] Confucianism and Taoism were reinstated as the national religions, and the Chinese experienced cultural stagnation. During the early years of the Ming dynasty , despite the voyages of Zheng He , trade with the rest of the world overall declined. This is attributed to wars, epidemics and widespread disruptions rather than "symbolic policy change". Economic difficulties also contributed to the decline as an important world trade player. The Black Death quickly spread to the rest of the world trade system, and the long-distance trading that was common and applauded during the Pax Mongolica almost entirely stopped.

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Bubonic plague

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Mass grave

A mass grave is a grave containing multiple human corpses, which may or may not be identified prior to burial. The United Nations has defined a criminal mass grave as a burial site containing three or more victims of execution , although an exact definition is not unanimously agreed upon. Mass graves are usually created after many people die or are killed, and there is a desire to bury the corpses quickly for sanitation concerns. Although mass graves can be used during major conflicts such as war and crime , in modern times they may be used after a famine , epidemic , or natural disaster . In disasters , mass graves are used for infection and disease control. In such cases, there is often a breakdown of the social infrastructure that would enable proper identification and disposal of individual bodies. Mass or communal burial was a common practice before the development of a dependable crematory chamber by Ludovico Brunetti in 1873. In ancient Rome waste and dead bodies of the poor were dumped into mass graves called puticuli . In Paris, the practice of mass burial, and in particular, the condition of the Cimetière des Innocents , led Louis XVI to eliminate Parisian cemeteries. The remains were removed and placed in the Paris underground forming the early Catacombs . Le Cimetière des Innocents alone had 6,000,000 dead to remove. Burial commenced outside the city limits in what is now Père Lachaise Cemetery . A mass grave containing at least 300 bodies of victims of a Mongol invasion of Kievan Rus' in the year 1238, was discovered during an excavation in 2005, in Yaroslavl, Russia. The Thirty Years' War , in the 17th century, was Europe's deadliest religious conflict. In the Battle of Lützen , 47 soldiers who perished were buried in a mass grave. Archaeological and osteological analyses found that the soldiers ranged in age from 15–50 years. Most corpses had evidence of blunt force trauma to the head while seven men had stabbing injuries. Most of the soldiers died from gunshot wounds inflicted by pistols and cavalry carbines. Several mass graves have been discovered that were the result of Napoleonic battles, mass graves were dug for expeditious disposal of deceased soldiers and horses. Often soldiers would plunder the substantial quantity of corpses prior to burial. Generally the mass graves were dug by soldiers or members of logistical corps. If these units were not available, the corpses would be left to rot or would be burned. Such examples have been found scattered throughout Europe. There are over 2,000 known mass graves throughout Spain from the Spanish Civil War wherein an estimated 500,000 people died between 1936 and 1939, and approximately 135,000 were killed after the war ended. Exhumations are ongoing. Some are conducted on the basis of information given in witnesses' and relatives' testimonies to the Asociación para la Recuperación de la Memoria Histórica (ARMH). These testimonies serve the purpose of helping geophysicists , archaeologists and forensic scientists to locate graves in order to identify bodies and allow families to rebury their relatives. In the summer of 2008, information from these testimonies was used to unearth a 4 meter long square grave containing five skeletons near the town of San Juan del Monte. These five remains are believed to be of people that were kidnapped and killed after the July 18, 1936 military coup. Another mass grave from the Spanish Civil War was found using Ground Penetrating Radar (GPR). Eyewitness accounts identified two potential locations for an unmarked grave in mountains of Lena in Northern Spain. Both sites were examined and an unmarked mass grave of approximately 1 meter by 5 meters was found. Approximately 100,000–200,000 civilians were killed at the start of the Korean War . These people were flagged by the government of South Korea for potentially collaborating with or sympathizing with North Korea . They were arrested and subsequently executed without trial. The sites where the massacres occurred were forbidden to the public. The bodies were considered to be traitors and the act of associating with them was considered treasonous. Despite this, families retrieved bodies from the shallow forbidden mass graves at the massacre sites. In 1956, bereaved families and villagers exhumed over 100 decomposed and unidentifiable bodies, ensuring that the complete human skeleton was intact. Each exhumed body was buried in its own "nameless grave" in a cemetery on Jeju Island . There is a granite memorial within the cemetery which bears the cemetery's local name, "Graves of One Hundred Ancestors and One Descendant." This name functions to express the opposite of how the genealogy should be as typically many descendants derive from one ancestor. The Chilean military coup against President Salvador Allende occurred on September 11, 1973. The military surrounded Santiago and searched for people hiding in potential guerilla insurgent locations. Civilians were detained for long periods of time and some disappeared. Following the coup, bodies were abundant in the streets and in the Mapocho River . It is estimated that 3,200 people were executed or disappeared between 1973 and 1990 in Chile. Higher estimates are up to 4,500 people. These bodies were taken to morgues to be identified and claimed. Unidentified bodies were buried in marked mass graves. From this conflict, several hidden mass graves have been identified. In December 1978, 15 bodies were discovered in an abandoned limestone mine in Lonquén . In October 1979, 19 bodies were exhumed after being secretly buried at the cemetery of Yumbel . Mass graves were also identified in Santiago's General Cemetery with multiple bodies being forced into a single coffin. This cemetery had an influx of over 300 bodies within a three-month time span. These mass graves were distinguished by a cross with the initials "NN." "NN" is indicative of the phrase " Nomen Nescio " or " no name ." Following extensive media coverage of these mass graves, the Chilean military decided to exhume the bodies from Lonquén , Yumbel , and Santiago's General Cemetery . The military airdropped the exhumed bodies over open water or remote mountain locations. Many mass graves of both Turkish and Greek Cypriots were found in Cyprus after Turkey invaded the island in 1974 . On August 3, 14 Greek Cypriot civilians were executed and buried in a mass grave. In Eptakomi 12 Greek Cypriots were found in a mass grave executed with their hands tied. On the other hand, during the Maratha, Santalaris and Aloda massacre , 126 Turkish Cypriots including elderly people and children were murdered by EOKA B and the inhabitants of the three villages were buried in mass graves with a bulldozer . The villagers of Maratha and Santalaris , 84 to 89 people in total, were buried in the same grave. Mass graves were used to bury Turkish Cypriot victims of Tochni massacre too. On March 24, 1976 at 3:21 AM, the media told the people of Argentina that the country was now under the "operational control of the Junta of General Commanders of the Armed Forces." This event and years following it became known as the 1976 Argentine coup d'état . President Isabel Perón had been taken captive two hours prior to the media announcement. The new dictatorship implemented travel bans, public gatherings, and a nighttime curfew. Additionally, the new dictatorship resulted in widespread violence, leading to executions and casualties. Abducted captives were disposed of in one of the five defense zones within Argentina where they were held. The bodies were typically buried in individual marked anonymous graves. Three mass graves are known to exist on Argentinian police and military premises although other bodies were disposed of through cremation or by being airdropped over the Atlantic Ocean . Approximately 15,000 people are estimated to have been assassinated. Argentina's largest mass grave's exhumation began in March 1984 at the San Vicente Cemetery in Cordoba. The grave was 3.5 meters deep and 25 by 2.5 meters across. It contained approximately 400 bodies. Of the recovered and exhumed bodies, 123 were of young people violently killed during the 1976–1983 dictatorship . The remaining bodies were identified as older and having died nonviolent deaths such as leprosy . Many mass graves were discovered during the Vietnam War . In the fall of 1969, the body count unearthed from mass graves was around 2,800. During the months and years that followed the Battle of Huế , dozens of mass graves were discovered in and around Huế . The victims of the Huế massacre buried in mass graves included government officials, innocent civilians, women and children. They were tortured, executed and in some cases, buried alive. The estimated death toll was between 2,800 and 6,000 civilians and prisoners of war, or 5–10% of the total population of Huế . In Quang Ngai , a mass grave of 10 soldiers was discovered on December 28, 2011. These soldiers were buried alongside their belongings including wallets, backpacks, guns, ammunition, mirrors, and combs. Other larger mass graves of Vietnamese soldiers are believed to exist, with hundreds of soldiers in each grave. The Second Libyan Civil War that began in 2014 is a proxy war between the UN-recognized Government of National Accord (GNA) of Fayez al-Sarraj and the Libyan National Army (LNA) of the militia leader Khalifa Haftar . In 2020, the GNA ousted the forces of Haftar, who is backed by the United Arab Emirates and Russia , and captured Tarhuna . The GNA discovered mass graves in the Harouda farm of the town that was under the control of the Kaniyat militiamen, who allied with Haftar in 2019. For a decade, the Kaniyat militia brutalized and killed more than a thousand civilians, where around 650 were murdered in 14 months under the UAE-backed Haftar forces. Thousands of holes were dug by government workers, where 120 bodies recovered. The unearthed remains were used by the families to identify the missing members and only 59 bodies were claimed. Survivors reported that the Kaniyat militia aligned with the UAE-backed Haftar tortured or electrocuted them. Many also reported being beaten by the militia. Main article: Bucha massacre On 1 April 2022, following the Russian withdrawal, video footage was posted to social media, that showed mass civilian casualties. By 9 April, Ukrainian forensic investigators had begun recovering bodies from mass graves, such as at the church of Andrew the Apostle. 116 bodies were found in the mass grave near the Church of Andrew the Apostle. On 21 April, Human Rights Watch published an extensive report that summarized their own investigation in Bucha , implicating Russian troops in summary executions, other unlawful killings, enforced disappearances, and torture. Main article: Siege of Mariupol Mariupol's deputy mayor Serhii Orlov stated on 9 March 2022 that at least 1,170 civilians in the city had been killed in the city since Russia's invasion began and the dead were being buried in mass graves. By April 2022 several new mass graves located in vicinity of Mariupol were discovered using satellite footage. In early November 2022, Ukraine stated that at least 25,000 civilians had been killed in Mariupol. In late December 2022, based on the discovery of 10,300 new mass graves, the Associated Press estimated that the true death toll may be up to three times that figure. Main article: Izium mass graves On 15 September 2022, several mass graves, including one site containing at least 440 bodies were found in woods near the Ukrainian city of Izium after it was recaptured by Ukrainian forces. The graves contained bodies of people who were killed by Russian forces. One of the victims was a Ukrainian poet, children's writer, activist and Wikipedian Volodymyr Vakulenko . According to Ukrainian investigators, 447 bodies were discovered: 414 bodies of civilians (215 men, 194 women, 5 children), 22 servicemen, and 11 bodies whose gender had not yet been determined as of 23 September 2022. Most of the dead showed signs of violent death and 30 presented traces of torture and summary execution, including ropes around their necks, bound hands, broken limbs and genital amputation. A mass grave containing at least 300 bodies of victims of a Mongol invasion of Kievan Rus' in the year 1238, was discovered during an excavation in 2005, in Yaroslavl, Russia. The Thirty Years' War , in the 17th century, was Europe's deadliest religious conflict. In the Battle of Lützen , 47 soldiers who perished were buried in a mass grave. Archaeological and osteological analyses found that the soldiers ranged in age from 15–50 years. Most corpses had evidence of blunt force trauma to the head while seven men had stabbing injuries. Most of the soldiers died from gunshot wounds inflicted by pistols and cavalry carbines. Several mass graves have been discovered that were the result of Napoleonic battles, mass graves were dug for expeditious disposal of deceased soldiers and horses. Often soldiers would plunder the substantial quantity of corpses prior to burial. Generally the mass graves were dug by soldiers or members of logistical corps. If these units were not available, the corpses would be left to rot or would be burned. Such examples have been found scattered throughout Europe. There are over 2,000 known mass graves throughout Spain from the Spanish Civil War wherein an estimated 500,000 people died between 1936 and 1939, and approximately 135,000 were killed after the war ended. Exhumations are ongoing. Some are conducted on the basis of information given in witnesses' and relatives' testimonies to the Asociación para la Recuperación de la Memoria Histórica (ARMH). These testimonies serve the purpose of helping geophysicists , archaeologists and forensic scientists to locate graves in order to identify bodies and allow families to rebury their relatives. In the summer of 2008, information from these testimonies was used to unearth a 4 meter long square grave containing five skeletons near the town of San Juan del Monte. These five remains are believed to be of people that were kidnapped and killed after the July 18, 1936 military coup. Another mass grave from the Spanish Civil War was found using Ground Penetrating Radar (GPR). Eyewitness accounts identified two potential locations for an unmarked grave in mountains of Lena in Northern Spain. Both sites were examined and an unmarked mass grave of approximately 1 meter by 5 meters was found. Approximately 100,000–200,000 civilians were killed at the start of the Korean War . These people were flagged by the government of South Korea for potentially collaborating with or sympathizing with North Korea . They were arrested and subsequently executed without trial. The sites where the massacres occurred were forbidden to the public. The bodies were considered to be traitors and the act of associating with them was considered treasonous. Despite this, families retrieved bodies from the shallow forbidden mass graves at the massacre sites. In 1956, bereaved families and villagers exhumed over 100 decomposed and unidentifiable bodies, ensuring that the complete human skeleton was intact. Each exhumed body was buried in its own "nameless grave" in a cemetery on Jeju Island . There is a granite memorial within the cemetery which bears the cemetery's local name, "Graves of One Hundred Ancestors and One Descendant." This name functions to express the opposite of how the genealogy should be as typically many descendants derive from one ancestor. The Chilean military coup against President Salvador Allende occurred on September 11, 1973. The military surrounded Santiago and searched for people hiding in potential guerilla insurgent locations. Civilians were detained for long periods of time and some disappeared. Following the coup, bodies were abundant in the streets and in the Mapocho River . It is estimated that 3,200 people were executed or disappeared between 1973 and 1990 in Chile. Higher estimates are up to 4,500 people. These bodies were taken to morgues to be identified and claimed. Unidentified bodies were buried in marked mass graves. From this conflict, several hidden mass graves have been identified. In December 1978, 15 bodies were discovered in an abandoned limestone mine in Lonquén . In October 1979, 19 bodies were exhumed after being secretly buried at the cemetery of Yumbel . Mass graves were also identified in Santiago's General Cemetery with multiple bodies being forced into a single coffin. This cemetery had an influx of over 300 bodies within a three-month time span. These mass graves were distinguished by a cross with the initials "NN." "NN" is indicative of the phrase " Nomen Nescio " or " no name ." Following extensive media coverage of these mass graves, the Chilean military decided to exhume the bodies from Lonquén , Yumbel , and Santiago's General Cemetery . The military airdropped the exhumed bodies over open water or remote mountain locations. Many mass graves of both Turkish and Greek Cypriots were found in Cyprus after Turkey invaded the island in 1974 . On August 3, 14 Greek Cypriot civilians were executed and buried in a mass grave. In Eptakomi 12 Greek Cypriots were found in a mass grave executed with their hands tied. On the other hand, during the Maratha, Santalaris and Aloda massacre , 126 Turkish Cypriots including elderly people and children were murdered by EOKA B and the inhabitants of the three villages were buried in mass graves with a bulldozer . The villagers of Maratha and Santalaris , 84 to 89 people in total, were buried in the same grave. Mass graves were used to bury Turkish Cypriot victims of Tochni massacre too. On March 24, 1976 at 3:21 AM, the media told the people of Argentina that the country was now under the "operational control of the Junta of General Commanders of the Armed Forces." This event and years following it became known as the 1976 Argentine coup d'état . President Isabel Perón had been taken captive two hours prior to the media announcement. The new dictatorship implemented travel bans, public gatherings, and a nighttime curfew. Additionally, the new dictatorship resulted in widespread violence, leading to executions and casualties. Abducted captives were disposed of in one of the five defense zones within Argentina where they were held. The bodies were typically buried in individual marked anonymous graves. Three mass graves are known to exist on Argentinian police and military premises although other bodies were disposed of through cremation or by being airdropped over the Atlantic Ocean . Approximately 15,000 people are estimated to have been assassinated. Argentina's largest mass grave's exhumation began in March 1984 at the San Vicente Cemetery in Cordoba. The grave was 3.5 meters deep and 25 by 2.5 meters across. It contained approximately 400 bodies. Of the recovered and exhumed bodies, 123 were of young people violently killed during the 1976–1983 dictatorship . The remaining bodies were identified as older and having died nonviolent deaths such as leprosy . Many mass graves were discovered during the Vietnam War . In the fall of 1969, the body count unearthed from mass graves was around 2,800. During the months and years that followed the Battle of Huế , dozens of mass graves were discovered in and around Huế . The victims of the Huế massacre buried in mass graves included government officials, innocent civilians, women and children. They were tortured, executed and in some cases, buried alive. The estimated death toll was between 2,800 and 6,000 civilians and prisoners of war, or 5–10% of the total population of Huế . In Quang Ngai , a mass grave of 10 soldiers was discovered on December 28, 2011. These soldiers were buried alongside their belongings including wallets, backpacks, guns, ammunition, mirrors, and combs. Other larger mass graves of Vietnamese soldiers are believed to exist, with hundreds of soldiers in each grave. The Second Libyan Civil War that began in 2014 is a proxy war between the UN-recognized Government of National Accord (GNA) of Fayez al-Sarraj and the Libyan National Army (LNA) of the militia leader Khalifa Haftar . In 2020, the GNA ousted the forces of Haftar, who is backed by the United Arab Emirates and Russia , and captured Tarhuna . The GNA discovered mass graves in the Harouda farm of the town that was under the control of the Kaniyat militiamen, who allied with Haftar in 2019. For a decade, the Kaniyat militia brutalized and killed more than a thousand civilians, where around 650 were murdered in 14 months under the UAE-backed Haftar forces. Thousands of holes were dug by government workers, where 120 bodies recovered. The unearthed remains were used by the families to identify the missing members and only 59 bodies were claimed. Survivors reported that the Kaniyat militia aligned with the UAE-backed Haftar tortured or electrocuted them. Many also reported being beaten by the militia. Main article: Bucha massacre On 1 April 2022, following the Russian withdrawal, video footage was posted to social media, that showed mass civilian casualties. By 9 April, Ukrainian forensic investigators had begun recovering bodies from mass graves, such as at the church of Andrew the Apostle. 116 bodies were found in the mass grave near the Church of Andrew the Apostle. On 21 April, Human Rights Watch published an extensive report that summarized their own investigation in Bucha , implicating Russian troops in summary executions, other unlawful killings, enforced disappearances, and torture. Main article: Siege of Mariupol Mariupol's deputy mayor Serhii Orlov stated on 9 March 2022 that at least 1,170 civilians in the city had been killed in the city since Russia's invasion began and the dead were being buried in mass graves. By April 2022 several new mass graves located in vicinity of Mariupol were discovered using satellite footage. In early November 2022, Ukraine stated that at least 25,000 civilians had been killed in Mariupol. In late December 2022, based on the discovery of 10,300 new mass graves, the Associated Press estimated that the true death toll may be up to three times that figure. Main article: Izium mass graves On 15 September 2022, several mass graves, including one site containing at least 440 bodies were found in woods near the Ukrainian city of Izium after it was recaptured by Ukrainian forces. The graves contained bodies of people who were killed by Russian forces. One of the victims was a Ukrainian poet, children's writer, activist and Wikipedian Volodymyr Vakulenko . According to Ukrainian investigators, 447 bodies were discovered: 414 bodies of civilians (215 men, 194 women, 5 children), 22 servicemen, and 11 bodies whose gender had not yet been determined as of 23 September 2022. Most of the dead showed signs of violent death and 30 presented traces of torture and summary execution, including ropes around their necks, bound hands, broken limbs and genital amputation. Main article: Bucha massacre On 1 April 2022, following the Russian withdrawal, video footage was posted to social media, that showed mass civilian casualties. By 9 April, Ukrainian forensic investigators had begun recovering bodies from mass graves, such as at the church of Andrew the Apostle. 116 bodies were found in the mass grave near the Church of Andrew the Apostle. On 21 April, Human Rights Watch published an extensive report that summarized their own investigation in Bucha , implicating Russian troops in summary executions, other unlawful killings, enforced disappearances, and torture. Main article: Siege of Mariupol Mariupol's deputy mayor Serhii Orlov stated on 9 March 2022 that at least 1,170 civilians in the city had been killed in the city since Russia's invasion began and the dead were being buried in mass graves. By April 2022 several new mass graves located in vicinity of Mariupol were discovered using satellite footage. In early November 2022, Ukraine stated that at least 25,000 civilians had been killed in Mariupol. In late December 2022, based on the discovery of 10,300 new mass graves, the Associated Press estimated that the true death toll may be up to three times that figure. Main article: Izium mass graves On 15 September 2022, several mass graves, including one site containing at least 440 bodies were found in woods near the Ukrainian city of Izium after it was recaptured by Ukrainian forces. The graves contained bodies of people who were killed by Russian forces. One of the victims was a Ukrainian poet, children's writer, activist and Wikipedian Volodymyr Vakulenko . According to Ukrainian investigators, 447 bodies were discovered: 414 bodies of civilians (215 men, 194 women, 5 children), 22 servicemen, and 11 bodies whose gender had not yet been determined as of 23 September 2022. Most of the dead showed signs of violent death and 30 presented traces of torture and summary execution, including ropes around their necks, bound hands, broken limbs and genital amputation. The Rwandan genocide began after the unsolved death of the Rwandan president, Juvénal Habyarimana , on April 6, 1994. Extremist members of the Hutu government formed an interim wartime government. They called for an extermination of the Tutsi population, Hutu political opponents and Hutu who resisted the violence. The genocide lasted 100 days and resulted in an estimated 800,000 killings. Rwandan people sought refuge in gathering places such as churches and stadiums. An estimated 4,000–6,000 people gathered in Kibuye Catholic Church. Around April 17, 1994, the church was surrounded by armed civilians , police and gendarmes . Those inside were attacked with a variety of weapons including grenades , guns , and machetes . Survivors of the attack were sought after and killed in the following days. Burial of these bodies took place in at least four mass graves. The first mass grave resulting from this attack was discovered behind the church where several bodies were left unburied and scattered. In December 1995, archaeologists surveyed the area and flagged any potential human remains. In January 1996, forensic anthropologists located and exhumed 53 skeletal assemblages. A second mass grave was found under a tree marked with wire, indicating a memorial . Below the tree was a trench filled with multiple bodies. The third and fourth mass graves were found using a probe to test for deteriorating remains. The third grave was marked by the local population, similar to the second grave. The fourth grave was identified by a priest. Throughout the Rwandan genocide , bodies were buried in mass graves, left exposed, or disposed of through rivers. At least 40,000 bodies have been discovered in Lake Victoria which connects to Akagera River. Mass grave mapping teams have located 125 Khmer Rouge prison facilities and corresponding gravesites to date in Cambodia while researching the Killing Fields . These mass graves are believed by villagers to possess tutelary spirits and signify the dead bodies becoming one with the earth. Buddhist rituals, which were taboo at the time, were performed in the 1980s which transformed the anonymous bodies into "spirits of the departed." In the 1990s, religious ceremonies were re-established and the Festival of the Dead was celebrated annually. The Mittelbau camps held about 60,000 prisoners of The Holocaust between August 1943 and March 1945. Conservative estimates assume that at least 20,000 inmates perished at the Mittelbau-Dora concentration camp. In early April 1945, an unknown number of prisoners perished in death marches following the evacuation of prisoners from Mittelbau camps to Bergen-Belsen concentration camp in northern Germany . In April 1945, U.S. soldiers liberated the Mittelbau-Dora concentration camp. Only a few prisoners were still in the camp and the U.S. soldiers found the remains of approximately 1,300 prisoners in the Boelcke barracks. The names of these prisoners are unknown. Mass graves of the dead prisoners from the Mittelbau-Dora concentration camp were dug by German civilians under orders from U.S. soldiers. Victims of the Srebrenica massacre were murdered by the Army of Republika Srpska and buried in mass graves. Serb forces used mass graves throughout the Bosnian War and thousands of victims remain unidentified as of 2017. The Rwandan genocide began after the unsolved death of the Rwandan president, Juvénal Habyarimana , on April 6, 1994. Extremist members of the Hutu government formed an interim wartime government. They called for an extermination of the Tutsi population, Hutu political opponents and Hutu who resisted the violence. The genocide lasted 100 days and resulted in an estimated 800,000 killings. Rwandan people sought refuge in gathering places such as churches and stadiums. An estimated 4,000–6,000 people gathered in Kibuye Catholic Church. Around April 17, 1994, the church was surrounded by armed civilians , police and gendarmes . Those inside were attacked with a variety of weapons including grenades , guns , and machetes . Survivors of the attack were sought after and killed in the following days. Burial of these bodies took place in at least four mass graves. The first mass grave resulting from this attack was discovered behind the church where several bodies were left unburied and scattered. In December 1995, archaeologists surveyed the area and flagged any potential human remains. In January 1996, forensic anthropologists located and exhumed 53 skeletal assemblages. A second mass grave was found under a tree marked with wire, indicating a memorial . Below the tree was a trench filled with multiple bodies. The third and fourth mass graves were found using a probe to test for deteriorating remains. The third grave was marked by the local population, similar to the second grave. The fourth grave was identified by a priest. Throughout the Rwandan genocide , bodies were buried in mass graves, left exposed, or disposed of through rivers. At least 40,000 bodies have been discovered in Lake Victoria which connects to Akagera River. Mass grave mapping teams have located 125 Khmer Rouge prison facilities and corresponding gravesites to date in Cambodia while researching the Killing Fields . These mass graves are believed by villagers to possess tutelary spirits and signify the dead bodies becoming one with the earth. Buddhist rituals, which were taboo at the time, were performed in the 1980s which transformed the anonymous bodies into "spirits of the departed." In the 1990s, religious ceremonies were re-established and the Festival of the Dead was celebrated annually. The Mittelbau camps held about 60,000 prisoners of The Holocaust between August 1943 and March 1945. Conservative estimates assume that at least 20,000 inmates perished at the Mittelbau-Dora concentration camp. In early April 1945, an unknown number of prisoners perished in death marches following the evacuation of prisoners from Mittelbau camps to Bergen-Belsen concentration camp in northern Germany . In April 1945, U.S. soldiers liberated the Mittelbau-Dora concentration camp. Only a few prisoners were still in the camp and the U.S. soldiers found the remains of approximately 1,300 prisoners in the Boelcke barracks. The names of these prisoners are unknown. Mass graves of the dead prisoners from the Mittelbau-Dora concentration camp were dug by German civilians under orders from U.S. soldiers. Victims of the Srebrenica massacre were murdered by the Army of Republika Srpska and buried in mass graves. Serb forces used mass graves throughout the Bosnian War and thousands of victims remain unidentified as of 2017. Ireland's Great Famine lasted from 1845 to 1849, a period wherein about one million people died. Because of the excessive number of deaths and extreme poverty , many families were unable to provide a wake or proper burial for loved ones and used mass graves instead. Archaeological excavations have taken place on Irish mass burial sites. One excavation revealed a mass grave of nearly 1,000 individuals. The skeletons within the grave were layered on top of each other in multiple sub-rectangular pits positioned less than a meter apart. Ireland's Great Famine lasted from 1845 to 1849, a period wherein about one million people died. Because of the excessive number of deaths and extreme poverty , many families were unable to provide a wake or proper burial for loved ones and used mass graves instead. Archaeological excavations have taken place on Irish mass burial sites. One excavation revealed a mass grave of nearly 1,000 individuals. The skeletons within the grave were layered on top of each other in multiple sub-rectangular pits positioned less than a meter apart. The bubonic plague outbreak existed in three pandemic waves and is known as the Black Death . In the 1300s alone, an estimated 20–30 million people were killed in Europe and approximately 12 million people were killed in China . These deaths were at least 30 percent of the European population at that time. The last major outbreak of the bubonic plague occurred in London from 1665–1666 and is known as The Great Plague . In March 2013, a plague pit of 25 skeletons was found in a 5.5 meter-wide shaft during the construction of a new railway in London. The skeletons were neatly lined up in two rows and were about 8 feet underground. Samples from 12 corpses were taken and forensic analysis confirmed traces of DNA from Yersinia pestis . In several territories, the amount of death caused by the 1918 Spanish flu pandemic was beyond the capacities of funeral industry, requiring the use of mass graves. Several mass graves of Spanish flu victims were created in Australia , Canada , and the United States . Reports of mass graves having been dug for COVID-19 victims have been made about Iran , using satellite pictures of sites near Qom as evidence. In New York City , mass graves have been prepared in Hart Island for an afflux of dead; however, other reports said mass graves would be unlikely in the United States. University of Huddersfield experts said mass graves might be considered if local services end up overwhelmed. Following the rise of deaths and morgues being overwhelmed, New York City temporarily allowed for mass graves on Hart Island for unclaimed bodies. In Brazil , the city of Manaus , in the state of Amazonas , used mass graves after a large spike in deaths attributed to the pandemic.The bubonic plague outbreak existed in three pandemic waves and is known as the Black Death . In the 1300s alone, an estimated 20–30 million people were killed in Europe and approximately 12 million people were killed in China . These deaths were at least 30 percent of the European population at that time. The last major outbreak of the bubonic plague occurred in London from 1665–1666 and is known as The Great Plague . In March 2013, a plague pit of 25 skeletons was found in a 5.5 meter-wide shaft during the construction of a new railway in London. The skeletons were neatly lined up in two rows and were about 8 feet underground. Samples from 12 corpses were taken and forensic analysis confirmed traces of DNA from Yersinia pestis . In several territories, the amount of death caused by the 1918 Spanish flu pandemic was beyond the capacities of funeral industry, requiring the use of mass graves. Several mass graves of Spanish flu victims were created in Australia , Canada , and the United States . Reports of mass graves having been dug for COVID-19 victims have been made about Iran , using satellite pictures of sites near Qom as evidence. In New York City , mass graves have been prepared in Hart Island for an afflux of dead; however, other reports said mass graves would be unlikely in the United States. University of Huddersfield experts said mass graves might be considered if local services end up overwhelmed. Following the rise of deaths and morgues being overwhelmed, New York City temporarily allowed for mass graves on Hart Island for unclaimed bodies. In Brazil , the city of Manaus , in the state of Amazonas , used mass graves after a large spike in deaths attributed to the pandemic.The Brunner Mine disaster occurred at 9:30 a.m. on March 26, 1896. An underground explosion caused the death of 65 miners, making it New Zealand 's deadliest mining disaster. Of the 53 victims buried in Stillwater cemetery, 33 victims were in one mass grave. Following the 2010 Haiti earthquake , thousands of bodies were left in the streets on Port-au-Prince , exposed to the sun and beginning to decompose and smell. The government of Haiti collected the bodies on the street, along with rubble through use of dump trucks and other heavy machinery. The bodies and rubble were then transported to empty rectangular holes, 20 feet deep, 20 feet wide and 100 feet long. No efforts were taken to identify the dead that were transported and buried. Within Haitian culture, burial rituals hold great significance and the sacred ceremonies can cost more than their own homes. There is a Haitian Vodou belief that the dead continue to live and are connected to their ancestors through these rituals. The burial of unidentified corpses in mass graves rather than familial plots severs this spiritual link between the living and dead. As the casualties of the Typhoon Haiyan were in the thousands, unidentified or unknown corpses were buried in several mass graves in Leyte (especially in Tacloban City where the most deaths happened), Samar, and other areas, while identified corpses were given to their families for burial.The Brunner Mine disaster occurred at 9:30 a.m. on March 26, 1896. An underground explosion caused the death of 65 miners, making it New Zealand 's deadliest mining disaster. Of the 53 victims buried in Stillwater cemetery, 33 victims were in one mass grave. Following the 2010 Haiti earthquake , thousands of bodies were left in the streets on Port-au-Prince , exposed to the sun and beginning to decompose and smell. The government of Haiti collected the bodies on the street, along with rubble through use of dump trucks and other heavy machinery. The bodies and rubble were then transported to empty rectangular holes, 20 feet deep, 20 feet wide and 100 feet long. No efforts were taken to identify the dead that were transported and buried. Within Haitian culture, burial rituals hold great significance and the sacred ceremonies can cost more than their own homes. There is a Haitian Vodou belief that the dead continue to live and are connected to their ancestors through these rituals. The burial of unidentified corpses in mass graves rather than familial plots severs this spiritual link between the living and dead. As the casualties of the Typhoon Haiyan were in the thousands, unidentified or unknown corpses were buried in several mass graves in Leyte (especially in Tacloban City where the most deaths happened), Samar, and other areas, while identified corpses were given to their families for burial.The debate surrounding mass graves amongst epidemiologists includes whether or not, in a natural disaster, to leave corpses for traditional individual burials, or to bury corpses in mass graves. For example, if an epidemic occurs during winter, flies are less likely to infest corpses, reducing the risk of outbreaks of dysentery , diarrhea , diphtheria , or tetanus , which decreases the urgency to use mass graves. A research published in 2004 indicates that the health risks from dead bodies after natural disasters are relatively limited.

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Bubonic plague

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Yersinia pestis

Bacille de la peste Yersin, 1894 Bacterium pestis Lehmann & Neumann, 1896 Pasteurella pestis (Lehmann & Neumann, 1896) The Netherlands, 1920 Yersinia pestis ( Y. pestis ; formerly Pasteurella pestis ) is a gram-negative , non-motile , coccobacillus bacterium without spores that is related to both Yersinia enterocolitica and Yersinia pseudotuberculosis , the pathogen from which Y. pestis evolved and responsible for the Far East scarlet-like fever . It is a facultative anaerobic organism that can infect humans via the Oriental rat flea ( Xenopsylla cheopis ). It causes the disease plague , which caused the Plague of Justinian and the Black Death , the deadliest pandemic in recorded history. Plague takes three main forms: pneumonic , septicemic , and bubonic . Yersinia pestis is a parasite of its host, the rat flea , which is also a parasite of rats, hence Y. pestis is a hyperparasite . Y. pestis was discovered in 1894 by Alexandre Yersin , a Swiss/French physician and bacteriologist from the Pasteur Institute , during an epidemic of the plague in Hong Kong . Yersin was a member of the Pasteur school of thought. Kitasato Shibasaburō , a Japanese bacteriologist who practised Koch's methodology , was also engaged at the time in finding the causative agent of the plague. However, Yersin actually linked plague with a bacillus, initially named Pasteurella pestis ; it was renamed Yersinia pestis in 1944. Every year, between one thousand and two thousand cases of the plague are still reported to the World Health Organization . With proper antibiotic treatment, the prognosis for victims is much better than before antibiotics were developed. A five- to six-fold increase in cases occurred in Asia during the time of the Vietnam War , possibly due to the disruption of ecosystems and closer proximity between people and animals. The plague is now commonly found in sub-Saharan Africa and Madagascar, areas that now account for over 95% of reported cases. The plague also has a detrimental effect on non-human mammals; in the United States, these include the black-tailed prairie dog and the endangered black-footed ferret .Y. pestis is a non-motile coccobacillus , a facultative anaerobic bacterium with bipolar staining (giving it a safety pin appearance) that produces an antiphagocytic slime layer. Similar to other Yersinia species, it tests negative for urease , lactose fermentation, and indole . Its closest relatives are the gastrointestinal pathogen Yersinia pseudotuberculosis , and, more distantly, Yersinia enterocolitica . [ citation needed ]Several complete genome sequences are available for various strains and subspecies of Y. pestis : strain KIM (of biovar Y. p. medievalis ), and strain CO92 (of biovar Y. p. orientalis , obtained from a clinical isolate in the United States). In 2006 the genome sequence of a strain of biovar Antiqua was completed. Some strains are non-pathogenic, such as that of strain 91001 , whose sequence was published in 2004. Like Y. pseudotuberculosis and Y. enterocolitica , Y. pestis is host to the plasmid pCD1. It also hosts two other plasmids, pPCP1 (also called pPla or pPst) and pMT1 (also called pFra) that are not carried by the other Yersinia species. pFra codes for a phospholipase D that is important for the ability of Y. pestis to be transmitted by fleas. pPla codes for a protease , Pla, that activates plasmin in human hosts and is a very important virulence factor for pneumonic plague. Together, these plasmids, and a pathogenicity island called HPI, encode several proteins that cause the pathogenesis for which Y. pestis is famous. Among other things, these virulence factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria in the host cell (via a type-III secretion system ), and acquisition and binding of iron harvested from red blood cells (by siderophores ). Y. pestis is thought to be descended from Y. pseudotuberculosis , differing only in the presence of specific virulence plasmids. [ citation needed ] A comprehensive and comparative proteomics analysis of Y. pestis strain KIM was performed in 2006. The analysis focused on the transition to a growth condition mimicking growth in host cells. [ citation needed ] Numerous bacterial small noncoding RNAs have been identified to play regulatory functions. Some can regulate the virulence genes. Some 63 novel putative sRNAs were identified through deep sequencing of the Y. pestis sRNA-ome. Among them was Yersinia -specific (also present in Y. pseudotuberculosis and Y. enterocolitica ) Ysr141 ( Yersinia small RNA 141). Ysr141 sRNA was shown to regulate the synthesis of the type III secretion system (T3SS) effector protein YopJ. The Yop-Ysc T3SS is a critical component of virulence for Yersinia species. Many novel sRNAs were identified from Y. pestis grown in vitro and in the infected lungs of mice suggesting they play role in bacterial physiology or pathogenesis. Among them sR035 predicted to pair with SD region and transcription initiation site of a thermo-sensitive regulator ymoA, and sR084 predicted to pair with fur, ferric uptake regulator . Several complete genome sequences are available for various strains and subspecies of Y. pestis : strain KIM (of biovar Y. p. medievalis ), and strain CO92 (of biovar Y. p. orientalis , obtained from a clinical isolate in the United States). In 2006 the genome sequence of a strain of biovar Antiqua was completed. Some strains are non-pathogenic, such as that of strain 91001 , whose sequence was published in 2004. Like Y. pseudotuberculosis and Y. enterocolitica , Y. pestis is host to the plasmid pCD1. It also hosts two other plasmids, pPCP1 (also called pPla or pPst) and pMT1 (also called pFra) that are not carried by the other Yersinia species. pFra codes for a phospholipase D that is important for the ability of Y. pestis to be transmitted by fleas. pPla codes for a protease , Pla, that activates plasmin in human hosts and is a very important virulence factor for pneumonic plague. Together, these plasmids, and a pathogenicity island called HPI, encode several proteins that cause the pathogenesis for which Y. pestis is famous. Among other things, these virulence factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria in the host cell (via a type-III secretion system ), and acquisition and binding of iron harvested from red blood cells (by siderophores ). Y. pestis is thought to be descended from Y. pseudotuberculosis , differing only in the presence of specific virulence plasmids. [ citation needed ]A comprehensive and comparative proteomics analysis of Y. pestis strain KIM was performed in 2006. The analysis focused on the transition to a growth condition mimicking growth in host cells. [ citation needed ]Numerous bacterial small noncoding RNAs have been identified to play regulatory functions. Some can regulate the virulence genes. Some 63 novel putative sRNAs were identified through deep sequencing of the Y. pestis sRNA-ome. Among them was Yersinia -specific (also present in Y. pseudotuberculosis and Y. enterocolitica ) Ysr141 ( Yersinia small RNA 141). Ysr141 sRNA was shown to regulate the synthesis of the type III secretion system (T3SS) effector protein YopJ. The Yop-Ysc T3SS is a critical component of virulence for Yersinia species. Many novel sRNAs were identified from Y. pestis grown in vitro and in the infected lungs of mice suggesting they play role in bacterial physiology or pathogenesis. Among them sR035 predicted to pair with SD region and transcription initiation site of a thermo-sensitive regulator ymoA, and sR084 predicted to pair with fur, ferric uptake regulator . In the urban and sylvatic (forest) cycles of Y. pestis, most of the spreading occurs between rodents and fleas. In the sylvatic cycle, the rodent is wild, but in the urban cycle, the rodent is primarily the brown rat ( Rattus norvegicus ). In addition, Y. pestis can spread from the urban environment and back. Transmission to humans is usually through the bite of infected fleas. If the disease has progressed to the pneumonic form, humans can spread the bacterium to others by coughing, vomiting, and possibly sneezing. [ citation needed ] Several species of rodents serve as the main reservoir for Y. pestis in the environment. In the steppes , the natural reservoir is believed to be principally the marmot . In the western United States, several species of rodents are thought to maintain Y. pestis . However, the expected disease dynamics have not been found in any rodent. Several species of rodents are known to have a variable resistance, which could lead to an asymptomatic carrier status. Evidence indicates fleas from other mammals have a role in human plague outbreaks. The lack of knowledge of the dynamics of plague in mammal species is also true among susceptible rodents such as the black-tailed prairie dog ( Cynomys ludovicianus ), in which plague can cause colony collapse, resulting in a massive effect on prairie food webs. However, the transmission dynamics within prairie dogs do not follow the dynamics of blocked fleas; carcasses, unblocked fleas, or another vector could possibly be important, instead. The CO92 strain was isolated from a patient who died from pneumonia and who contracted the infection from an infected cat. In other regions of the world, the reservoir of the infection is not clearly identified, which complicates prevention and early-warning programs. One such example was seen in a 2003 outbreak in Algeria . The transmission of Y. pestis by fleas is well characterized. Initial acquisition of Y. pestis by the vector occurs during feeding on an infected animal. Several proteins then contribute to the maintenance of the bacteria in the flea digestive tract, among them the hemin storage system and Yersinia murine toxin (Ymt). Although Ymt is highly toxic to rodents and was once thought to be produced to ensure reinfection of new hosts, it is essential for flea colonization and for the survival of Y. pestis in fleas. The hemin storage system plays an important role in the transmission of Y. pestis back to a mammalian host. While in the insect vector, proteins encoded by hemin storage system genetic loci induce biofilm formation in the proventriculus , a valve connecting the midgut to the esophagus . The presence of this biofilm seems likely to be required for stable infection of the flea. Aggregation in the biofilm inhibits feeding, as a mass of clotted blood and bacteria forms (referred to as "Bacot's block" after entomologist A.W. Bacot , the first to describe this phenomenon). Transmission of Y. pestis occurs during the futile attempts of the flea to feed. Ingested blood is pumped into the esophagus, where it dislodges bacteria lodged in the proventriculus, which is regurgitated back into the host circulatory system. Pathogenesis due to Y. pestis infection of mammalian hosts is due to several factors, including an ability of these bacteria to suppress and avoid normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to pass the skin barrier. Y. pestis expresses a plasmin activator that is an important virulence factor for pneumonic plague and that might degrade on blood clots to facilitate systematic invasion. Many of the bacteria's virulence factors are antiphagocytic in nature. Two important antiphagocytic antigens , named F1 (fraction 1) and V or LcrV , are both important for virulence . These antigens are produced by the bacterium at normal human body temperature. Furthermore, Y. pestis survives and produces F1 and V antigens while it is residing within white blood cells such as monocytes , but not in neutrophils . Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils. In addition, the type-III secretion system (T3SS) allows Y. pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins, called Yersinia outer proteins (Yops), include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis . The YopO, YopH , YopM, YopT, YopJ, and YopE are injected into the cytoplasm of host cells by T3SS into the pore created in part by YopB and YopD. The injected Yops limit phagocytosis and cell signaling pathways important in the innate immune system , as discussed below. In addition, some Y. pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines ). [ citation needed ] Y. pestis proliferates inside lymph nodes , where it is able to avoid destruction by cells of the immune system such as macrophages . The ability of Y. pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause lymphadenopathy . YopH is a protein tyrosine phosphatase that contributes to the ability of Y. pestis to evade immune system cells. In macrophages, YopH has been shown to dephosphorylate p130Cas , Fyb ( FYN binding protein) SKAP-HOM and Pyk , a tyrosine kinase homologous to FAK . YopH also binds the p85 subunit of phosphoinositide 3-kinase , the Gab1 , the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor . [ citation needed ] YopE functions as a GTPase-activating protein for members of the Rho family of GTPases such as RAC1 . YopT is a cysteine protease that inhibits RhoA by removing the isoprenyl group , which is important for localizing the protein to the cell membrane . YopE and YopT has been proposed to function to limit YopB/D-induced cytolysis. This might limit the function of YopB/D to create the pores used for Yop insertion into host cells and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses. [ citation needed ] YopJ is an acetyltransferase that binds to a conserved α-helix of MAPK kinases . YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade . YopJ is activated in eukaryotic cells by interaction with target cell phytic acid (IP6). This disruption of host cell protein kinase activity causes apoptosis of macrophages, and this is proposed to be important for the establishment of infection and for evasion of the host immune response. YopO is a protein kinase also known as Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage apoptosis. It has also been suggested that a bacteriophage – Ypφ – may have been responsible for increasing the virulence of this organism. Depending on which form of the plague infects the individual, the plague develops a different illness; however, the plague overall affects the host cell's ability to communicate with the immune system, hindering the body bringing phagocytic cells to the area of infection. Y. pestis is a versatile killer. In addition to rodents and humans, it is known to have killed camels, chickens, and pigs. Domestic dogs and cats are susceptible to plague, as well, but cats are more likely to develop illness when infected. In either, the symptoms are similar to those experienced by humans, and can be deadly to the animal. People can be exposed by coming into contact with an infected animal (dead or alive), or inhaling infectious droplets that a sick dog or cat has coughed into the air. A formalin -inactivated vaccine was available in the United States for adults in 1993 at high risk of contracting the plague until removal from the market by the Food and Drug Administration . It was of limited effectiveness and could cause severe inflammation . Experiments with genetic engineering of a vaccine based on F1 and V antigens are underway and show promise. However, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable such that vaccines composed of these antigens may not be fully protective. The United States Army Medical Research Institute of Infectious Diseases has found that an experimental F1/V antigen-based vaccine protects crab-eating macaques , but fails to protect African green monkey species . A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine. Several species of rodents serve as the main reservoir for Y. pestis in the environment. In the steppes , the natural reservoir is believed to be principally the marmot . In the western United States, several species of rodents are thought to maintain Y. pestis . However, the expected disease dynamics have not been found in any rodent. Several species of rodents are known to have a variable resistance, which could lead to an asymptomatic carrier status. Evidence indicates fleas from other mammals have a role in human plague outbreaks. The lack of knowledge of the dynamics of plague in mammal species is also true among susceptible rodents such as the black-tailed prairie dog ( Cynomys ludovicianus ), in which plague can cause colony collapse, resulting in a massive effect on prairie food webs. However, the transmission dynamics within prairie dogs do not follow the dynamics of blocked fleas; carcasses, unblocked fleas, or another vector could possibly be important, instead. The CO92 strain was isolated from a patient who died from pneumonia and who contracted the infection from an infected cat. In other regions of the world, the reservoir of the infection is not clearly identified, which complicates prevention and early-warning programs. One such example was seen in a 2003 outbreak in Algeria . The transmission of Y. pestis by fleas is well characterized. Initial acquisition of Y. pestis by the vector occurs during feeding on an infected animal. Several proteins then contribute to the maintenance of the bacteria in the flea digestive tract, among them the hemin storage system and Yersinia murine toxin (Ymt). Although Ymt is highly toxic to rodents and was once thought to be produced to ensure reinfection of new hosts, it is essential for flea colonization and for the survival of Y. pestis in fleas. The hemin storage system plays an important role in the transmission of Y. pestis back to a mammalian host. While in the insect vector, proteins encoded by hemin storage system genetic loci induce biofilm formation in the proventriculus , a valve connecting the midgut to the esophagus . The presence of this biofilm seems likely to be required for stable infection of the flea. Aggregation in the biofilm inhibits feeding, as a mass of clotted blood and bacteria forms (referred to as "Bacot's block" after entomologist A.W. Bacot , the first to describe this phenomenon). Transmission of Y. pestis occurs during the futile attempts of the flea to feed. Ingested blood is pumped into the esophagus, where it dislodges bacteria lodged in the proventriculus, which is regurgitated back into the host circulatory system. Pathogenesis due to Y. pestis infection of mammalian hosts is due to several factors, including an ability of these bacteria to suppress and avoid normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to pass the skin barrier. Y. pestis expresses a plasmin activator that is an important virulence factor for pneumonic plague and that might degrade on blood clots to facilitate systematic invasion. Many of the bacteria's virulence factors are antiphagocytic in nature. Two important antiphagocytic antigens , named F1 (fraction 1) and V or LcrV , are both important for virulence . These antigens are produced by the bacterium at normal human body temperature. Furthermore, Y. pestis survives and produces F1 and V antigens while it is residing within white blood cells such as monocytes , but not in neutrophils . Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils. In addition, the type-III secretion system (T3SS) allows Y. pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins, called Yersinia outer proteins (Yops), include Yop B/D, which form pores in the host cell membrane and have been linked to cytolysis . The YopO, YopH , YopM, YopT, YopJ, and YopE are injected into the cytoplasm of host cells by T3SS into the pore created in part by YopB and YopD. The injected Yops limit phagocytosis and cell signaling pathways important in the innate immune system , as discussed below. In addition, some Y. pestis strains are capable of interfering with immune signaling (e.g., by preventing the release of some cytokines ). [ citation needed ] Y. pestis proliferates inside lymph nodes , where it is able to avoid destruction by cells of the immune system such as macrophages . The ability of Y. pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause lymphadenopathy . YopH is a protein tyrosine phosphatase that contributes to the ability of Y. pestis to evade immune system cells. In macrophages, YopH has been shown to dephosphorylate p130Cas , Fyb ( FYN binding protein) SKAP-HOM and Pyk , a tyrosine kinase homologous to FAK . YopH also binds the p85 subunit of phosphoinositide 3-kinase , the Gab1 , the Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor . [ citation needed ] YopE functions as a GTPase-activating protein for members of the Rho family of GTPases such as RAC1 . YopT is a cysteine protease that inhibits RhoA by removing the isoprenyl group , which is important for localizing the protein to the cell membrane . YopE and YopT has been proposed to function to limit YopB/D-induced cytolysis. This might limit the function of YopB/D to create the pores used for Yop insertion into host cells and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses. [ citation needed ] YopJ is an acetyltransferase that binds to a conserved α-helix of MAPK kinases . YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade . YopJ is activated in eukaryotic cells by interaction with target cell phytic acid (IP6). This disruption of host cell protein kinase activity causes apoptosis of macrophages, and this is proposed to be important for the establishment of infection and for evasion of the host immune response. YopO is a protein kinase also known as Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage apoptosis. It has also been suggested that a bacteriophage – Ypφ – may have been responsible for increasing the virulence of this organism. Depending on which form of the plague infects the individual, the plague develops a different illness; however, the plague overall affects the host cell's ability to communicate with the immune system, hindering the body bringing phagocytic cells to the area of infection. Y. pestis is a versatile killer. In addition to rodents and humans, it is known to have killed camels, chickens, and pigs. Domestic dogs and cats are susceptible to plague, as well, but cats are more likely to develop illness when infected. In either, the symptoms are similar to those experienced by humans, and can be deadly to the animal. People can be exposed by coming into contact with an infected animal (dead or alive), or inhaling infectious droplets that a sick dog or cat has coughed into the air. A formalin -inactivated vaccine was available in the United States for adults in 1993 at high risk of contracting the plague until removal from the market by the Food and Drug Administration . It was of limited effectiveness and could cause severe inflammation . Experiments with genetic engineering of a vaccine based on F1 and V antigens are underway and show promise. However, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable such that vaccines composed of these antigens may not be fully protective. The United States Army Medical Research Institute of Infectious Diseases has found that an experimental F1/V antigen-based vaccine protects crab-eating macaques , but fails to protect African green monkey species . A systematic review by the Cochrane Collaboration found no studies of sufficient quality to make any statement on the efficacy of the vaccine. In 1894, two bacteriologists, Alexandre Yersin of Switzerland and Kitasato Shibasaburō of Japan, independently isolated in Hong Kong the bacterium responsible for the 1894 Hong Kong plague . Though both investigators reported their findings, a series of confusing and contradictory statements by Kitasato eventually led to the acceptance of Yersin as the primary discoverer of the organism. Yersin named it Pasteurella pestis in honor of the Pasteur Institute , where he worked. In 1967, it was moved to a new genus and renamed Yersinia pestis in his honor. Yersin also noted that rats were affected by plague not only during plague epidemics, but also often preceding such epidemics in humans and that plague was regarded by many locals as a disease of rats; villagers in China and India asserted that when large numbers of rats were found dead, plague outbreaks soon followed. [ citation needed ] In 1898, French scientist Paul-Louis Simond (who had also come to China to battle the Third Pandemic) discovered the rat–flea vector that drives the disease. He had noted that persons who became ill did not have to be in close contact with each other to acquire the disease. In Yunnan , China, inhabitants would flee from their homes as soon as they saw dead rats, and on the island of Formosa ( Taiwan ), residents considered the handling of dead rats heightened the risks of developing plague. These observations led him to suspect that the flea might be an intermediary factor in the transmission of plague, since people acquired plague only if they were in contact with rats that had died less than 24 hours before. In a now classic experiment, Simond demonstrated how a healthy rat died of the plague after infected fleas had jumped to it from a rat that had recently died of the plague. The outbreak spread to Chinatown, San Francisco, from 1900 to 1904 and then to Oakland and the East Bay from 1907 to 1909. It has been present in the rodents of western North America ever since, as fear of the consequences of the outbreak on trade caused authorities to hide the dead of the Chinatown residents long enough for the disease to be passed to widespread species of native rodents in outlying areas. Three main strains are recognised: Y. p. antiqua , which caused a plague pandemic in the sixth century; Y. p. medievalis , which caused the Black Death and subsequent epidemics during the second pandemic wave; and Y. p. orientalis , which is responsible for current plague outbreaks. On January 15, 2018, researchers at the University of Oslo and the University of Ferrara suggested that humans and their parasites (most likely fleas and lice at the time) were the biggest carriers of the plague. In 2010, researchers in Germany definitively established, using PCR evidence from samples obtained from Black Death victims, that Y. pestis was the cause of the medieval Black Death . In 2011, the first genome of Y. pestis isolated from Black Death victims was published, and concluded that this medieval strain was ancestral to most modern forms of Y. pestis . In 2015, Cell published results from a study of ancient graves. Plasmids of Y. pestis were detected in archaeological samples of the teeth of seven Bronze Age individuals, in the Afanasievo culture in Siberia, the Corded Ware culture in Estonia, the Sintashta culture in Russia, the Unetice culture in Poland, and the Andronovo culture in Siberia. In 2018, the emergence and spread of the pathogen during the Neolithic decline (as far back as 6,000 years ago) was published. A site in Sweden was the source of the DNA evidence and trade networks were proposed as the likely avenue of spread rather than migrations of populations. There is evidence that suggests Y. pestis may have originated in Europe in the Cucuteni–Trypillia culture , not in Asia as is more commonly believed. DNA evidence published in 2015 indicates Y. pestis infected humans 5,000 years ago in Bronze Age Eurasia, but genetic changes that made it highly virulent did not occur until about 4,000 years ago. The highly virulent version capable of transmission by fleas through rodents, humans, and other mammals was found in two individuals associated with the Srubnaya culture from the Samara region in Russia from around 3,800 years ago and an Iron Age individual from Kapan , Armenia, from around 2,900 years ago. This indicates that at least two lineages of Y. pestis were circulating during the Bronze Age in Eurasia. The Y. pestis bacterium has a relatively large number of nonfunctioning genes and three "ungainly" plasmids, suggesting an origin less than 20,000 years ago. One such strain has been identified from about 4000 BP (the "LNBA lineage" (Late Neolithic and Bronze Age lineage)) in western Britain, indicating that this highly transmissible form spread from Eurasia to the far north-western edges of Europe. On September 8, 2016, the Y. pestis bacterium was identified from DNA in teeth found at a Crossrail building site in London . The human remains were found to be victims of the Great Plague of London , which lasted from 1665 to 1666. In 2021, researchers found a 5,000-year-old victim of Y. pestis , the world's oldest-known, in hunter-gatherer remains in the modern Latvian and Estonian border area. Between 1970 and 2020, 496 cases were reported in the United States. Cases have been found predominantly in New Mexico, Arizona, Colorado, California, Oregon, and Nevada. In 2008, plague was commonly found in sub-Saharan Africa and Madagascar, areas that accounted for over 95% of the reported cases. In September 2009, the death of Malcolm Casadaban , a molecular genetics professor at the University of Chicago , was linked to his work on a weakened laboratory strain of Y. pestis . Hemochromatosis was hypothesised to be a predisposing factor in Casadaban's death from this attenuated strain used for research. On November 3, 2019, two cases of pneumonic plague were diagnosed at a hospital in Beijing's Chaoyang district, prompting fears of an outbreak. The patient was a middle-aged man with fever, who had complained of difficulty breathing for some ten days, accompanied by his wife with similar symptoms. Police quarantined the emergency room at the hospital and controls were placed on Chinese news aggregators. On 18 November a third case was reported, in a 55-year-old man from Xilingol League , one of the twelve Mongolian autonomous regions in Northern China. The patient received treatment, and 28 symptomless contacts were placed in quarantine. In July 2020, officials increased precautions after a case of bubonic plague was confirmed in Bayannur , a city in China's Inner Mongolia autonomous region. The patient was quarantined and treated. According to China's Global Times , a second suspected case was also investigated, and a level 3 alert was issued, in effect until the end of the year. It forbade hunting and eating of animals that could carry plague, and called on the public to report suspected cases. In 2010, researchers in Germany definitively established, using PCR evidence from samples obtained from Black Death victims, that Y. pestis was the cause of the medieval Black Death . In 2011, the first genome of Y. pestis isolated from Black Death victims was published, and concluded that this medieval strain was ancestral to most modern forms of Y. pestis . In 2015, Cell published results from a study of ancient graves. Plasmids of Y. pestis were detected in archaeological samples of the teeth of seven Bronze Age individuals, in the Afanasievo culture in Siberia, the Corded Ware culture in Estonia, the Sintashta culture in Russia, the Unetice culture in Poland, and the Andronovo culture in Siberia. In 2018, the emergence and spread of the pathogen during the Neolithic decline (as far back as 6,000 years ago) was published. A site in Sweden was the source of the DNA evidence and trade networks were proposed as the likely avenue of spread rather than migrations of populations. There is evidence that suggests Y. pestis may have originated in Europe in the Cucuteni–Trypillia culture , not in Asia as is more commonly believed. DNA evidence published in 2015 indicates Y. pestis infected humans 5,000 years ago in Bronze Age Eurasia, but genetic changes that made it highly virulent did not occur until about 4,000 years ago. The highly virulent version capable of transmission by fleas through rodents, humans, and other mammals was found in two individuals associated with the Srubnaya culture from the Samara region in Russia from around 3,800 years ago and an Iron Age individual from Kapan , Armenia, from around 2,900 years ago. This indicates that at least two lineages of Y. pestis were circulating during the Bronze Age in Eurasia. The Y. pestis bacterium has a relatively large number of nonfunctioning genes and three "ungainly" plasmids, suggesting an origin less than 20,000 years ago. One such strain has been identified from about 4000 BP (the "LNBA lineage" (Late Neolithic and Bronze Age lineage)) in western Britain, indicating that this highly transmissible form spread from Eurasia to the far north-western edges of Europe. On September 8, 2016, the Y. pestis bacterium was identified from DNA in teeth found at a Crossrail building site in London . The human remains were found to be victims of the Great Plague of London , which lasted from 1665 to 1666. In 2021, researchers found a 5,000-year-old victim of Y. pestis , the world's oldest-known, in hunter-gatherer remains in the modern Latvian and Estonian border area. Between 1970 and 2020, 496 cases were reported in the United States. Cases have been found predominantly in New Mexico, Arizona, Colorado, California, Oregon, and Nevada. In 2008, plague was commonly found in sub-Saharan Africa and Madagascar, areas that accounted for over 95% of the reported cases. In September 2009, the death of Malcolm Casadaban , a molecular genetics professor at the University of Chicago , was linked to his work on a weakened laboratory strain of Y. pestis . Hemochromatosis was hypothesised to be a predisposing factor in Casadaban's death from this attenuated strain used for research. On November 3, 2019, two cases of pneumonic plague were diagnosed at a hospital in Beijing's Chaoyang district, prompting fears of an outbreak. The patient was a middle-aged man with fever, who had complained of difficulty breathing for some ten days, accompanied by his wife with similar symptoms. Police quarantined the emergency room at the hospital and controls were placed on Chinese news aggregators. On 18 November a third case was reported, in a 55-year-old man from Xilingol League , one of the twelve Mongolian autonomous regions in Northern China. The patient received treatment, and 28 symptomless contacts were placed in quarantine. In July 2020, officials increased precautions after a case of bubonic plague was confirmed in Bayannur , a city in China's Inner Mongolia autonomous region. The patient was quarantined and treated. According to China's Global Times , a second suspected case was also investigated, and a level 3 alert was issued, in effect until the end of the year. It forbade hunting and eating of animals that could carry plague, and called on the public to report suspected cases.

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Bubonic plague

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Chinatown, San Francisco

The Chinatown centered on Grant Avenue and Stockton Street in San Francisco , California , ( Chinese : 唐人街 ; pinyin : tángrénjiē ; Jyutping : tong4 jan4 gaai1 ) is the oldest Chinatown in North America and one of the largest Chinese enclaves outside Asia . It is also the oldest and largest of the four notable Chinese enclaves within San Francisco . Since its establishment in the early 1850s, it has been important and influential in the history and culture of ethnic Chinese immigrants in North America. Chinatown is an enclave that has retained its own customs, languages , places of worship , social clubs , and identity. There are two hospitals, several parks and squares, numerous churches, a post office, and other infrastructure. Recent immigrants, many of whom are elderly, opt to live in Chinatown because of the availability of affordable housing and their familiarity with the culture. Due to a combination of factors, some more broad-based related to difficult circumstances for San Francisco itself, while other factors are more specific to this neighborhood, San Francisco's Chinatown faces a struggle for survival. Points of interest Parks and open spaces Hospital Officially, Chinatown is located in downtown San Francisco, covers 24 square blocks, and overlaps five postal ZIP codes (94108, 94133, 94111, 94102, and 94109). It is within an area of roughly 1 ⁄ 2 mi (0.80 km) long (north to south) by 1 ⁄ 4 mi (0.40 km) wide (east to west) with the current boundaries being, approximately, Kearny Street in the east, Broadway in the north, Powell in the west, and Bush Street in the south. Owing to a combination of multifactorial issues, some more generally tied to socioeconomic difficulties afflicting downtown San Francisco itself, while other factors are more specific to this neighborhood, San Francisco's Chinatown faces a struggle for survival and is shrinking. Within Chinatown there are two major north–south thoroughfares . One is Grant Avenue (都板街), with the Dragon Gate ("Chinatown Gate" on some maps) at the intersection of Bush Street and Grant Avenue, designed by landscape architects Melvin Lee and Joseph Yee and architect Clayton Lee; Saint Mary's Square with a statue of Sun Yat-sen by Benjamin Bufano ; a war memorial to Chinese war veterans; and stores, restaurants and mini-malls that cater mainly to tourists. The other, Stockton Street (å¸‚å¾·é “è¡—), is frequented less often by tourists, and it presents an authentic Chinese look and feel reminiscent of Hong Kong , with its produce and fish markets, stores, and restaurants. It is dominated by mixed-use buildings that are three to four stories high, with shops on the ground floor and residential apartments upstairs. A major focal point in Chinatown is Portsmouth Square . Since it is one of the few open spaces in Chinatown and sits above a large underground parking lot, Portsmouth Square is used by people such as tai chi practitioners and old men playing Chinese chess . A replica of the Goddess of Democracy used in the Tiananmen Square protest was built in 1999 by Thomas Marsh and stands in the square. It is made of bronze and weighs approximately 600 lb (270 kg) .According to the San Francisco Planning Department , Chinatown is "the most densely populated urban area west of Manhattan ", with 15,000 residents living in 20 square blocks . In the 1970s, the population density in Chinatown was seven times the San Francisco average. During the time from 2009 to 2013, the median household income was $20,000 – compared to $76,000 citywide – with 29% of residents below the national poverty threshold . The median age was 50 years, the oldest of any neighborhood. As of 2015, two thirds of the residents lived in one of Chinatown's 105 single room occupancy hotels (SRO), 96 of which had private owners and nine were owned by nonprofits. There are two public housing projects in Chinatown, Ping Yuen and North Ping Yuen. Most residents are monolingual speakers of mutually unintelligible dialects of the Chinese language: historically Hoisanese , now Cantonese and some Mandarin . In 2015, only 14% of households in the SROs were headed by a person that spoke English fluently. The areas of Stockton and Washington Streets and Jackson and Kearny Streets in Chinatown are almost entirely Chinese or Asian, with blocks ranging from 93% to 100% Asian. According to a study by the San Francisco Planning Department in 2018, 81% of the residents in the neighborhood were Asian. Many of the Chinese immigrants who managed to accumulate wealth while living in Chinatown move to the Richmond District , the Sunset District , or the suburbs. In the 1850s, Chinese pioneers, mainly from villages in the Pearl River Delta in Guangdong , began immigrating in large numbers to San Francisco, initially drawn by the California Gold Rush and the building of the first transcontinental railroad , and settling in Chinatown for refuge from the hostilities in the West. The main dialect spoken in Chinatown then was Hoisan-wa (aka Hoisanese; Toisanese in Cantonese and Taishanese in Mandarin), native to the emigrants from Hoisan (aka Toisan in Cantonese and Taishan in Mandarin), Sze Yup , in the Pearl River Delta. Surviving the ravages of the 1880s, Chinatown became a haven for later waves of emigrants from China in the 20th century. : 2–4 : 71 Working-class Hongkonger emigrants began arriving in large numbers in the late 1960s. Despite their status and professional qualifications in Hong Kong, many took low-paying employment in restaurants and garment factories in Chinatown because of limited English. An increase in Cantonese -speaking emigrants from Hong Kong and Mainland China has gradually led to the replacement in Chinatown of the Hoisanese dialect by the standard Cantonese dialect. Due to such overcrowding and poverty, other Chinese areas have been established within the city of San Francisco proper, including one in its Richmond and three more in its Sunset districts, as well as a recently established one in the Visitacion Valley neighborhood. These outer neighborhoods have been settled largely by Chinese from Southeast Asia. There are also many suburban Chinese communities in the San Francisco Bay Area , especially in Silicon Valley , such as Cupertino , Fremont , and Milpitas , where many Mandarin-speaking Taiwanese Americans settled. Despite these developments, many continue to commute in from these outer neighborhoods and cities to shop in Chinatown, causing gridlock on roads and delays in public transit, especially on weekends. To address this problem, the local public transit agency, Muni extended the city's subway network to the neighborhood via the new Central Subway . Unlike in most Chinatowns in the United States , ethnic Chinese refugees from Vietnam have not established businesses in San Francisco's Chinatown district, due to high property values and rents. Instead, many Chinese-Vietnamese – as opposed to ethnic Vietnamese who tended to congregate in larger numbers in San Jose – have established a separate Vietnamese enclave on Larkin Street in the heavily working-class Tenderloin district of San Francisco, where it is now known as the city's " Little Saigon ".In the 1850s, Chinese pioneers, mainly from villages in the Pearl River Delta in Guangdong , began immigrating in large numbers to San Francisco, initially drawn by the California Gold Rush and the building of the first transcontinental railroad , and settling in Chinatown for refuge from the hostilities in the West. The main dialect spoken in Chinatown then was Hoisan-wa (aka Hoisanese; Toisanese in Cantonese and Taishanese in Mandarin), native to the emigrants from Hoisan (aka Toisan in Cantonese and Taishan in Mandarin), Sze Yup , in the Pearl River Delta. Surviving the ravages of the 1880s, Chinatown became a haven for later waves of emigrants from China in the 20th century. : 2–4 : 71 Working-class Hongkonger emigrants began arriving in large numbers in the late 1960s. Despite their status and professional qualifications in Hong Kong, many took low-paying employment in restaurants and garment factories in Chinatown because of limited English. An increase in Cantonese -speaking emigrants from Hong Kong and Mainland China has gradually led to the replacement in Chinatown of the Hoisanese dialect by the standard Cantonese dialect. Due to such overcrowding and poverty, other Chinese areas have been established within the city of San Francisco proper, including one in its Richmond and three more in its Sunset districts, as well as a recently established one in the Visitacion Valley neighborhood. These outer neighborhoods have been settled largely by Chinese from Southeast Asia. There are also many suburban Chinese communities in the San Francisco Bay Area , especially in Silicon Valley , such as Cupertino , Fremont , and Milpitas , where many Mandarin-speaking Taiwanese Americans settled. Despite these developments, many continue to commute in from these outer neighborhoods and cities to shop in Chinatown, causing gridlock on roads and delays in public transit, especially on weekends. To address this problem, the local public transit agency, Muni extended the city's subway network to the neighborhood via the new Central Subway . Unlike in most Chinatowns in the United States , ethnic Chinese refugees from Vietnam have not established businesses in San Francisco's Chinatown district, due to high property values and rents. Instead, many Chinese-Vietnamese – as opposed to ethnic Vietnamese who tended to congregate in larger numbers in San Jose – have established a separate Vietnamese enclave on Larkin Street in the heavily working-class Tenderloin district of San Francisco, where it is now known as the city's " Little Saigon ".San Francisco's Chinatown was the port of entry for early Chinese immigrants from the west side of the Pearl River Delta , speaking mainly Hoisanese and Zhongshanese , in the Guangdong province of southern China from the 1850s to the 1900s. On August 28, 1850, at Portsmouth Square, : 9 San Francisco's first mayor , John Geary , officially welcomed 300 "China Boys" to San Francisco. : 34–38 By 1854, the Alta California , a local newspaper which had previously taken a supportive stance on Chinese immigrants in San Francisco, began attacking them, writing after a recent influx that "if the city continues to fill up with these people, it will be ere long become necessary to make them subject of special legislation". : 54–55 These early immigrants settled near Portsmouth Square and around Dupont Street (now called Grant Ave). : 54–55 As the settlement grew in the early 1850s, Chinese shops opened on Sacramento St, which the Guangdong pioneers called " Tang people street" (唐人街); : 13 and the settlement became known as " Tang people town" (å”äººåŸ ), which in Cantonese is Tong Yun Fow . : 9–40 By the 1870s, the economic center of Chinatown moved from Sacramento St to Dupont St; : 15–16 e.g., in 1878, out of 423 Chinese firms in Chinatown, 121 were located on Dupont St, 60 on Sacramento St, 60 on Jackson St, and the remainder elsewhere. : 15 The area was the one geographical region deeded by the city government and private property owners which allowed Chinese persons to inherit and inhabit dwellings within the city. The majority of these Chinese shopkeepers, restaurant owners, and hired workers in San Francisco Chinatown were predominantly Hoisanese and male. For example, in 1851, the reported Chinese population in California was about 12,000 men and less than ten women. : 41 Some of the early immigrants worked as mine workers or independent prospectors hoping to strike it rich during the 1849 Gold Rush . Many Chinese found jobs working for large companies seeking a source of labor, most famously as part of the Central Pacific on the Transcontinental Railroad , from 1865 to 1869. : 71–72 The west side of the Pearl River Delta of Guangdong, where most of the Chinese emigrated from, was subdivided into many distinct districts and some with distinct dialects. Several district associations, open to anyone emigrating from that district(s), were formed in the 1850s to act as a culture-shock absorber for newly arrived immigrants and to settle disputes among their members. Although there are some disagreements about which association formed first, by 1854, six such district associations were formed, of various size and influence, and disputes between members of different associations became more frequent. Thus, in 1862, the six district associations (commonly called the Chinese Six Companies, even though the number of member associations varied through the years) banded together to resolve inter-district disputes. This was made formal in 1882 and incorporated in 1901 as the Chinese Consolidated Benevolent Association (on Stockton Street) to look after the general interest of the Chinese people living in a hostile western world. : 1–9 Founded purportedly in roughly 1852 or 1853, the Tin How Temple (Queen of Heaven and Goddess of the Seven Seas) on Waverly Place is the oldest Chinese temple in the United States. It is dedicated to the goddess Tin How or Mazu , the Divine Protector of seafarers, much honored by Chinese immigrants, especially arriving by ship, to San Francisco. The original building was destroyed in the 1906 earthquake, and it opened on the top floor of a four-story building at 125 Waverly Place in 1910. After closing in 1955, the temple reopened in 1975, due to a resurgence of interest from a new immigrant population following the Immigration and Nationality Act of 1965 . : 207–209 Another Mazu temple, known as Ma-Tsu Temple was established in 1986 by Taiwanese American community and affiliated to Chaotian Temple in Taiwan. The Chinese Presbyterian Church on Stockton Street can trace its roots to October 1852, when Cantonese-speaking Rev. William Speer , a missionary in Canton, came to work with the Chinese immigrants in San Francisco. In November 1853 he organized the first Chinese mission in the United States, which provided much needed medical aid and conducted day and night schools that taught English to Chinese immigrants. He also published a Chinese/English newspaper, the Oriental , which staunchly defended the Chinese as anti-Chinese sentiment began to grow in the 1850s. The original building was destroyed by the earthquake, and the present church building on 925 Stockton Street was built in 1907. : 173–174 Other Christian denominations followed, including the Methodist Church on Washington Street (founded 1870, rebuilt 1911) and the First Baptist Church (founded 1880, rebuilt 1908 on Waverly Place) as well as Catholic, Congregational, and Episcopal. The pattern these early missions followed was to first conduct English language classes and Sunday schools. In these decades, the only English classes available to Chinese immigrants were those offered by these Christian missions. Some added rescue homes (e.g., from prostitution), and social services for the sick and protection from racial discrimination. With such tactics, the early Christian missions and churches in Chinatown gained widespread respect and new converts. : 28–34 In the 1850s, San Francisco "was all but submerged in Caucasian forms of gambling and prostitution and lewdness" . : 57 During the late period of the California Gold Rush , a few Chinese female prostitutes began their sexual businesses in Chinatown. In addition, the major prostitution enterprises had been raised by criminal gang group "Tong", importing unmarried Chinese women to San Francisco. During the 1870s to 1880s, the population of Chinese sex workers in Chinatown grew rapidly to more than 1,800, accounting for 70% of the total Chinese female population. In the mid-19th century, police harassment reshaped the urban geography and the social life of Chinese prostitutes. Consequently, hundreds of Chinese prostitutes were expelled to side streets and alleys hidden from public traffic. From 1870 to 1874, the California legislature formally criminalized the immigrant Asian women who were transported into California. In 1875, the U.S. Congress followed California's action and passed the Page Law , which was the first major legal restriction to prohibit the immigration of Chinese, Japanese, and Mongolian women into America. In 1882, the Chinese Exclusion Act declared that no more skilled or unskilled immigrants would be allowed to enter the country, which meant that many Chinese and Chinese Americans could not have families in America, because their wives and children were prohibited to immigrate. Simultaneously, the public discourse began to accuse Chinese prostitutes of transmitting venereal diseases. Dr. Hugh Huger Toland , a member of the San Francisco Board of Health, reported that white boys and men contracted diseases when they visited "Chinese houses of prostitution" in Chinatown, in order to warn white citizens to stay away; Toland asserted that nine-tenths of his patients had patronized Chinese prostitutes. "When these persons come to me I ask them where they got the disease, and they generally tell me that they have been with Chinawomen." : 12–13 : 27 All great cities have their slums and localities where filth, disease, crime and misery abound; but in the very best aspect which "Chinatown" can be made to present, it must stand apart, conspicuous and beyond them all in the extreme degree of all these horrible attributes, the rankest outgrowth of human degradation that can be found upon this continent. Here it may truly be said that human beings exist under conditions (as regards their mode of life and the air they breathe) scarcely one degree above those under which the rats of our water-front and other vermin live, breathe and have their being. And this order of things seems inseparable from the very nature of the race, and probably must be accepted and borne with—must be endured, if it cannot be cured—restricted and looked after, so far as possible, with unceasing vigilance, so that, whatever of benefit, "of degree," even, that may be derived from such modification of the evil of their presence among us, may at least be attained, not daring to hope that there can be any radical remedy for the great, overshadowing evil which Chinese immigration has inflicted upon this people. The Report of the Special Committee of the Board of Supervisors of San Francisco, on the Condition of the Chinese Quarter of that City (1885) : 5 By the end of the 19th century, Chinatown's assumed reputation as a place of vice caused it to become a tourist destination, attracting numerous working-class white people, who sought the oriental mystery of Chinese culture and sought to fulfill their expectations and fantasies about the filth and depravity. The white customers' patronization of Chinatown prostitutes was more extensive than gambling. After catering for three decades to white people as well as Chinese bachelors, Chinatown's prostitution sector developed into a powerful vested interest, favoring the vice industry. As the tourist industry grew up, the visitors came to include members of the white middle class, which pushed the vice businesses to transform into an entertainment industry as a more respectable form in which to serve white customers. After the completion of the transcontinental railroad in 1869, San Francisco saw the birth of its tourism industry. By the 1870s and further established in the 1880s and 1890s, Chinatown's exotic, infamous reputation began to attract tourists. Tour providers emphasized the vice-ridden elements of the area, strongly encouraging any curious visitors to take a professional guide or police escort with them to venture into Chinatown. These early tours often included staged reenactments of the "depravity of the locals" who were paid by tour operators to participate in the reenactments. Such reenactments exacerbated the perceptions of Chinatown as a problematic, vice-ridden location among San Francisco visitors and San Franciscans. The emphasis on the danger and depravity of the community ignored deeper issues of poverty, racial discrimination, and problems of overcrowding with overtaxed infrastructure. Ah Toy (18 May 1829 – 1 February 1928) was a Cantonese prostitute and madam in San Francisco during the California Gold Rush , and purportedly the first Chinese prostitute in San Francisco. Arriving from Hong Kong in 1848, she became the best-known Asian woman in the American frontier . When Ah Toy left China for the United States , she originally traveled with her husband, who died during the voyage. Toy became the mistress of the ship's captain, who showered gold upon her, so much so that by the time she arrived in San Francisco in the 1840s, Toy had a fair bit of money. Noticing the looks she drew from the men in her new town, she figured they would pay for a closer look. Her peep shows became quite successful, and she eventually became a high-priced prostitute. In 1850, Toy opened a chain of brothels at 34 and 36 Waverly Place (then called Pike Street), importing girls from China in their teens, 20s and 30s, as well as some as young as eleven years old, to work in them. Her neighbors on Pike Street—conveniently linked to San Francisco's business district by Commercial Street—included the elegant new "parlour house" of madame Belle Cora, and the cottage of Fanny Perrier, mistress of Judge Edward (Ned) McGowan. In 1857, Ah Toy returned to China a wealthy woman to live the rest of her days in comfort, but came back to California in 1859. From 1868 until her death in 1928, she lived a largely quiet life in Santa Clara County , returning to public attention only upon dying at age 98 in San Jose , three months short of her ninety ninth birthday. Relations between the United States and Qing China were normalized through the Burlingame Treaty of 1868. Among other terms, the treaty promised the right of free immigration and travel within the United States for Chinese. Business leaders saw China as a plentiful source of cheap labor, and celebrated the treaty's ratification. But this did not last for long. The mostly male Chinese immigrants came to the United States with the intent of sending money home to support their families; coupled with the high cost of repaying their loans for travel, they often had to take any work that was available. Fears began to arise among non-Chinese workers that they could be replaced, and resentment towards Chinese immigrants rose. With extensive nationwide unemployment in the wake of the Panic of 1873 , racial tensions in the city boiled over into full blown race riots. The two-day San Francisco riot of 1877 raged through Chinatown in July; four were killed and US$100,000 (equivalent to $2,860,000 in 2023) in property damage was done to Chinese-owned businesses. In response to the violence, the Chinese Consolidated Benevolent Association , also known as the Chinese Six Companies , which evolved out of the labor recruiting organizations for different areas of Guangdong, was created to provide the community with a unified voice. The heads of these companies advocated for the Chinese community to the wider business community as a whole and to the city government. The state legislature of California passed several measures to restrict the rights of Chinese immigrants, but these were largely superseded by the terms of the Burlingame Treaty of 1868. In 1880, the Burlingame Treaty was renegotiated and the United States ratified the Angell Treaty , which allowed federal restrictions on Chinese immigration and temporarily suspended the immigration of unskilled laborers. Anti-immigrant sentiment became federal law once the United States Government passed the Chinese Exclusion Act of 1882: the first immigration restriction law aimed at a single ethnic group. This law, along with other immigration restriction laws such as the Geary Act , greatly reduced the numbers of Chinese allowed into the country and the city, and in theory limited Chinese immigration to single males only. Exceptions were in fact granted to the wives and minor children of wealthy merchants; immigrants would purchase or partner in businesses to declare themselves merchants in order to bring their families to America. Alternatively, prospective immigrants could become " paper sons " by purchasing the identity of Americans whose citizenship had been established by birthright. : 38–39 However, the Exclusion Act was credited with reducing the population of the neighborhood to an all-time low in the 1920s. Many early Chinese immigrants to San Francisco and beyond were processed at Angel Island , in the San Francisco Bay , which is now a state park. Unlike Ellis Island on the east coast where prospective European immigrants might be held for up to a week, Angel Island typically detained Chinese immigrants for months while they were interrogated closely to validate their papers. The detention facility was renovated in 2005 and 2006 under a federal grant. As in much of San Francisco, a period of criminality existed during the late 19th century; many tongs arose, trafficking in smuggling, gambling, and prostitution. From the mid-1870s, turf battles sprang up over competing criminal enterprises. By the early 1880s, the term tong war was being popularly used to describe these periods of violence in Chinatown. At their height in the 1880s and 1890s, twenty to thirty tongs ran highly profitable gambling houses, brothels, opium dens, and slave trade enterprises in Chinatown. Overcrowding, segregation, graft, and the lack of governmental control contributed to conditions that sustained the criminal tongs until the early 1920s. Chinatown's isolation and compact geography intensified the criminal behavior that terrorized the community for decades despite efforts by the Six Companies and police/city officials to stem the tide. The San Francisco Police Department established its so-called Chinatown Squad in the 1880s, consisting of six patrolmen led by a sergeant. However, the Squad was ineffective largely by design. An investigation published in 1901 by the California state legislature found that Mayor James D. Phelan and Police Chief William P. Sullivan Jr. had knowingly tolerated gambling and prostitution in Chinatown in the interest of bolstering municipal revenue, calling the police department "so apathetic in putting down the horrible system of slavery existing in Chinatown as to justify your committee in believing it criminally negligent." Phelan and Sullivan testified it would take between 180 and 400 policemen to enforce the laws against gambling and prostitution, which was contradicted by the ex-Chief of Police William J. Biggy , who said 30 "earnestly directed" policemen would suffice. : 625–630 Chinatown, as it is at present, cannot be rendered sanitary except by total obliteration. It should be depopulated, its buildings leveled by fire and its tunnels and cellars laid bare. Its occupants should be colonized on some distant portion of the peninsula, where every building should be constructed under strict municipal regulation and where every violation of the sanitary laws could be at once detected. The day has passed when a progressive city like San Francisco should feel compelled to tolerate in its midst a foreign community, perpetuated in filth, for the curiosity of tourists, the cupidity of lawyers and the adoration of artists. Dr. Williamson, Annual Report to the Board of Health (quoted in 1901) In March 1900, a Chinese-born man who was a long-time resident of Chinatown was found dead of bubonic plague . The next morning, all of Chinatown was quarantined, with policemen preventing "Asiatics" (people of Asian heritage) from either entering or leaving. The San Francisco Board of Health began looking for more cases of plague and began burning personal property and sanitizing buildings, streets and sewers within Chinatown. Chinese Americans protested and the Chinese Consolidated Benevolent Association threatened lawsuits. The quarantine was lifted but the burning and fumigating continued. A federal court ruled that public health officials could not close off Chinatown without any proof that Chinese Americans were anymore susceptible to plague than Anglo Americans. The Chinatown neighborhood was completely destroyed in the 1906 earthquake and fire that leveled most of the city. "The fire had full sway, and Chinatown, for the removal of which many a scheme has been devised, is but a memory." Oakland Tribune, April 1906. : 33 Plans to relocate Chinatown predated the earthquake several years. At the 1901 Chinese Exclusion Convention held in San Francisco, A. Sbarboro called Chinatown "synonymous with disease, dirt and unlawful deeds" that "give[s] us nothing but evil habits and noxious stenches". With Chinatown completely demolished by the Great Fire, which ended on April 21, 1906, the City seized the chance to remove the Chinese from the old downtown business district. Certain city officials and real-estate developers made more formal plans to move Chinatown to the Hunters Point neighborhood at the southern edge of the city, or even further south to Daly City . Abe Ruef , the political boss widely considered to be the power behind Mayor Eugene Schmitz , invited himself to become part of the Committee of Fifty and, within a week of the end of the Great Fire, on Saturday, April 27, 1906, : 61–63 formed an additional Subcommittee on Relocating the Chinese, because he felt the land was too valuable for Chinese. Opposition arose, however, from politicians who feared that the removal of the Chinese would affect San Francisco's lucrative trade with Asian countries. Moreover, the government of China was also opposed, and soon after the earthquake, Tsi Chi Chow, the first secretary of the Chinese legation in Washington, DC, arrived in San Francisco, conveying to California governor George Pardee the opposition of China's Empress Dowager Cixi to the plan. The representatives, "acting unofficially", stated "the only way to remove the Chinese from the old Chinatown would be to give them a place elsewhere that would be acceptable for their purpose, when they might be willing to move." The San Francisco Call reported it as "a vigorous protest" and noted that as the site of the Chinese consulate was the property of Imperial China, it could not be reassigned by the city. On May 10, 1906, the subcommittee met with representatives from the Chinese community, the Chinese Six Companies , who said that they would either rebuild in their old Chinatown quarters or move across the bay to Oakland, where most of the Chinatown refugees had fled. : 65 Other community leaders pointed out that displaced residents may not stop to resettle in Hunters Point, moving further to other West Coast cities like Seattle or Los Angeles, taking the pool of cheap labor with them. On July 8, 1906, after 25 committee meetings and considering various alternative sites in the city, the subcommittee submitted a final report stating their inability to drive the Chinese from their old Chinatown quarters. : 66 Ironically, plans to relocate Chinatown failed in the end because restrictive housing covenants in other areas of the city prohibited Chinese from settling elsewhere. : 92 In any event, the ability to rebuild in their old Chinatown quarters was the first significant victory for the Chinese community in Chinatown. : 83 Even when the Subcommittee was bringing its relocation attempt to an end, the Chinese were already rebuilding, albeit with temporary wooden buildings which did not require permits. By June 10, 1906, twelve Chinese businesses were opened in Chinatown, including a couple of cafes. The actual reconstruction did not begin until October 1, 1906, when the City granted 43 building permits to Chinese businesses. By the time of the first post-quake Chinese New Year in 1907, several dozen buildings were completed, using old bricks unburnt by the fire, and Chinatown was filled with happy people. The reconstruction of Chinatown was completed more or less in 1908, a year ahead of the rest of the city. : 92–94 While the city's proposals to relocate Chinatown failed, the directive of rebuilding Chinatown into an attractive district along orientalized and stereotyped conceptions still gained traction. A group of Chinese merchants, including Mendocino -born Look Tin Eli , hired American architects to design in a Chinese-motif " Oriental " style in order to promote tourism in the rebuilt Chinatown. The results of this design strategy were the pagoda-topped buildings of the Sing Chong and Sing Fat bazaars on the west corners of Grant Ave (then Dupont St) and California St, which have become icons of San Francisco Chinatown. : 113–115 This design strategy leveraged the ethnic identity and exoticness that city planners used to justify the relocation of Chinatown to become the same forces that made the area an attractive tourist location. In constructing "Oriental" style architecture, the area gratified Western fascination with and perception of a stereotyped Chinese identity. Opportunistic individuals from within the Chinese community and from outside the Chinese community made entrepreneurial gains from this "ethnic tourism" as it emerged in the early 1900s and boosted local business. In November 1907, an article extolling the virtues of the "new Chinatown of San Francisco" was written, praising the new "substantial, modern, fireproof buildings of brick and stone ... following the Oriental style of architecture" and declaring "[n]o more picturesque squalor, no more gambling dens, opium joints or public haunts of vice" would be tolerated, at the command of the Chinese Six Companies. By then, 5,000 residents had returned, of the estimated 30,000 that lived in Chinatown prior to the quake. When the earthquake destroyed Chinatown's wooden tenements, it also dealt a blow to the tongs. Criminal tongs continued on until the 1920s, when legitimate Chinese merchants and a more capable Chinatown Squad under Sgt. Jack Manion gained the upper hand. Manion was appointed leader of the Squad in 1921 and served for two decades. Stiffer legislation against prostitution and drugs ended the tongs. The Chinatown Squad was finally disbanded in August 1955 by Police Chief George Healey , upon the request of the influential Chinese World newspaper, which had editorialized the Squad was an "affront to Americans of Chinese descent". The rhetoric of a "New Chinatown" obscured the reality of the community's perpetuating problems, particularly those of poverty, overcrowding, and racial discrimination. While the Chinese merchants succeeded in rebuilding in a tourist-attractive way, they could not influence the landlords, most of which were not Chinese, to provide adequate housing for the Chinese residents. In a 1930 Community Chest Survey of 153 Chinatown families, 32 families, with an average of five persons each, lived in one room each; only 19 families had complete bath tub, kitchen, and toilet facilities; on the average, there was one kitchen for 3.1 families and one toilet for 4.6 families (or 28.3 persons). Crowded inadequate living conditions contributed to a high death rate for the Chinese. The Chinese were no longer a problem for the city; they were forgotten. : 61–62 By 1947, Chinatown established itself as a central tourist destination and a rapidly developing community. Tension began to arise between businesses in Chinatown seeking to modernize and city planning committees seeking to maintain the "Oriental" look of the area. Similar to the post-earthquake discussion, Chinatown remained a contested space for conflicting visions of the area's development. In 1947, the Board of Supervisors proposed a building code prohibiting architectural changes to the area. Opposition to these preservationist initiatives came from Chinese business owners and some of the architects who designed the buildings, among others. These individuals saw such building codes or architectural regulations as hindering the progress of the community and treating it as a static ethnic icon. The famous Sam Wo restaurant opened in 1912. In 1925 for the celebration of the San Francisco Diamond Jubilee, the Downtown Merchants Association, the Chinese Chamber of Commerce, and the San Francisco Diamond Jubilee Festival jointly raised $18,000 for 43 dragon street lamps to be cast in China and installed along Grant Avenue from Bush Street to Broadway. Designed by W(alter) D'Arcy Ryan, who also designed the "Path of Gold" streetlights along Market Street , : 124–125 the distinctive 2,750 pounds (1,250 kg) street lamp, painted in traditional Chinese colors of red, gold and green, was composed of a cast-iron hexagonal base supporting a lotus and bamboo shaft surmounted with two cast-aluminum dragons below a pagoda lantern with bells and topped by a stylized hexagonal red roof —all in keeping with the Oriental style pioneered by Look Tin Eli (1910). The new lamps made Grant Avenue one of the brightest streets in the City at night, : 51 at a cost of US$418 (equivalent to $7,300 in 2023) each. Since then, the original molds were used to add 24 more dragon street lamps were in 1996 (distinguishable by the foundry, whose name and location in Emporia, Kansas is cast on an access door at the base), and later, 23 more were added along Pacific by PG&E. During the Great Depression, many nightclubs and cocktail bars were started in Chinatown. The Forbidden City nightclub, located at 369 Sutter Street just outside Chinatown and run by Charlie Low, became one of the most famous entertainment places in San Francisco. While it was doing business, from the late 1930s to the late 1950s, the Forbidden City gained an international reputation with its unique showcase of exotic oriental performance from Chinese American performers. Another popular club for tourists and LGBT clients was Li Po, which, like Forbidden City, combined western entertainment with "Oriental" culture. It was advertised in a 1939 tourism guide book as a "jovial and informal Chinatown cocktail lounge" where one could find "love, passion, and nighttime". As of 2018, it was still in operation at 916 Grant Avenue. For the Chinese in Chinatown, the war came upon them in September 1931, when Japan attacked the Manchurian city of Mukden, and became impossible to ignore in July 1937, when Japan launched a major offensive southward from their base in Manchuria towards the heart of China. In response, the Chinese Six Companies convened many community organizations together, from which was founded the Chinese War Relief Association, to raise funds from the Chinatown communities throughout the U.S. to aid civilians trapped by the war in China. In San Francisco's Chinatown, a popular means to raise money for war relief was through the Rice Bowl parades and parties, where the appeal to fill the rice bowls of starving children victimized by the war in China resonated with the Chinatown community. One hallmark of the Rice Bowl parade was the striking scene of a large number of Chinese-American women in fashionable Chinese dress (the cheongsam) carrying one huge Chinese flag spanning the width of the street, onto which money was thrown from balconies, windows, and sidewalks. In the Rice Bowl parade and party of 1938, San Francisco Chinatown raised $55,000; the second Rice Bowl in 1940 collected $87,000; and the third in 1941 brought in $93,000—all for war and hunger relief of civilians in war-torn China. : 33–44 As Chinese Americans became more visible in the public eye during the period leading to the U.S. involvement in the war, the negative image of China and the Chinese began to erode. — K. Scott Wong : 42 Once China became an ally to the U.S. in World War II , a positive image of the Chinese began to emerge. In October 1942, Earl Warren , running for Governor of California, wrote, "Like all native born Californians, I have cherished during my entire life a warm and cordial feeling for the Chinese people." : 89 In her goodwill tour of the U.S. starting in February 1943, Madame Chiang Kai Shek probably did more to change the American attitude towards the Chinese people than any other single person. : 53–54 She was hosted by the First Lady and President Franklin D. Roosevelt ; she was the second woman and the first Chinese to address the U.S. Congress. The American public embraced her with respect and kindness, which is in stark contrast to the treatment of most Chinese immigrants and Chinese Americans. : 89–109 To the Chinese in Chinatown, she became an icon of the war years. In December 1943, in recognition of the important role of China as an ally in the war, the Chinese Exclusion Act was repealed by the Magnuson Act , which allowed for naturalization but restricted Chinese immigrants to a small annual quota of 105 new entry visas. The repeal of the Exclusion Act and other immigration restriction laws, in conjunction with passage of the War Brides Act in December 1945, allowed Chinese-American veterans to bring their families outside of national quotas and led to a major population boom in the area during the 1950s. However, tight quotas on new immigration from China still applied until the Immigration and Nationality Act of 1965 was passed. In the 1948 landmark case of Shelley v. Kraemer , the U.S. Supreme Court ruled without dissent that enforcing racially restrictive covenants in property deeds violates the Equal Protection Clause of the Fourteenth Amendment and thus such covenants are unenforceable in court, which lifted the invisible walls around Chinatown, permitting some Chinese Americans to move out of the Gilded Ghetto into other neighborhoods of the city and gain a foothold on the middle class. Twenty years later, such racially restrictive covenants were outlawed in the 1968 Fair Housing Act . San Francisco artist Frank Wong created miniature dioramas that depict Chinatown during the 1930s and 1940s. In 2004, Wong donated seven miniatures of scenes of Chinatown, titled "The Chinatown Miniatures Collection," to the Chinese Historical Society of America (CHSA). The dioramas are on permanent display in CHSA's Main Gallery. In the 1960s, the shifting of under-utilized national immigration quotas brought in another huge wave of immigrants, mostly from Hong Kong. This changed San Francisco Chinatown from predominantly Hlay Yip Wah ( Sze Yup or Hoisan Wah )-speaking to Sam Yup Wah (standard Cantonese )-speaking. During the same decade, many stores moved from Grant Avenue to Stockton Street, drawn by lower rents and the better transportation enabled by the 30-Stockton Muni trolleybus line. There were areas where many Chinese in Northern California living outside of San Francisco Chinatown could maintain small communities or individual businesses. Nonetheless, the historic rights of property owners to deed or sell their property to whomever they pleased was exercised enough to keep the Chinese community from spreading. However, in 1948, Shelley v. Kraemer , the Supreme Court had ruled that racially restrictive covenants in deeds are unenforceable in courts due to the 14th amendment equal protection clause; and in 1968 the Fair Housing Act outlawed racially restrictive covenants. This ruling and law allowed the enlargement of Chinatown and an increase in the Chinese population of the city. At the same time, the declining white population of the city as a result of White Flight combined to change the demographics of the city. Neighborhoods that were once predominately white, such as Richmond District and Sunset District and in other suburbs across the San Francisco Bay Area became centers of new Chinese immigrant communities. Until 1979, the United States recognized the Republic of China in Taiwan as the sole legitimate government of all of China, and emigration from Taiwan was counted under the same grouping as that for mainland China, from which little emigration to the United States existed from 1949 on. In 1979, the opening up of the People's Republic of China and the breaking of diplomatic relations with the Republic of China led to the passage of the Taiwan Relations Act , which placed Taiwan under a separate immigration group from the People's Republic of China. As a result of the Immigration Act of 1990 , emigration from Hong Kong was also considered a separate jurisdiction for the purpose of recording such statistics. Thus, Mandarin-speaking emigrants from Taiwan began to arrive in the Bay Area, and they have tended to settle in suburban Millbrae , Cupertino , Milpitas , Mountain View , and even San Jose – avoiding San Francisco as well as Oakland Chinatowns. [ citation needed ] With these changes came a weakening of the Tongs' traditional grip on Chinese life. Newer Chinese groups often came from areas outside of the Tongs' control, so the influence of the Tongs and criminal groups associated with them, such as the Triads , grew weaker in Chinatown and the Chinese community. [ citation needed ] However, the presence of the Asian gangs remained significant in the immigrant community, and in the summer of 1977, an ongoing rivalry between two street gangs, the Wah Ching and the Joe Boys , erupted in violence and bloodshed, culminating in a shooting spree at the Golden Dragon Restaurant on Washington Street (è¯ç››é “è¡—). Five people were killed and eleven wounded, none of whom were gang members. The incident has become infamously known as the Golden Dragon massacre . Five perpetrators, who were members of the Joe Boys gang, were convicted of murder and assault charges and were sentenced to prison. The Golden Dragon closed in January 2006 because of health violations, and later reopened as the Imperial Palace Restaurant. Other notorious acts of violence have taken place in Chinatown since 1977. At 2 a.m. on May 14, 1990, San Francisco residents who had just left The Purple Onion , a nightclub located where Chinatown borders on North Beach , were shot as they entered their cars. 35-year-old Michael Bit Chen Wu was killed and six others were injured, among them a critically wounded pregnant woman. In June 1998, shots were fired at Chinese Playground , wounding six teenagers, three of them critically. A 16-year-old boy was arrested for the shooting, which was believed to be gang-related. On February 27, 2006, Allen Leung was shot to death in his business on Jackson Street; Raymond "Shrimp Boy" Chow , who succeeded Leung as head of the Ghee Kung Tong , was later convicted in 2016 of soliciting Leung's murder as fallout from the corruption investigation of Leland Yee , and Raymond "Skinny Ray" Lei was indicted for committing the murder in 2017. As Chinatown's ill reputation reemerged in the 1970s with the publicized gang crimes and continued neglect of substandard housing in the area, tourism began to decline. Visitors perceived the area as a "ghetto" taking their commercial business elsewhere. As Chinatown's tourist industry suffered, the entire area's once stable economy suffered. To counter this image, the Chinese Six Companies and other Chinese merchants began heavily emphasizing the safety and attractiveness of visiting the area. These marketing efforts alongside quieter initiatives to improve conditions for residents throughout the 1970s enabled the area's tourism-dependent economy to continue functioning. Similar dynamics of area leaders internally addressing social issues while externally maintaining commercial tourist appeal continued to the end of the 1900s. Now, However, San Francisco's Chinatown is now shrinking and faces an existential threat to it survival, due to macroeconomic ills afflicting downtown and San Francisco as a whole, in addition to its aging infrastructure and residential inhabitants. San Francisco's Chinatown was the port of entry for early Chinese immigrants from the west side of the Pearl River Delta , speaking mainly Hoisanese and Zhongshanese , in the Guangdong province of southern China from the 1850s to the 1900s. On August 28, 1850, at Portsmouth Square, : 9 San Francisco's first mayor , John Geary , officially welcomed 300 "China Boys" to San Francisco. : 34–38 By 1854, the Alta California , a local newspaper which had previously taken a supportive stance on Chinese immigrants in San Francisco, began attacking them, writing after a recent influx that "if the city continues to fill up with these people, it will be ere long become necessary to make them subject of special legislation". : 54–55 These early immigrants settled near Portsmouth Square and around Dupont Street (now called Grant Ave). : 54–55 As the settlement grew in the early 1850s, Chinese shops opened on Sacramento St, which the Guangdong pioneers called " Tang people street" (唐人街); : 13 and the settlement became known as " Tang people town" (å”äººåŸ ), which in Cantonese is Tong Yun Fow . : 9–40 By the 1870s, the economic center of Chinatown moved from Sacramento St to Dupont St; : 15–16 e.g., in 1878, out of 423 Chinese firms in Chinatown, 121 were located on Dupont St, 60 on Sacramento St, 60 on Jackson St, and the remainder elsewhere. : 15 The area was the one geographical region deeded by the city government and private property owners which allowed Chinese persons to inherit and inhabit dwellings within the city. The majority of these Chinese shopkeepers, restaurant owners, and hired workers in San Francisco Chinatown were predominantly Hoisanese and male. For example, in 1851, the reported Chinese population in California was about 12,000 men and less than ten women. : 41 Some of the early immigrants worked as mine workers or independent prospectors hoping to strike it rich during the 1849 Gold Rush . Many Chinese found jobs working for large companies seeking a source of labor, most famously as part of the Central Pacific on the Transcontinental Railroad , from 1865 to 1869. : 71–72 The west side of the Pearl River Delta of Guangdong, where most of the Chinese emigrated from, was subdivided into many distinct districts and some with distinct dialects. Several district associations, open to anyone emigrating from that district(s), were formed in the 1850s to act as a culture-shock absorber for newly arrived immigrants and to settle disputes among their members. Although there are some disagreements about which association formed first, by 1854, six such district associations were formed, of various size and influence, and disputes between members of different associations became more frequent. Thus, in 1862, the six district associations (commonly called the Chinese Six Companies, even though the number of member associations varied through the years) banded together to resolve inter-district disputes. This was made formal in 1882 and incorporated in 1901 as the Chinese Consolidated Benevolent Association (on Stockton Street) to look after the general interest of the Chinese people living in a hostile western world. : 1–9 Founded purportedly in roughly 1852 or 1853, the Tin How Temple (Queen of Heaven and Goddess of the Seven Seas) on Waverly Place is the oldest Chinese temple in the United States. It is dedicated to the goddess Tin How or Mazu , the Divine Protector of seafarers, much honored by Chinese immigrants, especially arriving by ship, to San Francisco. The original building was destroyed in the 1906 earthquake, and it opened on the top floor of a four-story building at 125 Waverly Place in 1910. After closing in 1955, the temple reopened in 1975, due to a resurgence of interest from a new immigrant population following the Immigration and Nationality Act of 1965 . : 207–209 Another Mazu temple, known as Ma-Tsu Temple was established in 1986 by Taiwanese American community and affiliated to Chaotian Temple in Taiwan. The Chinese Presbyterian Church on Stockton Street can trace its roots to October 1852, when Cantonese-speaking Rev. William Speer , a missionary in Canton, came to work with the Chinese immigrants in San Francisco. In November 1853 he organized the first Chinese mission in the United States, which provided much needed medical aid and conducted day and night schools that taught English to Chinese immigrants. He also published a Chinese/English newspaper, the Oriental , which staunchly defended the Chinese as anti-Chinese sentiment began to grow in the 1850s. The original building was destroyed by the earthquake, and the present church building on 925 Stockton Street was built in 1907. : 173–174 Other Christian denominations followed, including the Methodist Church on Washington Street (founded 1870, rebuilt 1911) and the First Baptist Church (founded 1880, rebuilt 1908 on Waverly Place) as well as Catholic, Congregational, and Episcopal. The pattern these early missions followed was to first conduct English language classes and Sunday schools. In these decades, the only English classes available to Chinese immigrants were those offered by these Christian missions. Some added rescue homes (e.g., from prostitution), and social services for the sick and protection from racial discrimination. With such tactics, the early Christian missions and churches in Chinatown gained widespread respect and new converts. : 28–34 In the 1850s, San Francisco "was all but submerged in Caucasian forms of gambling and prostitution and lewdness" . : 57 During the late period of the California Gold Rush , a few Chinese female prostitutes began their sexual businesses in Chinatown. In addition, the major prostitution enterprises had been raised by criminal gang group "Tong", importing unmarried Chinese women to San Francisco. During the 1870s to 1880s, the population of Chinese sex workers in Chinatown grew rapidly to more than 1,800, accounting for 70% of the total Chinese female population. In the mid-19th century, police harassment reshaped the urban geography and the social life of Chinese prostitutes. Consequently, hundreds of Chinese prostitutes were expelled to side streets and alleys hidden from public traffic. From 1870 to 1874, the California legislature formally criminalized the immigrant Asian women who were transported into California. In 1875, the U.S. Congress followed California's action and passed the Page Law , which was the first major legal restriction to prohibit the immigration of Chinese, Japanese, and Mongolian women into America. In 1882, the Chinese Exclusion Act declared that no more skilled or unskilled immigrants would be allowed to enter the country, which meant that many Chinese and Chinese Americans could not have families in America, because their wives and children were prohibited to immigrate. Simultaneously, the public discourse began to accuse Chinese prostitutes of transmitting venereal diseases. Dr. Hugh Huger Toland , a member of the San Francisco Board of Health, reported that white boys and men contracted diseases when they visited "Chinese houses of prostitution" in Chinatown, in order to warn white citizens to stay away; Toland asserted that nine-tenths of his patients had patronized Chinese prostitutes. "When these persons come to me I ask them where they got the disease, and they generally tell me that they have been with Chinawomen." : 12–13 : 27 All great cities have their slums and localities where filth, disease, crime and misery abound; but in the very best aspect which "Chinatown" can be made to present, it must stand apart, conspicuous and beyond them all in the extreme degree of all these horrible attributes, the rankest outgrowth of human degradation that can be found upon this continent. Here it may truly be said that human beings exist under conditions (as regards their mode of life and the air they breathe) scarcely one degree above those under which the rats of our water-front and other vermin live, breathe and have their being. And this order of things seems inseparable from the very nature of the race, and probably must be accepted and borne with—must be endured, if it cannot be cured—restricted and looked after, so far as possible, with unceasing vigilance, so that, whatever of benefit, "of degree," even, that may be derived from such modification of the evil of their presence among us, may at least be attained, not daring to hope that there can be any radical remedy for the great, overshadowing evil which Chinese immigration has inflicted upon this people. The Report of the Special Committee of the Board of Supervisors of San Francisco, on the Condition of the Chinese Quarter of that City (1885) : 5 By the end of the 19th century, Chinatown's assumed reputation as a place of vice caused it to become a tourist destination, attracting numerous working-class white people, who sought the oriental mystery of Chinese culture and sought to fulfill their expectations and fantasies about the filth and depravity. The white customers' patronization of Chinatown prostitutes was more extensive than gambling. After catering for three decades to white people as well as Chinese bachelors, Chinatown's prostitution sector developed into a powerful vested interest, favoring the vice industry. As the tourist industry grew up, the visitors came to include members of the white middle class, which pushed the vice businesses to transform into an entertainment industry as a more respectable form in which to serve white customers. After the completion of the transcontinental railroad in 1869, San Francisco saw the birth of its tourism industry. By the 1870s and further established in the 1880s and 1890s, Chinatown's exotic, infamous reputation began to attract tourists. Tour providers emphasized the vice-ridden elements of the area, strongly encouraging any curious visitors to take a professional guide or police escort with them to venture into Chinatown. These early tours often included staged reenactments of the "depravity of the locals" who were paid by tour operators to participate in the reenactments. Such reenactments exacerbated the perceptions of Chinatown as a problematic, vice-ridden location among San Francisco visitors and San Franciscans. The emphasis on the danger and depravity of the community ignored deeper issues of poverty, racial discrimination, and problems of overcrowding with overtaxed infrastructure. Ah Toy (18 May 1829 – 1 February 1928) was a Cantonese prostitute and madam in San Francisco during the California Gold Rush , and purportedly the first Chinese prostitute in San Francisco. Arriving from Hong Kong in 1848, she became the best-known Asian woman in the American frontier . When Ah Toy left China for the United States , she originally traveled with her husband, who died during the voyage. Toy became the mistress of the ship's captain, who showered gold upon her, so much so that by the time she arrived in San Francisco in the 1840s, Toy had a fair bit of money. Noticing the looks she drew from the men in her new town, she figured they would pay for a closer look. Her peep shows became quite successful, and she eventually became a high-priced prostitute. In 1850, Toy opened a chain of brothels at 34 and 36 Waverly Place (then called Pike Street), importing girls from China in their teens, 20s and 30s, as well as some as young as eleven years old, to work in them. Her neighbors on Pike Street—conveniently linked to San Francisco's business district by Commercial Street—included the elegant new "parlour house" of madame Belle Cora, and the cottage of Fanny Perrier, mistress of Judge Edward (Ned) McGowan. In 1857, Ah Toy returned to China a wealthy woman to live the rest of her days in comfort, but came back to California in 1859. From 1868 until her death in 1928, she lived a largely quiet life in Santa Clara County , returning to public attention only upon dying at age 98 in San Jose , three months short of her ninety ninth birthday. San Francisco's Chinatown was the port of entry for early Chinese immigrants from the west side of the Pearl River Delta , speaking mainly Hoisanese and Zhongshanese , in the Guangdong province of southern China from the 1850s to the 1900s. On August 28, 1850, at Portsmouth Square, : 9 San Francisco's first mayor , John Geary , officially welcomed 300 "China Boys" to San Francisco. : 34–38 By 1854, the Alta California , a local newspaper which had previously taken a supportive stance on Chinese immigrants in San Francisco, began attacking them, writing after a recent influx that "if the city continues to fill up with these people, it will be ere long become necessary to make them subject of special legislation". : 54–55 These early immigrants settled near Portsmouth Square and around Dupont Street (now called Grant Ave). : 54–55 As the settlement grew in the early 1850s, Chinese shops opened on Sacramento St, which the Guangdong pioneers called " Tang people street" (唐人街); : 13 and the settlement became known as " Tang people town" (å”äººåŸ ), which in Cantonese is Tong Yun Fow . : 9–40 By the 1870s, the economic center of Chinatown moved from Sacramento St to Dupont St; : 15–16 e.g., in 1878, out of 423 Chinese firms in Chinatown, 121 were located on Dupont St, 60 on Sacramento St, 60 on Jackson St, and the remainder elsewhere. : 15 The area was the one geographical region deeded by the city government and private property owners which allowed Chinese persons to inherit and inhabit dwellings within the city. The majority of these Chinese shopkeepers, restaurant owners, and hired workers in San Francisco Chinatown were predominantly Hoisanese and male. For example, in 1851, the reported Chinese population in California was about 12,000 men and less than ten women. : 41 Some of the early immigrants worked as mine workers or independent prospectors hoping to strike it rich during the 1849 Gold Rush . Many Chinese found jobs working for large companies seeking a source of labor, most famously as part of the Central Pacific on the Transcontinental Railroad , from 1865 to 1869. : 71–72The west side of the Pearl River Delta of Guangdong, where most of the Chinese emigrated from, was subdivided into many distinct districts and some with distinct dialects. Several district associations, open to anyone emigrating from that district(s), were formed in the 1850s to act as a culture-shock absorber for newly arrived immigrants and to settle disputes among their members. Although there are some disagreements about which association formed first, by 1854, six such district associations were formed, of various size and influence, and disputes between members of different associations became more frequent. Thus, in 1862, the six district associations (commonly called the Chinese Six Companies, even though the number of member associations varied through the years) banded together to resolve inter-district disputes. This was made formal in 1882 and incorporated in 1901 as the Chinese Consolidated Benevolent Association (on Stockton Street) to look after the general interest of the Chinese people living in a hostile western world. : 1–9 Founded purportedly in roughly 1852 or 1853, the Tin How Temple (Queen of Heaven and Goddess of the Seven Seas) on Waverly Place is the oldest Chinese temple in the United States. It is dedicated to the goddess Tin How or Mazu , the Divine Protector of seafarers, much honored by Chinese immigrants, especially arriving by ship, to San Francisco. The original building was destroyed in the 1906 earthquake, and it opened on the top floor of a four-story building at 125 Waverly Place in 1910. After closing in 1955, the temple reopened in 1975, due to a resurgence of interest from a new immigrant population following the Immigration and Nationality Act of 1965 . : 207–209 Another Mazu temple, known as Ma-Tsu Temple was established in 1986 by Taiwanese American community and affiliated to Chaotian Temple in Taiwan. The Chinese Presbyterian Church on Stockton Street can trace its roots to October 1852, when Cantonese-speaking Rev. William Speer , a missionary in Canton, came to work with the Chinese immigrants in San Francisco. In November 1853 he organized the first Chinese mission in the United States, which provided much needed medical aid and conducted day and night schools that taught English to Chinese immigrants. He also published a Chinese/English newspaper, the Oriental , which staunchly defended the Chinese as anti-Chinese sentiment began to grow in the 1850s. The original building was destroyed by the earthquake, and the present church building on 925 Stockton Street was built in 1907. : 173–174 Other Christian denominations followed, including the Methodist Church on Washington Street (founded 1870, rebuilt 1911) and the First Baptist Church (founded 1880, rebuilt 1908 on Waverly Place) as well as Catholic, Congregational, and Episcopal. The pattern these early missions followed was to first conduct English language classes and Sunday schools. In these decades, the only English classes available to Chinese immigrants were those offered by these Christian missions. Some added rescue homes (e.g., from prostitution), and social services for the sick and protection from racial discrimination. With such tactics, the early Christian missions and churches in Chinatown gained widespread respect and new converts. : 28–34In the 1850s, San Francisco "was all but submerged in Caucasian forms of gambling and prostitution and lewdness" . : 57 During the late period of the California Gold Rush , a few Chinese female prostitutes began their sexual businesses in Chinatown. In addition, the major prostitution enterprises had been raised by criminal gang group "Tong", importing unmarried Chinese women to San Francisco. During the 1870s to 1880s, the population of Chinese sex workers in Chinatown grew rapidly to more than 1,800, accounting for 70% of the total Chinese female population. In the mid-19th century, police harassment reshaped the urban geography and the social life of Chinese prostitutes. Consequently, hundreds of Chinese prostitutes were expelled to side streets and alleys hidden from public traffic. From 1870 to 1874, the California legislature formally criminalized the immigrant Asian women who were transported into California. In 1875, the U.S. Congress followed California's action and passed the Page Law , which was the first major legal restriction to prohibit the immigration of Chinese, Japanese, and Mongolian women into America. In 1882, the Chinese Exclusion Act declared that no more skilled or unskilled immigrants would be allowed to enter the country, which meant that many Chinese and Chinese Americans could not have families in America, because their wives and children were prohibited to immigrate. Simultaneously, the public discourse began to accuse Chinese prostitutes of transmitting venereal diseases. Dr. Hugh Huger Toland , a member of the San Francisco Board of Health, reported that white boys and men contracted diseases when they visited "Chinese houses of prostitution" in Chinatown, in order to warn white citizens to stay away; Toland asserted that nine-tenths of his patients had patronized Chinese prostitutes. "When these persons come to me I ask them where they got the disease, and they generally tell me that they have been with Chinawomen." : 12–13 : 27 All great cities have their slums and localities where filth, disease, crime and misery abound; but in the very best aspect which "Chinatown" can be made to present, it must stand apart, conspicuous and beyond them all in the extreme degree of all these horrible attributes, the rankest outgrowth of human degradation that can be found upon this continent. Here it may truly be said that human beings exist under conditions (as regards their mode of life and the air they breathe) scarcely one degree above those under which the rats of our water-front and other vermin live, breathe and have their being. And this order of things seems inseparable from the very nature of the race, and probably must be accepted and borne with—must be endured, if it cannot be cured—restricted and looked after, so far as possible, with unceasing vigilance, so that, whatever of benefit, "of degree," even, that may be derived from such modification of the evil of their presence among us, may at least be attained, not daring to hope that there can be any radical remedy for the great, overshadowing evil which Chinese immigration has inflicted upon this people. The Report of the Special Committee of the Board of Supervisors of San Francisco, on the Condition of the Chinese Quarter of that City (1885) : 5By the end of the 19th century, Chinatown's assumed reputation as a place of vice caused it to become a tourist destination, attracting numerous working-class white people, who sought the oriental mystery of Chinese culture and sought to fulfill their expectations and fantasies about the filth and depravity. The white customers' patronization of Chinatown prostitutes was more extensive than gambling. After catering for three decades to white people as well as Chinese bachelors, Chinatown's prostitution sector developed into a powerful vested interest, favoring the vice industry. As the tourist industry grew up, the visitors came to include members of the white middle class, which pushed the vice businesses to transform into an entertainment industry as a more respectable form in which to serve white customers. After the completion of the transcontinental railroad in 1869, San Francisco saw the birth of its tourism industry. By the 1870s and further established in the 1880s and 1890s, Chinatown's exotic, infamous reputation began to attract tourists. Tour providers emphasized the vice-ridden elements of the area, strongly encouraging any curious visitors to take a professional guide or police escort with them to venture into Chinatown. These early tours often included staged reenactments of the "depravity of the locals" who were paid by tour operators to participate in the reenactments. Such reenactments exacerbated the perceptions of Chinatown as a problematic, vice-ridden location among San Francisco visitors and San Franciscans. The emphasis on the danger and depravity of the community ignored deeper issues of poverty, racial discrimination, and problems of overcrowding with overtaxed infrastructure. Ah Toy (18 May 1829 – 1 February 1928) was a Cantonese prostitute and madam in San Francisco during the California Gold Rush , and purportedly the first Chinese prostitute in San Francisco. Arriving from Hong Kong in 1848, she became the best-known Asian woman in the American frontier . When Ah Toy left China for the United States , she originally traveled with her husband, who died during the voyage. Toy became the mistress of the ship's captain, who showered gold upon her, so much so that by the time she arrived in San Francisco in the 1840s, Toy had a fair bit of money. Noticing the looks she drew from the men in her new town, she figured they would pay for a closer look. Her peep shows became quite successful, and she eventually became a high-priced prostitute. In 1850, Toy opened a chain of brothels at 34 and 36 Waverly Place (then called Pike Street), importing girls from China in their teens, 20s and 30s, as well as some as young as eleven years old, to work in them. Her neighbors on Pike Street—conveniently linked to San Francisco's business district by Commercial Street—included the elegant new "parlour house" of madame Belle Cora, and the cottage of Fanny Perrier, mistress of Judge Edward (Ned) McGowan. In 1857, Ah Toy returned to China a wealthy woman to live the rest of her days in comfort, but came back to California in 1859. From 1868 until her death in 1928, she lived a largely quiet life in Santa Clara County , returning to public attention only upon dying at age 98 in San Jose , three months short of her ninety ninth birthday. Relations between the United States and Qing China were normalized through the Burlingame Treaty of 1868. Among other terms, the treaty promised the right of free immigration and travel within the United States for Chinese. Business leaders saw China as a plentiful source of cheap labor, and celebrated the treaty's ratification. But this did not last for long. The mostly male Chinese immigrants came to the United States with the intent of sending money home to support their families; coupled with the high cost of repaying their loans for travel, they often had to take any work that was available. Fears began to arise among non-Chinese workers that they could be replaced, and resentment towards Chinese immigrants rose. With extensive nationwide unemployment in the wake of the Panic of 1873 , racial tensions in the city boiled over into full blown race riots. The two-day San Francisco riot of 1877 raged through Chinatown in July; four were killed and US$100,000 (equivalent to $2,860,000 in 2023) in property damage was done to Chinese-owned businesses. In response to the violence, the Chinese Consolidated Benevolent Association , also known as the Chinese Six Companies , which evolved out of the labor recruiting organizations for different areas of Guangdong, was created to provide the community with a unified voice. The heads of these companies advocated for the Chinese community to the wider business community as a whole and to the city government. The state legislature of California passed several measures to restrict the rights of Chinese immigrants, but these were largely superseded by the terms of the Burlingame Treaty of 1868. In 1880, the Burlingame Treaty was renegotiated and the United States ratified the Angell Treaty , which allowed federal restrictions on Chinese immigration and temporarily suspended the immigration of unskilled laborers. Anti-immigrant sentiment became federal law once the United States Government passed the Chinese Exclusion Act of 1882: the first immigration restriction law aimed at a single ethnic group. This law, along with other immigration restriction laws such as the Geary Act , greatly reduced the numbers of Chinese allowed into the country and the city, and in theory limited Chinese immigration to single males only. Exceptions were in fact granted to the wives and minor children of wealthy merchants; immigrants would purchase or partner in businesses to declare themselves merchants in order to bring their families to America. Alternatively, prospective immigrants could become " paper sons " by purchasing the identity of Americans whose citizenship had been established by birthright. : 38–39 However, the Exclusion Act was credited with reducing the population of the neighborhood to an all-time low in the 1920s. Many early Chinese immigrants to San Francisco and beyond were processed at Angel Island , in the San Francisco Bay , which is now a state park. Unlike Ellis Island on the east coast where prospective European immigrants might be held for up to a week, Angel Island typically detained Chinese immigrants for months while they were interrogated closely to validate their papers. The detention facility was renovated in 2005 and 2006 under a federal grant. As in much of San Francisco, a period of criminality existed during the late 19th century; many tongs arose, trafficking in smuggling, gambling, and prostitution. From the mid-1870s, turf battles sprang up over competing criminal enterprises. By the early 1880s, the term tong war was being popularly used to describe these periods of violence in Chinatown. At their height in the 1880s and 1890s, twenty to thirty tongs ran highly profitable gambling houses, brothels, opium dens, and slave trade enterprises in Chinatown. Overcrowding, segregation, graft, and the lack of governmental control contributed to conditions that sustained the criminal tongs until the early 1920s. Chinatown's isolation and compact geography intensified the criminal behavior that terrorized the community for decades despite efforts by the Six Companies and police/city officials to stem the tide. The San Francisco Police Department established its so-called Chinatown Squad in the 1880s, consisting of six patrolmen led by a sergeant. However, the Squad was ineffective largely by design. An investigation published in 1901 by the California state legislature found that Mayor James D. Phelan and Police Chief William P. Sullivan Jr. had knowingly tolerated gambling and prostitution in Chinatown in the interest of bolstering municipal revenue, calling the police department "so apathetic in putting down the horrible system of slavery existing in Chinatown as to justify your committee in believing it criminally negligent." Phelan and Sullivan testified it would take between 180 and 400 policemen to enforce the laws against gambling and prostitution, which was contradicted by the ex-Chief of Police William J. Biggy , who said 30 "earnestly directed" policemen would suffice. : 625–630 Chinatown, as it is at present, cannot be rendered sanitary except by total obliteration. It should be depopulated, its buildings leveled by fire and its tunnels and cellars laid bare. Its occupants should be colonized on some distant portion of the peninsula, where every building should be constructed under strict municipal regulation and where every violation of the sanitary laws could be at once detected. The day has passed when a progressive city like San Francisco should feel compelled to tolerate in its midst a foreign community, perpetuated in filth, for the curiosity of tourists, the cupidity of lawyers and the adoration of artists. Dr. Williamson, Annual Report to the Board of Health (quoted in 1901) In March 1900, a Chinese-born man who was a long-time resident of Chinatown was found dead of bubonic plague . The next morning, all of Chinatown was quarantined, with policemen preventing "Asiatics" (people of Asian heritage) from either entering or leaving. The San Francisco Board of Health began looking for more cases of plague and began burning personal property and sanitizing buildings, streets and sewers within Chinatown. Chinese Americans protested and the Chinese Consolidated Benevolent Association threatened lawsuits. The quarantine was lifted but the burning and fumigating continued. A federal court ruled that public health officials could not close off Chinatown without any proof that Chinese Americans were anymore susceptible to plague than Anglo Americans. In 1880, the Burlingame Treaty was renegotiated and the United States ratified the Angell Treaty , which allowed federal restrictions on Chinese immigration and temporarily suspended the immigration of unskilled laborers. Anti-immigrant sentiment became federal law once the United States Government passed the Chinese Exclusion Act of 1882: the first immigration restriction law aimed at a single ethnic group. This law, along with other immigration restriction laws such as the Geary Act , greatly reduced the numbers of Chinese allowed into the country and the city, and in theory limited Chinese immigration to single males only. Exceptions were in fact granted to the wives and minor children of wealthy merchants; immigrants would purchase or partner in businesses to declare themselves merchants in order to bring their families to America. Alternatively, prospective immigrants could become " paper sons " by purchasing the identity of Americans whose citizenship had been established by birthright. : 38–39 However, the Exclusion Act was credited with reducing the population of the neighborhood to an all-time low in the 1920s. Many early Chinese immigrants to San Francisco and beyond were processed at Angel Island , in the San Francisco Bay , which is now a state park. Unlike Ellis Island on the east coast where prospective European immigrants might be held for up to a week, Angel Island typically detained Chinese immigrants for months while they were interrogated closely to validate their papers. The detention facility was renovated in 2005 and 2006 under a federal grant.As in much of San Francisco, a period of criminality existed during the late 19th century; many tongs arose, trafficking in smuggling, gambling, and prostitution. From the mid-1870s, turf battles sprang up over competing criminal enterprises. By the early 1880s, the term tong war was being popularly used to describe these periods of violence in Chinatown. At their height in the 1880s and 1890s, twenty to thirty tongs ran highly profitable gambling houses, brothels, opium dens, and slave trade enterprises in Chinatown. Overcrowding, segregation, graft, and the lack of governmental control contributed to conditions that sustained the criminal tongs until the early 1920s. Chinatown's isolation and compact geography intensified the criminal behavior that terrorized the community for decades despite efforts by the Six Companies and police/city officials to stem the tide. The San Francisco Police Department established its so-called Chinatown Squad in the 1880s, consisting of six patrolmen led by a sergeant. However, the Squad was ineffective largely by design. An investigation published in 1901 by the California state legislature found that Mayor James D. Phelan and Police Chief William P. Sullivan Jr. had knowingly tolerated gambling and prostitution in Chinatown in the interest of bolstering municipal revenue, calling the police department "so apathetic in putting down the horrible system of slavery existing in Chinatown as to justify your committee in believing it criminally negligent." Phelan and Sullivan testified it would take between 180 and 400 policemen to enforce the laws against gambling and prostitution, which was contradicted by the ex-Chief of Police William J. Biggy , who said 30 "earnestly directed" policemen would suffice. : 625–630Chinatown, as it is at present, cannot be rendered sanitary except by total obliteration. It should be depopulated, its buildings leveled by fire and its tunnels and cellars laid bare. Its occupants should be colonized on some distant portion of the peninsula, where every building should be constructed under strict municipal regulation and where every violation of the sanitary laws could be at once detected. The day has passed when a progressive city like San Francisco should feel compelled to tolerate in its midst a foreign community, perpetuated in filth, for the curiosity of tourists, the cupidity of lawyers and the adoration of artists. Dr. Williamson, Annual Report to the Board of Health (quoted in 1901) In March 1900, a Chinese-born man who was a long-time resident of Chinatown was found dead of bubonic plague . The next morning, all of Chinatown was quarantined, with policemen preventing "Asiatics" (people of Asian heritage) from either entering or leaving. The San Francisco Board of Health began looking for more cases of plague and began burning personal property and sanitizing buildings, streets and sewers within Chinatown. Chinese Americans protested and the Chinese Consolidated Benevolent Association threatened lawsuits. The quarantine was lifted but the burning and fumigating continued. A federal court ruled that public health officials could not close off Chinatown without any proof that Chinese Americans were anymore susceptible to plague than Anglo Americans. The Chinatown neighborhood was completely destroyed in the 1906 earthquake and fire that leveled most of the city. "The fire had full sway, and Chinatown, for the removal of which many a scheme has been devised, is but a memory." Oakland Tribune, April 1906. : 33 Plans to relocate Chinatown predated the earthquake several years. At the 1901 Chinese Exclusion Convention held in San Francisco, A. Sbarboro called Chinatown "synonymous with disease, dirt and unlawful deeds" that "give[s] us nothing but evil habits and noxious stenches". With Chinatown completely demolished by the Great Fire, which ended on April 21, 1906, the City seized the chance to remove the Chinese from the old downtown business district. Certain city officials and real-estate developers made more formal plans to move Chinatown to the Hunters Point neighborhood at the southern edge of the city, or even further south to Daly City . Abe Ruef , the political boss widely considered to be the power behind Mayor Eugene Schmitz , invited himself to become part of the Committee of Fifty and, within a week of the end of the Great Fire, on Saturday, April 27, 1906, : 61–63 formed an additional Subcommittee on Relocating the Chinese, because he felt the land was too valuable for Chinese. Opposition arose, however, from politicians who feared that the removal of the Chinese would affect San Francisco's lucrative trade with Asian countries. Moreover, the government of China was also opposed, and soon after the earthquake, Tsi Chi Chow, the first secretary of the Chinese legation in Washington, DC, arrived in San Francisco, conveying to California governor George Pardee the opposition of China's Empress Dowager Cixi to the plan. The representatives, "acting unofficially", stated "the only way to remove the Chinese from the old Chinatown would be to give them a place elsewhere that would be acceptable for their purpose, when they might be willing to move." The San Francisco Call reported it as "a vigorous protest" and noted that as the site of the Chinese consulate was the property of Imperial China, it could not be reassigned by the city. On May 10, 1906, the subcommittee met with representatives from the Chinese community, the Chinese Six Companies , who said that they would either rebuild in their old Chinatown quarters or move across the bay to Oakland, where most of the Chinatown refugees had fled. : 65 Other community leaders pointed out that displaced residents may not stop to resettle in Hunters Point, moving further to other West Coast cities like Seattle or Los Angeles, taking the pool of cheap labor with them. On July 8, 1906, after 25 committee meetings and considering various alternative sites in the city, the subcommittee submitted a final report stating their inability to drive the Chinese from their old Chinatown quarters. : 66 Ironically, plans to relocate Chinatown failed in the end because restrictive housing covenants in other areas of the city prohibited Chinese from settling elsewhere. : 92 In any event, the ability to rebuild in their old Chinatown quarters was the first significant victory for the Chinese community in Chinatown. : 83 Even when the Subcommittee was bringing its relocation attempt to an end, the Chinese were already rebuilding, albeit with temporary wooden buildings which did not require permits. By June 10, 1906, twelve Chinese businesses were opened in Chinatown, including a couple of cafes. The actual reconstruction did not begin until October 1, 1906, when the City granted 43 building permits to Chinese businesses. By the time of the first post-quake Chinese New Year in 1907, several dozen buildings were completed, using old bricks unburnt by the fire, and Chinatown was filled with happy people. The reconstruction of Chinatown was completed more or less in 1908, a year ahead of the rest of the city. : 92–94 While the city's proposals to relocate Chinatown failed, the directive of rebuilding Chinatown into an attractive district along orientalized and stereotyped conceptions still gained traction. A group of Chinese merchants, including Mendocino -born Look Tin Eli , hired American architects to design in a Chinese-motif " Oriental " style in order to promote tourism in the rebuilt Chinatown. The results of this design strategy were the pagoda-topped buildings of the Sing Chong and Sing Fat bazaars on the west corners of Grant Ave (then Dupont St) and California St, which have become icons of San Francisco Chinatown. : 113–115 This design strategy leveraged the ethnic identity and exoticness that city planners used to justify the relocation of Chinatown to become the same forces that made the area an attractive tourist location. In constructing "Oriental" style architecture, the area gratified Western fascination with and perception of a stereotyped Chinese identity. Opportunistic individuals from within the Chinese community and from outside the Chinese community made entrepreneurial gains from this "ethnic tourism" as it emerged in the early 1900s and boosted local business. In November 1907, an article extolling the virtues of the "new Chinatown of San Francisco" was written, praising the new "substantial, modern, fireproof buildings of brick and stone ... following the Oriental style of architecture" and declaring "[n]o more picturesque squalor, no more gambling dens, opium joints or public haunts of vice" would be tolerated, at the command of the Chinese Six Companies. By then, 5,000 residents had returned, of the estimated 30,000 that lived in Chinatown prior to the quake. When the earthquake destroyed Chinatown's wooden tenements, it also dealt a blow to the tongs. Criminal tongs continued on until the 1920s, when legitimate Chinese merchants and a more capable Chinatown Squad under Sgt. Jack Manion gained the upper hand. Manion was appointed leader of the Squad in 1921 and served for two decades. Stiffer legislation against prostitution and drugs ended the tongs. The Chinatown Squad was finally disbanded in August 1955 by Police Chief George Healey , upon the request of the influential Chinese World newspaper, which had editorialized the Squad was an "affront to Americans of Chinese descent". The rhetoric of a "New Chinatown" obscured the reality of the community's perpetuating problems, particularly those of poverty, overcrowding, and racial discrimination. While the Chinese merchants succeeded in rebuilding in a tourist-attractive way, they could not influence the landlords, most of which were not Chinese, to provide adequate housing for the Chinese residents. In a 1930 Community Chest Survey of 153 Chinatown families, 32 families, with an average of five persons each, lived in one room each; only 19 families had complete bath tub, kitchen, and toilet facilities; on the average, there was one kitchen for 3.1 families and one toilet for 4.6 families (or 28.3 persons). Crowded inadequate living conditions contributed to a high death rate for the Chinese. The Chinese were no longer a problem for the city; they were forgotten. : 61–62 By 1947, Chinatown established itself as a central tourist destination and a rapidly developing community. Tension began to arise between businesses in Chinatown seeking to modernize and city planning committees seeking to maintain the "Oriental" look of the area. Similar to the post-earthquake discussion, Chinatown remained a contested space for conflicting visions of the area's development. In 1947, the Board of Supervisors proposed a building code prohibiting architectural changes to the area. Opposition to these preservationist initiatives came from Chinese business owners and some of the architects who designed the buildings, among others. These individuals saw such building codes or architectural regulations as hindering the progress of the community and treating it as a static ethnic icon. The famous Sam Wo restaurant opened in 1912. In 1925 for the celebration of the San Francisco Diamond Jubilee, the Downtown Merchants Association, the Chinese Chamber of Commerce, and the San Francisco Diamond Jubilee Festival jointly raised $18,000 for 43 dragon street lamps to be cast in China and installed along Grant Avenue from Bush Street to Broadway. Designed by W(alter) D'Arcy Ryan, who also designed the "Path of Gold" streetlights along Market Street , : 124–125 the distinctive 2,750 pounds (1,250 kg) street lamp, painted in traditional Chinese colors of red, gold and green, was composed of a cast-iron hexagonal base supporting a lotus and bamboo shaft surmounted with two cast-aluminum dragons below a pagoda lantern with bells and topped by a stylized hexagonal red roof —all in keeping with the Oriental style pioneered by Look Tin Eli (1910). The new lamps made Grant Avenue one of the brightest streets in the City at night, : 51 at a cost of US$418 (equivalent to $7,300 in 2023) each. Since then, the original molds were used to add 24 more dragon street lamps were in 1996 (distinguishable by the foundry, whose name and location in Emporia, Kansas is cast on an access door at the base), and later, 23 more were added along Pacific by PG&E. During the Great Depression, many nightclubs and cocktail bars were started in Chinatown. The Forbidden City nightclub, located at 369 Sutter Street just outside Chinatown and run by Charlie Low, became one of the most famous entertainment places in San Francisco. While it was doing business, from the late 1930s to the late 1950s, the Forbidden City gained an international reputation with its unique showcase of exotic oriental performance from Chinese American performers. Another popular club for tourists and LGBT clients was Li Po, which, like Forbidden City, combined western entertainment with "Oriental" culture. It was advertised in a 1939 tourism guide book as a "jovial and informal Chinatown cocktail lounge" where one could find "love, passion, and nighttime". As of 2018, it was still in operation at 916 Grant Avenue. For the Chinese in Chinatown, the war came upon them in September 1931, when Japan attacked the Manchurian city of Mukden, and became impossible to ignore in July 1937, when Japan launched a major offensive southward from their base in Manchuria towards the heart of China. In response, the Chinese Six Companies convened many community organizations together, from which was founded the Chinese War Relief Association, to raise funds from the Chinatown communities throughout the U.S. to aid civilians trapped by the war in China. In San Francisco's Chinatown, a popular means to raise money for war relief was through the Rice Bowl parades and parties, where the appeal to fill the rice bowls of starving children victimized by the war in China resonated with the Chinatown community. One hallmark of the Rice Bowl parade was the striking scene of a large number of Chinese-American women in fashionable Chinese dress (the cheongsam) carrying one huge Chinese flag spanning the width of the street, onto which money was thrown from balconies, windows, and sidewalks. In the Rice Bowl parade and party of 1938, San Francisco Chinatown raised $55,000; the second Rice Bowl in 1940 collected $87,000; and the third in 1941 brought in $93,000—all for war and hunger relief of civilians in war-torn China. : 33–44 As Chinese Americans became more visible in the public eye during the period leading to the U.S. involvement in the war, the negative image of China and the Chinese began to erode. — K. Scott Wong : 42 Once China became an ally to the U.S. in World War II , a positive image of the Chinese began to emerge. In October 1942, Earl Warren , running for Governor of California, wrote, "Like all native born Californians, I have cherished during my entire life a warm and cordial feeling for the Chinese people." : 89 In her goodwill tour of the U.S. starting in February 1943, Madame Chiang Kai Shek probably did more to change the American attitude towards the Chinese people than any other single person. : 53–54 She was hosted by the First Lady and President Franklin D. Roosevelt ; she was the second woman and the first Chinese to address the U.S. Congress. The American public embraced her with respect and kindness, which is in stark contrast to the treatment of most Chinese immigrants and Chinese Americans. : 89–109 To the Chinese in Chinatown, she became an icon of the war years. In December 1943, in recognition of the important role of China as an ally in the war, the Chinese Exclusion Act was repealed by the Magnuson Act , which allowed for naturalization but restricted Chinese immigrants to a small annual quota of 105 new entry visas. The repeal of the Exclusion Act and other immigration restriction laws, in conjunction with passage of the War Brides Act in December 1945, allowed Chinese-American veterans to bring their families outside of national quotas and led to a major population boom in the area during the 1950s. However, tight quotas on new immigration from China still applied until the Immigration and Nationality Act of 1965 was passed. In the 1948 landmark case of Shelley v. Kraemer , the U.S. Supreme Court ruled without dissent that enforcing racially restrictive covenants in property deeds violates the Equal Protection Clause of the Fourteenth Amendment and thus such covenants are unenforceable in court, which lifted the invisible walls around Chinatown, permitting some Chinese Americans to move out of the Gilded Ghetto into other neighborhoods of the city and gain a foothold on the middle class. Twenty years later, such racially restrictive covenants were outlawed in the 1968 Fair Housing Act . San Francisco artist Frank Wong created miniature dioramas that depict Chinatown during the 1930s and 1940s. In 2004, Wong donated seven miniatures of scenes of Chinatown, titled "The Chinatown Miniatures Collection," to the Chinese Historical Society of America (CHSA). The dioramas are on permanent display in CHSA's Main Gallery. Plans to relocate Chinatown predated the earthquake several years. At the 1901 Chinese Exclusion Convention held in San Francisco, A. Sbarboro called Chinatown "synonymous with disease, dirt and unlawful deeds" that "give[s] us nothing but evil habits and noxious stenches". With Chinatown completely demolished by the Great Fire, which ended on April 21, 1906, the City seized the chance to remove the Chinese from the old downtown business district. Certain city officials and real-estate developers made more formal plans to move Chinatown to the Hunters Point neighborhood at the southern edge of the city, or even further south to Daly City . Abe Ruef , the political boss widely considered to be the power behind Mayor Eugene Schmitz , invited himself to become part of the Committee of Fifty and, within a week of the end of the Great Fire, on Saturday, April 27, 1906, : 61–63 formed an additional Subcommittee on Relocating the Chinese, because he felt the land was too valuable for Chinese. Opposition arose, however, from politicians who feared that the removal of the Chinese would affect San Francisco's lucrative trade with Asian countries. Moreover, the government of China was also opposed, and soon after the earthquake, Tsi Chi Chow, the first secretary of the Chinese legation in Washington, DC, arrived in San Francisco, conveying to California governor George Pardee the opposition of China's Empress Dowager Cixi to the plan. The representatives, "acting unofficially", stated "the only way to remove the Chinese from the old Chinatown would be to give them a place elsewhere that would be acceptable for their purpose, when they might be willing to move." The San Francisco Call reported it as "a vigorous protest" and noted that as the site of the Chinese consulate was the property of Imperial China, it could not be reassigned by the city. On May 10, 1906, the subcommittee met with representatives from the Chinese community, the Chinese Six Companies , who said that they would either rebuild in their old Chinatown quarters or move across the bay to Oakland, where most of the Chinatown refugees had fled. : 65 Other community leaders pointed out that displaced residents may not stop to resettle in Hunters Point, moving further to other West Coast cities like Seattle or Los Angeles, taking the pool of cheap labor with them. On July 8, 1906, after 25 committee meetings and considering various alternative sites in the city, the subcommittee submitted a final report stating their inability to drive the Chinese from their old Chinatown quarters. : 66 Ironically, plans to relocate Chinatown failed in the end because restrictive housing covenants in other areas of the city prohibited Chinese from settling elsewhere. : 92 In any event, the ability to rebuild in their old Chinatown quarters was the first significant victory for the Chinese community in Chinatown. : 83Even when the Subcommittee was bringing its relocation attempt to an end, the Chinese were already rebuilding, albeit with temporary wooden buildings which did not require permits. By June 10, 1906, twelve Chinese businesses were opened in Chinatown, including a couple of cafes. The actual reconstruction did not begin until October 1, 1906, when the City granted 43 building permits to Chinese businesses. By the time of the first post-quake Chinese New Year in 1907, several dozen buildings were completed, using old bricks unburnt by the fire, and Chinatown was filled with happy people. The reconstruction of Chinatown was completed more or less in 1908, a year ahead of the rest of the city. : 92–94 While the city's proposals to relocate Chinatown failed, the directive of rebuilding Chinatown into an attractive district along orientalized and stereotyped conceptions still gained traction. A group of Chinese merchants, including Mendocino -born Look Tin Eli , hired American architects to design in a Chinese-motif " Oriental " style in order to promote tourism in the rebuilt Chinatown. The results of this design strategy were the pagoda-topped buildings of the Sing Chong and Sing Fat bazaars on the west corners of Grant Ave (then Dupont St) and California St, which have become icons of San Francisco Chinatown. : 113–115 This design strategy leveraged the ethnic identity and exoticness that city planners used to justify the relocation of Chinatown to become the same forces that made the area an attractive tourist location. In constructing "Oriental" style architecture, the area gratified Western fascination with and perception of a stereotyped Chinese identity. Opportunistic individuals from within the Chinese community and from outside the Chinese community made entrepreneurial gains from this "ethnic tourism" as it emerged in the early 1900s and boosted local business. In November 1907, an article extolling the virtues of the "new Chinatown of San Francisco" was written, praising the new "substantial, modern, fireproof buildings of brick and stone ... following the Oriental style of architecture" and declaring "[n]o more picturesque squalor, no more gambling dens, opium joints or public haunts of vice" would be tolerated, at the command of the Chinese Six Companies. By then, 5,000 residents had returned, of the estimated 30,000 that lived in Chinatown prior to the quake. When the earthquake destroyed Chinatown's wooden tenements, it also dealt a blow to the tongs. Criminal tongs continued on until the 1920s, when legitimate Chinese merchants and a more capable Chinatown Squad under Sgt. Jack Manion gained the upper hand. Manion was appointed leader of the Squad in 1921 and served for two decades. Stiffer legislation against prostitution and drugs ended the tongs. The Chinatown Squad was finally disbanded in August 1955 by Police Chief George Healey , upon the request of the influential Chinese World newspaper, which had editorialized the Squad was an "affront to Americans of Chinese descent". The rhetoric of a "New Chinatown" obscured the reality of the community's perpetuating problems, particularly those of poverty, overcrowding, and racial discrimination. While the Chinese merchants succeeded in rebuilding in a tourist-attractive way, they could not influence the landlords, most of which were not Chinese, to provide adequate housing for the Chinese residents. In a 1930 Community Chest Survey of 153 Chinatown families, 32 families, with an average of five persons each, lived in one room each; only 19 families had complete bath tub, kitchen, and toilet facilities; on the average, there was one kitchen for 3.1 families and one toilet for 4.6 families (or 28.3 persons). Crowded inadequate living conditions contributed to a high death rate for the Chinese. The Chinese were no longer a problem for the city; they were forgotten. : 61–62 By 1947, Chinatown established itself as a central tourist destination and a rapidly developing community. Tension began to arise between businesses in Chinatown seeking to modernize and city planning committees seeking to maintain the "Oriental" look of the area. Similar to the post-earthquake discussion, Chinatown remained a contested space for conflicting visions of the area's development. In 1947, the Board of Supervisors proposed a building code prohibiting architectural changes to the area. Opposition to these preservationist initiatives came from Chinese business owners and some of the architects who designed the buildings, among others. These individuals saw such building codes or architectural regulations as hindering the progress of the community and treating it as a static ethnic icon. The famous Sam Wo restaurant opened in 1912. In 1925 for the celebration of the San Francisco Diamond Jubilee, the Downtown Merchants Association, the Chinese Chamber of Commerce, and the San Francisco Diamond Jubilee Festival jointly raised $18,000 for 43 dragon street lamps to be cast in China and installed along Grant Avenue from Bush Street to Broadway. Designed by W(alter) D'Arcy Ryan, who also designed the "Path of Gold" streetlights along Market Street , : 124–125 the distinctive 2,750 pounds (1,250 kg) street lamp, painted in traditional Chinese colors of red, gold and green, was composed of a cast-iron hexagonal base supporting a lotus and bamboo shaft surmounted with two cast-aluminum dragons below a pagoda lantern with bells and topped by a stylized hexagonal red roof —all in keeping with the Oriental style pioneered by Look Tin Eli (1910). The new lamps made Grant Avenue one of the brightest streets in the City at night, : 51 at a cost of US$418 (equivalent to $7,300 in 2023) each. Since then, the original molds were used to add 24 more dragon street lamps were in 1996 (distinguishable by the foundry, whose name and location in Emporia, Kansas is cast on an access door at the base), and later, 23 more were added along Pacific by PG&E. During the Great Depression, many nightclubs and cocktail bars were started in Chinatown. The Forbidden City nightclub, located at 369 Sutter Street just outside Chinatown and run by Charlie Low, became one of the most famous entertainment places in San Francisco. While it was doing business, from the late 1930s to the late 1950s, the Forbidden City gained an international reputation with its unique showcase of exotic oriental performance from Chinese American performers. Another popular club for tourists and LGBT clients was Li Po, which, like Forbidden City, combined western entertainment with "Oriental" culture. It was advertised in a 1939 tourism guide book as a "jovial and informal Chinatown cocktail lounge" where one could find "love, passion, and nighttime". As of 2018, it was still in operation at 916 Grant Avenue. For the Chinese in Chinatown, the war came upon them in September 1931, when Japan attacked the Manchurian city of Mukden, and became impossible to ignore in July 1937, when Japan launched a major offensive southward from their base in Manchuria towards the heart of China. In response, the Chinese Six Companies convened many community organizations together, from which was founded the Chinese War Relief Association, to raise funds from the Chinatown communities throughout the U.S. to aid civilians trapped by the war in China. In San Francisco's Chinatown, a popular means to raise money for war relief was through the Rice Bowl parades and parties, where the appeal to fill the rice bowls of starving children victimized by the war in China resonated with the Chinatown community. One hallmark of the Rice Bowl parade was the striking scene of a large number of Chinese-American women in fashionable Chinese dress (the cheongsam) carrying one huge Chinese flag spanning the width of the street, onto which money was thrown from balconies, windows, and sidewalks. In the Rice Bowl parade and party of 1938, San Francisco Chinatown raised $55,000; the second Rice Bowl in 1940 collected $87,000; and the third in 1941 brought in $93,000—all for war and hunger relief of civilians in war-torn China. : 33–44 As Chinese Americans became more visible in the public eye during the period leading to the U.S. involvement in the war, the negative image of China and the Chinese began to erode. — K. Scott Wong : 42 Once China became an ally to the U.S. in World War II , a positive image of the Chinese began to emerge. In October 1942, Earl Warren , running for Governor of California, wrote, "Like all native born Californians, I have cherished during my entire life a warm and cordial feeling for the Chinese people." : 89 In her goodwill tour of the U.S. starting in February 1943, Madame Chiang Kai Shek probably did more to change the American attitude towards the Chinese people than any other single person. : 53–54 She was hosted by the First Lady and President Franklin D. Roosevelt ; she was the second woman and the first Chinese to address the U.S. Congress. The American public embraced her with respect and kindness, which is in stark contrast to the treatment of most Chinese immigrants and Chinese Americans. : 89–109 To the Chinese in Chinatown, she became an icon of the war years. In December 1943, in recognition of the important role of China as an ally in the war, the Chinese Exclusion Act was repealed by the Magnuson Act , which allowed for naturalization but restricted Chinese immigrants to a small annual quota of 105 new entry visas. The repeal of the Exclusion Act and other immigration restriction laws, in conjunction with passage of the War Brides Act in December 1945, allowed Chinese-American veterans to bring their families outside of national quotas and led to a major population boom in the area during the 1950s. However, tight quotas on new immigration from China still applied until the Immigration and Nationality Act of 1965 was passed. In the 1948 landmark case of Shelley v. Kraemer , the U.S. Supreme Court ruled without dissent that enforcing racially restrictive covenants in property deeds violates the Equal Protection Clause of the Fourteenth Amendment and thus such covenants are unenforceable in court, which lifted the invisible walls around Chinatown, permitting some Chinese Americans to move out of the Gilded Ghetto into other neighborhoods of the city and gain a foothold on the middle class. Twenty years later, such racially restrictive covenants were outlawed in the 1968 Fair Housing Act .San Francisco artist Frank Wong created miniature dioramas that depict Chinatown during the 1930s and 1940s. In 2004, Wong donated seven miniatures of scenes of Chinatown, titled "The Chinatown Miniatures Collection," to the Chinese Historical Society of America (CHSA). The dioramas are on permanent display in CHSA's Main Gallery. In the 1960s, the shifting of under-utilized national immigration quotas brought in another huge wave of immigrants, mostly from Hong Kong. This changed San Francisco Chinatown from predominantly Hlay Yip Wah ( Sze Yup or Hoisan Wah )-speaking to Sam Yup Wah (standard Cantonese )-speaking. During the same decade, many stores moved from Grant Avenue to Stockton Street, drawn by lower rents and the better transportation enabled by the 30-Stockton Muni trolleybus line. There were areas where many Chinese in Northern California living outside of San Francisco Chinatown could maintain small communities or individual businesses. Nonetheless, the historic rights of property owners to deed or sell their property to whomever they pleased was exercised enough to keep the Chinese community from spreading. However, in 1948, Shelley v. Kraemer , the Supreme Court had ruled that racially restrictive covenants in deeds are unenforceable in courts due to the 14th amendment equal protection clause; and in 1968 the Fair Housing Act outlawed racially restrictive covenants. This ruling and law allowed the enlargement of Chinatown and an increase in the Chinese population of the city. At the same time, the declining white population of the city as a result of White Flight combined to change the demographics of the city. Neighborhoods that were once predominately white, such as Richmond District and Sunset District and in other suburbs across the San Francisco Bay Area became centers of new Chinese immigrant communities. Until 1979, the United States recognized the Republic of China in Taiwan as the sole legitimate government of all of China, and emigration from Taiwan was counted under the same grouping as that for mainland China, from which little emigration to the United States existed from 1949 on. In 1979, the opening up of the People's Republic of China and the breaking of diplomatic relations with the Republic of China led to the passage of the Taiwan Relations Act , which placed Taiwan under a separate immigration group from the People's Republic of China. As a result of the Immigration Act of 1990 , emigration from Hong Kong was also considered a separate jurisdiction for the purpose of recording such statistics. Thus, Mandarin-speaking emigrants from Taiwan began to arrive in the Bay Area, and they have tended to settle in suburban Millbrae , Cupertino , Milpitas , Mountain View , and even San Jose – avoiding San Francisco as well as Oakland Chinatowns. [ citation needed ] With these changes came a weakening of the Tongs' traditional grip on Chinese life. Newer Chinese groups often came from areas outside of the Tongs' control, so the influence of the Tongs and criminal groups associated with them, such as the Triads , grew weaker in Chinatown and the Chinese community. [ citation needed ] However, the presence of the Asian gangs remained significant in the immigrant community, and in the summer of 1977, an ongoing rivalry between two street gangs, the Wah Ching and the Joe Boys , erupted in violence and bloodshed, culminating in a shooting spree at the Golden Dragon Restaurant on Washington Street (è¯ç››é “è¡—). Five people were killed and eleven wounded, none of whom were gang members. The incident has become infamously known as the Golden Dragon massacre . Five perpetrators, who were members of the Joe Boys gang, were convicted of murder and assault charges and were sentenced to prison. The Golden Dragon closed in January 2006 because of health violations, and later reopened as the Imperial Palace Restaurant. Other notorious acts of violence have taken place in Chinatown since 1977. At 2 a.m. on May 14, 1990, San Francisco residents who had just left The Purple Onion , a nightclub located where Chinatown borders on North Beach , were shot as they entered their cars. 35-year-old Michael Bit Chen Wu was killed and six others were injured, among them a critically wounded pregnant woman. In June 1998, shots were fired at Chinese Playground , wounding six teenagers, three of them critically. A 16-year-old boy was arrested for the shooting, which was believed to be gang-related. On February 27, 2006, Allen Leung was shot to death in his business on Jackson Street; Raymond "Shrimp Boy" Chow , who succeeded Leung as head of the Ghee Kung Tong , was later convicted in 2016 of soliciting Leung's murder as fallout from the corruption investigation of Leland Yee , and Raymond "Skinny Ray" Lei was indicted for committing the murder in 2017. As Chinatown's ill reputation reemerged in the 1970s with the publicized gang crimes and continued neglect of substandard housing in the area, tourism began to decline. Visitors perceived the area as a "ghetto" taking their commercial business elsewhere. As Chinatown's tourist industry suffered, the entire area's once stable economy suffered. To counter this image, the Chinese Six Companies and other Chinese merchants began heavily emphasizing the safety and attractiveness of visiting the area. These marketing efforts alongside quieter initiatives to improve conditions for residents throughout the 1970s enabled the area's tourism-dependent economy to continue functioning. Similar dynamics of area leaders internally addressing social issues while externally maintaining commercial tourist appeal continued to the end of the 1900s. Now, However, San Francisco's Chinatown is now shrinking and faces an existential threat to it survival, due to macroeconomic ills afflicting downtown and San Francisco as a whole, in addition to its aging infrastructure and residential inhabitants. With these changes came a weakening of the Tongs' traditional grip on Chinese life. Newer Chinese groups often came from areas outside of the Tongs' control, so the influence of the Tongs and criminal groups associated with them, such as the Triads , grew weaker in Chinatown and the Chinese community. [ citation needed ] However, the presence of the Asian gangs remained significant in the immigrant community, and in the summer of 1977, an ongoing rivalry between two street gangs, the Wah Ching and the Joe Boys , erupted in violence and bloodshed, culminating in a shooting spree at the Golden Dragon Restaurant on Washington Street (è¯ç››é “è¡—). Five people were killed and eleven wounded, none of whom were gang members. The incident has become infamously known as the Golden Dragon massacre . Five perpetrators, who were members of the Joe Boys gang, were convicted of murder and assault charges and were sentenced to prison. The Golden Dragon closed in January 2006 because of health violations, and later reopened as the Imperial Palace Restaurant. Other notorious acts of violence have taken place in Chinatown since 1977. At 2 a.m. on May 14, 1990, San Francisco residents who had just left The Purple Onion , a nightclub located where Chinatown borders on North Beach , were shot as they entered their cars. 35-year-old Michael Bit Chen Wu was killed and six others were injured, among them a critically wounded pregnant woman. In June 1998, shots were fired at Chinese Playground , wounding six teenagers, three of them critically. A 16-year-old boy was arrested for the shooting, which was believed to be gang-related. On February 27, 2006, Allen Leung was shot to death in his business on Jackson Street; Raymond "Shrimp Boy" Chow , who succeeded Leung as head of the Ghee Kung Tong , was later convicted in 2016 of soliciting Leung's murder as fallout from the corruption investigation of Leland Yee , and Raymond "Skinny Ray" Lei was indicted for committing the murder in 2017. As Chinatown's ill reputation reemerged in the 1970s with the publicized gang crimes and continued neglect of substandard housing in the area, tourism began to decline. Visitors perceived the area as a "ghetto" taking their commercial business elsewhere. As Chinatown's tourist industry suffered, the entire area's once stable economy suffered. To counter this image, the Chinese Six Companies and other Chinese merchants began heavily emphasizing the safety and attractiveness of visiting the area. These marketing efforts alongside quieter initiatives to improve conditions for residents throughout the 1970s enabled the area's tourism-dependent economy to continue functioning. Similar dynamics of area leaders internally addressing social issues while externally maintaining commercial tourist appeal continued to the end of the 1900s. Now, However, San Francisco's Chinatown is now shrinking and faces an existential threat to it survival, due to macroeconomic ills afflicting downtown and San Francisco as a whole, in addition to its aging infrastructure and residential inhabitants. San Francisco's Chinatown is home to the Chinese Consolidated Benevolent Association (known as the Chinese Six Companies ), which is the umbrella organization for local Chinese family and regional associations in this Chinatown. It has spawned lodges in other Western U.S. Chinatowns in the late 19th and early 20th centuries, including Chinatown, Los Angeles and Chinatown, Portland . The Chinese Culture Center is a community based non-profit organization located on the third floor of the Hilton San Francisco Financial District , across Kearny Street from Portsmouth Square. The Center promotes exhibitions about Chinese life in the United States and organizes tours of the area. The Chinese Historical Society of America is housed in a building designed by Julia Morgan as a YWCA, at 965 Clay. In the 1950s, : 71–73 during the Korean war, a number of Chinese-American leaders, led by W. K. Wong, organized the San Francisco Chinese New Year Festival and Parade , including art shows, street dances, martial arts, music, and a fashion show. The 1953 parade was led by Korean war veteran, Joe Wong, and featured the Miss Chinatown festival queen and the dragon. : 29 By 1958, the festival queen had been formally expanded into the pageant of "Miss Chinatown U.S.A". : 56 In 1994, around 120 queer Asian Americans joined the annual parade, which was the first time that Asian American queer community had appeared in public and gained acceptance from Chinese-American society. San Francisco Chinatown's annual Autumn Moon Festival celebrates seasonal change and the opportunity to give thanks to a bountiful summer harvest. The Moon Festival is popularly celebrated throughout China and surrounding countries each year, with local bazaars, entertainment, and mooncakes , a pastry filled with sweet bean paste and egg. The festival is held each year during mid-September, and is free to the public. Chinatown is frequently the venue of traditional Chinese funeral processions, where a marching band (playing Western songs such as Nearer, My God, to Thee ) takes the street with a motorcycle escort. The band is followed by a car displaying an image of the deceased (akin to the Chinese custom of parading a scroll with his or her name through the village), and the hearse and the mourners, who then usually travel to Colma south of San Francisco for the actual funeral. By union regulation, the procession route starts at the Green Street Mortuary proceeding on Stockton Street for six blocks and back on Grant Avenue, taking about one hour. Chinatown Community Development Center is an organization formed in 1977 after the merger of the Chinatown Resource center and the Chinese Community Housing Corporation. The organization was started by Gordon Chin, who served as executive director since 1977 until he was succeeded by the organization's Deputy Director Rev. Norman Fong on October 1, 2011. The organization advocates and provides services to San Francisco's Chinatown. They have also started many groups, Adopt-An-Alleyway Youth Empowerment Project being the most notable, and have been involved with many tenant programs. San Francisco's Chinatown is home to the Chinese Consolidated Benevolent Association (known as the Chinese Six Companies ), which is the umbrella organization for local Chinese family and regional associations in this Chinatown. It has spawned lodges in other Western U.S. Chinatowns in the late 19th and early 20th centuries, including Chinatown, Los Angeles and Chinatown, Portland . The Chinese Culture Center is a community based non-profit organization located on the third floor of the Hilton San Francisco Financial District , across Kearny Street from Portsmouth Square. The Center promotes exhibitions about Chinese life in the United States and organizes tours of the area. The Chinese Historical Society of America is housed in a building designed by Julia Morgan as a YWCA, at 965 Clay.In the 1950s, : 71–73 during the Korean war, a number of Chinese-American leaders, led by W. K. Wong, organized the San Francisco Chinese New Year Festival and Parade , including art shows, street dances, martial arts, music, and a fashion show. The 1953 parade was led by Korean war veteran, Joe Wong, and featured the Miss Chinatown festival queen and the dragon. : 29 By 1958, the festival queen had been formally expanded into the pageant of "Miss Chinatown U.S.A". : 56 In 1994, around 120 queer Asian Americans joined the annual parade, which was the first time that Asian American queer community had appeared in public and gained acceptance from Chinese-American society. San Francisco Chinatown's annual Autumn Moon Festival celebrates seasonal change and the opportunity to give thanks to a bountiful summer harvest. The Moon Festival is popularly celebrated throughout China and surrounding countries each year, with local bazaars, entertainment, and mooncakes , a pastry filled with sweet bean paste and egg. The festival is held each year during mid-September, and is free to the public. Chinatown is frequently the venue of traditional Chinese funeral processions, where a marching band (playing Western songs such as Nearer, My God, to Thee ) takes the street with a motorcycle escort. The band is followed by a car displaying an image of the deceased (akin to the Chinese custom of parading a scroll with his or her name through the village), and the hearse and the mourners, who then usually travel to Colma south of San Francisco for the actual funeral. By union regulation, the procession route starts at the Green Street Mortuary proceeding on Stockton Street for six blocks and back on Grant Avenue, taking about one hour. Chinatown Community Development Center is an organization formed in 1977 after the merger of the Chinatown Resource center and the Chinese Community Housing Corporation. The organization was started by Gordon Chin, who served as executive director since 1977 until he was succeeded by the organization's Deputy Director Rev. Norman Fong on October 1, 2011. The organization advocates and provides services to San Francisco's Chinatown. They have also started many groups, Adopt-An-Alleyway Youth Empowerment Project being the most notable, and have been involved with many tenant programs. In the citywide Board of Supervisors elections, Chinatown forms part of District Three and in 2014 accounted for 44% of both registered voters and ballots cast. The two main newspapers read among residents are Sing Tao Daily and World Journal . San Francisco Chinatown restaurants are considered to be the birthplace of Americanized Chinese cuisine such as food items like Chop Suey while introducing and popularizing Dim Sum to American tastes, as its Dim Sum tea houses are a major tourist attraction. Johnny Kan was the proprietor of one of the first modern style Chinese restaurants, which opened in 1953. Many of the district's restaurants have been featured in food television programs on Chinese cuisine such as Martin Yan 's Martin Yan - Quick & Easy . The Chinatown has served as a backdrop for several movies, television shows, plays and documentaries including The Maltese Falcon , Flower Drum Song , What's Up, Doc? , Chan Is Missing , Big Trouble in Little China , The Presidio , The Dead Pool , Jackie Chan Adventures , The Pursuit of Happyness , Godzilla , and Shang-Chi and the Legend of the Ten Rings . Noted Chinese American writers grew up there such as Russell Leong . Contrary to popular belief, while the Chinese-American writer Amy Tan was inspired by Chinatown and its culture for the basis of her book The Joy Luck Club and the subsequent movie , she did not grow up in this area; she was born and grew up in Oakland. Notable 1940s basketball player Willie "Woo Woo" Wong , who excelled in local schools, college and professional teams, was born in, and grew up playing basketball in, Chinatown; a local playground bears his name. Actor Bruce Lee , who was born at San Francisco Chinese Hospital before moving back to Hong Kong three months later, returned to the United States at the age of eighteen, residing in San Francisco's Chinatown for the first few months before moving to Seattle . [ citation needed ]San Francisco cable cars have long served areas of Chinatown; the modern system serves the southern (along California Street) and western (along Powell Street) sections of the neighborhood. The Stockton Street Tunnel was completed in 1914 and brought San Francisco Municipal Railway Streetcar service to Stockton Street. After the tracks were removed, the overhead wires were maintained and buses replaced streetcars along the route. The 30 Stockton and 45 Union-Stockton are among the most heavily ridden lines in the system. [ citation needed ] Modern rail service has returned in the form of Chinatown station upon the completion of the Muni Metro 's Central Subway . The Broadway Tunnel was completed in 1952 and was intended to serve as a connection between the Embarcadero Freeway and the Central Freeway . These plans did not materialize due to the highway revolts at the time. [ citation needed ] The tunnel currently serves to connect Chinatown with Russian Hill and Van Ness Avenue to the west. In the 1980s, Chinatown merchants were opposed to the removal of the Embarcadero Freeway, but these objections were overturned after it was damaged in the 1989 Loma Prieta earthquake . According to the San Francisco Chronicle , activist Rose Pak then "almost single-handedly persuaded the city to build" the $1.5 billion Central Subway project to compensate Chinatown for the demolition of the freeway. The 49-Mile Scenic Drive is routed through Chinatown, with particular attention paid to the corner of Grant and Clay. On October 20, 2022, Chinatown station was first shown to the public after years of development, with promises of completion of the station sometime in January. It opened with a soft launch as part of a shuttle service on November 12, 2022, introducing two new metro stations downtown before officially being connected to the T Third Street line on January 7, 2023.

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Bubonic plague

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Sylvatic plague

Sylvatic plague is an infectious bacterial disease caused by the plague bacterium ( Yersinia pestis ) that primarily affects rodents , such as prairie dogs . It is the same bacterium that causes bubonic and pneumonic plague in humans. Sylvatic, or sylvan, means 'occurring in woodland,' and refers specifically to the form of plague in rural wildlife. Urban plague refers to the form in urban wildlife. It is primarily transmitted among wildlife through flea bites and contact with infected tissue or fluids. Sylvatic plague is most commonly found in prairie dog colonies and some mustelids , like the black-footed ferret . The flea that feeds on prairie dogs and other mammals serves as the vector for transmission of sylvatic plague to the new host, primarily through flea bites, or contact with contaminated fluids or tissue, through predation or scavenging. Humans can contract plague from wildlife through flea bites and handling animal carcasses . Yersinia pestis circulates in rodent reservoirs on all continents except Australia. Sylvatic plague affects over 50 species of rodents worldwide. It is vectored by a variety of flea species. Non-rodent animals susceptible to the disease include shrews , lagomorphs , ferrets , badgers , skunks , weasels , coyotes , domestic dogs and cats , bobcats , cougars , camels , goats , sheep , pigs , deer , and primates , including humans . Birds are not known to be susceptible. Sylvatic plague is normally enzootic , meaning it occurs at regular, predictable rates in populations and specific areas. At unpredictable times, it becomes epizootic in unexpected places. It is during these epizootic outbreaks that transmission to humans is most common. Factors that predispose to epizootic cycles include dense populations of rodents, multiple species of rodents in a particular area, and multiple rodent species in diverse habitats. Prairie dog colonies reach nearly 100% mortality rates during outbreaks. Prairie dogs are a keystone species and play a vital role as the primary prey of black-footed ferrets. Developing methods to control plague is of high concern for preserving ferrets and the conservation of Western prairie and grassland ecosystems. In the absence of understanding the prairie dog/plague cycles, dusting rodent dens with pesticides to kill fleas is currently the main method of controlling sylvatic plague in the wild, with some interest in using vaccines developing. An oral live vaccine for prairie dogs was developed by the U.S. Geological Survey, National Wildlife Health Center, from a recombinant raccoon poxvirus expressing plague antigens. It was originally developed by a Fort Detrick company in 2003 which showed it protected mice against lethal plague.

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Bubonic plague

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Great Plague of Seville

The Great Plague of Seville (1647–1652) was a massive outbreak of disease in Spain that killed up to a quarter of Seville 's population.Unlike the plague of 1596–1602, which claimed 600,000 to 700,000 lives, or a little under 8% of the population and initially struck northern and central Spain and Andalusia in the south, the Great Plague, which may have arisen in Algeria, struck the Mediterranean side of Spain first. The coastal city of Valencia was the first city to be hit, losing an estimated 30,000 people. The disease raged through Andalucía, in addition to sweeping the north into Catalonia and Aragon. The coast of Málaga lost upwards of 50,000 people. In Seville, quarantine measures were evaded, ignored, unproposed and/or unenforced. The results were devastating. The city of Seville and its rural districts were thought to have lost 150,000 people—starting with a total population of 600,000. Altogether Spain was thought to have lost 500,000 people, out of a population of slightly fewer than 10,000,000, or nearly 5% of its entire population. This was the greatest, but not the only, plague of 17th century Spain. Almost 25 years later, another plague ravaged Spain. For nine years (1676–1685), great outbreaks of the disease attacked in waves across the country. It struck the areas of Andalucía and Valencia particularly hard. In conjunction with the poor harvest of 1682-83, which created famine conditions, the effects killed tens of thousands of the weakened and exhausted population. When it ended in 1685, it is estimated to have taken over 250,000 lives. This was the last outbreak of plague in Spain in the 17th century. Three great plagues ravaged Spain in the 17th century. They were: The Plague of 1596–1602 (arrived in Santander by ship from northern Europe, most likely the Netherlands, then spread south through the center of Castile, reaching Madrid by 1599 and arriving in the southern city of Seville by 1600.) The Plague of 1646–1652 ("The Great Plague of Seville"; believed to have arrived by ship from Algeria, it was spread north by coastal shipping, afflicting towns and their hinterlands along the Mediterranean coast as far north as Barcelona.) The Plague of 1676–1685 Factoring in normal births, deaths, plus emigration, historians reckon the total cost in human lives due to these plagues throughout Spain, throughout the entire 17th century, to be a minimum of nearly 1.25 million. As a result, the population of Spain scarcely budged between the years 1596 and 1696. The disease is generally believed to have been bubonic plague , an infection by the bacterium Yersinia pestis , transmitted via a rat vector . Other symptom patterns of the bubonic plague, such as septicemic plague and pneumonic plague , were also present.

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Bubonic plague

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Plague of Amwas

The plague of Amwas ( Arabic : طاعون ع٠واس , romanized : ṭāʿūn ʿAmwās ), also spelled plague of Emmaus , was an ancient bubonic plague epidemic that afflicted Islamic Syria in 638–639, during the first plague pandemic and toward the end of the Muslim conquest of the region . It was likely a reemergence of the mid-6th-century Plague of Justinian . Named after Amwas in Palestine , the principal camp of the Muslim Arab army, the plague killed up to 25,000 soldiers and their relatives, including most of the army's high command, and caused considerable loss of life and displacement among the indigenous Christians of Syria. The appointment of Mu'awiya ibn Abi Sufyan to the governorship of Syria in the wake of the commanders' deaths paved the way for his establishment of the Umayyad Caliphate in 661, while recurrences of the disease may have contributed to the Umayyad dynasty 's downfall in 750. Depopulation in the Syrian countryside may have been a factor in the resettlement of the land by the Arabs unlike in other conquered regions where the Arabs largely secluded themselves to new garrison cities . [ citation needed ] The plague of Amwas received more attention in the Arabic sources than any other epidemic until the 14th-century Black Death . Traditional narratives about reactions to the plague of Amwas by Caliph Umar and his top commander Abu Ubayda ibn al-Jarrah informed medieval Muslim theological responses to epidemics, including the Black Death. Principles derived from the narratives were cited in debates about predestination and free will, prohibitions on fleeing or entering plague-affected lands and contagion. [ citation needed ]The plague of Amwas was likely a bubonic plague epidemic, though the sources do not elaborate on specific symptoms of the disease. It was the second recorded plague of the Islamic era, which began in the 620s, and the first to directly afflict the Muslims. It was likely a reemergence of the Plague of Justinian , which originated in Pelusium (near modern Suez ) in 541 and spread west to Alexandria and east to Palestine before reaching the Byzantine capital Constantinople in 541–542 and afflicting the rest of Europe and the Sasanian Empire , as noted by the Byzantine historian Procopius (d. c. 570 ). The Plague of Justinian recurred in at least nine to twelve cycles throughout the mid-6th century and the 7th century. The first caliph (head of the Muslim community), Abu Bakr ( r. 632–634 ), dispatched four armies from Medina , led respectively by Amr ibn al-As , Yazid ibn Abi Sufyan , Shurahbil ibn Hasana and Abu Ubayda ibn al-Jarrah to conquer Byzantine Syria (Abu Ubayda may not have been dispatched until after the accession of Abu Bakr's successor, Umar , in mid-634. ) Amwas, the Arabic name for Emmaus Nicopolis , had been a fortified Roman army camp in the first century, which grew into a small city by the early third. It was captured by the Muslims from the Byzantines following the Battle of Ajnadayn in 634 or the Battle of the Yarmuk in 636. At the onset of the plague, the site served as the principal camp of the Arab Muslim troops in Syria where spoils were divided and soldiers paid. The plague of Amwas occurred in the Islamic calendar years of 17 AH /638 AD and/or 18 AH/639 AD. According to the 8th-century historian Sayf ibn Umar , it struck in Muharram – Safar 17 AH/January–February 638, then dissipated before returning once more and inflicting numerous deaths "to the advantage of the enemy [the Byzantines]." Al-Suyuti (d. 1505) holds the plague had reemerged not long after its initial outbreak, which the historian M. W. Dols suggests "accounts for the two dates [638 and 639]". The plague struck at some point during a nine-month drought in Syria referred to by the Arabs as the 'Year of the Ashes'. Widespread famine in Syria–Palestine possibly set the stage for the plague due to weakened immune resistance and the stockpiling of food reserves in towns and villages, which could attract plague-infected rodents and bring them into contact with the human population, according to Dols. It spread across Syria and also affected Iraq and Egypt, before subsiding in Shawwal 18 AH/ October 639. According to one of the main narratives of the Islamic traditional sources, Umar, intending to prevent the illness and death of his top commander Abu Ubayda, summoned the latter to Medina; Abu Ubayda, aware of Umar's intent, refused to abandon his men. Umar subsequently embarked for Syria to assess the situation, meeting with the army leaders at a desert way-stop called Sargh (thirteen days' march north of Medina). His first consultations were with leaders from the Muhajirun and Ansar factions, collectively the earliest Muslim converts and elite of the nascent Muslim state, who argued against fleeing the plague-affected areas. Disagreeing with their recommendations, he next consulted the leaders of the later converts from the Quraysh , the tribe to which the Islamic prophet Muhammad and the caliphs belonged, who proposed that the army should withdraw from the area of the epidemic, which Umar accepted. Abu Ubayda protested the army's withdrawal on the basis of a purported prohibition by Muhammad on Muslims fleeing or entering a plague-affected land. Umar retorted that a person would naturally choose the green side of a valley rather than the barren side, but regardless of the person's decision it would be God's will. This narrative was used by medieval Muslim scholars as a precedent justifying flight from an epidemic. The summit at Sargh concluded with Umar ordering Abu Ubdaya to lead the army to healthier grounds and the caliph's return to Medina. Abu Ubayda moved to encamp the army at the old Ghassanid capital of Jabiya in the highland region of the Hauran . Due to its healthy climate, Jabiya effectively acted as a sanatorium for plague-stricken troops and the center for the distribution of war spoils. On the way there, in 639, Abu Ubayda succumbed to the plague. His successor Mu'adh ibn Jabal and two of Mu'adh's wives and son (or his entire family) died immediately after, followed by Mu'adh's successor Yazid ibn Abi Sufyan. Shurahbil also died from the plague. Among the other prominent Muslims and companions of Muhammad in the army to succumb were Suhayl ibn Amr , Suhayl's son Abu Jandal , al-Fadl ibn Abbas , al-Harith ibn Hisham , and many of al-Harith's seventy family members who had settled in Syria. Amr ibn al-As is credited for leading the surviving Muslim troops to Jabiya. In December 639, he embarked on the conquest of Egypt . The Islamic traditional accounts maintain between 20,000 and 25,000 Muslim soldiers in Syria and their family members died in the plague. By 639, 4,000 Muslim troops were left in Jabiya out of some 24,000 in 637, though the modern historian Fred Donner notes that it is unclear how many of the missing troops had died or had temporarily fled and returned to Syria eventually. The plague caused substantial loss of life among the local Christian population in Syria. It also resulted in price rises and hoarding, prompting Umar to prohibit hoarding. According to al-Tabari (d. 923), after returning to Medina from Sargh, Umar informed his advisers of his intention to visit his troops in Syria–Palestine and assess the chaos wrought by the plague. During his purported visit in 639, he gave directions on the disposition of the estates of the Muslims who died in the epidemic and settled suspicious claims by some of the troops. As a result of the deaths of his top commanders in Syria, Umar appointed Yazid's brother and deputy, Mu'awiya ibn Abi Sufyan , commander of the army there, ultimately laying the foundation for the establishment of the Syria-centered Umayyad Caliphate by Mu'awiya in 661. The historian Wilferd Madelung surmises that the plague in Syria had precluded Umar from deploying commanders more preferable to him from Medina and he thus appointed Mu'awiya in lieu of a suitable alternative. The losses among the Muslim troops in Syria caused by the Amwas plague contributed to Mu'awiya's heavy military reliance on older-established, formerly Byzantine-allied and Christian Arab tribes in Syria, particularly the Banu Kalb , who had largely stayed neutral during the fighting between the Muslims and the Byzantines. Amwas was replaced as the Arabs' headquarters in Palestine first by Lydda and/or Jerusalem , followed by Ramla , which was founded by the Umayyad caliph Sulayman ibn Abd al-Malik in the early 8th century. As late as the 1870s a well in the village of Amwas bore the name bir al-ta'un (well of the plague). Jabiya remained the Arabs' principal military camp in Syria until the reign of Sulayman. There were recurrences of the plague in Syria–Palestine about every decade between 688/89 and 744/45. "The Umaiyad [sic] dynasty was literally plagued by this disease", in the words of Dols. The deaths of the Umayyad caliphs Mu'awiya II ( r. 683–684 ), Marwan I ( r. 684–685 ), Abd al-Malik ( r. 685–705 ), Sulayman ( r. 715–717 ) and the Umayyad governors in Iraq al-Mughira ibn Shu'ba ( r. 661–671 ) and Ziyad ibn Abihi ( r. 685–673 ) may all possibly have been caused by the plague epidemics in Syria and Iraq. The caliphs routinely withdrew from the cities to their desert palaces when the plague emerged during the summer months. Notable among them was Caliph Hisham ( r. 724–743 ), who preferred his palace at Rusafa over Damascus because he viewed the latter to be unhealthy. Dols speculates that the frequent recurrences may have consistently undercut natural population growth in Syria–Palestine, the center of the Umayyad Caliphate, and weakened Umayyad power. Concurrently, Arab tribal migrations into the far eastern province of Khurasan , which was spared from the plague epidemics, led to the lopsided growth and predominance of the eastern half of the Caliphate and the rise of the Abbasid Movement there, which toppled the Umayyads in 750. In the view of Conrad, by the end of these plague cycles, the Umayyads had lost practical control of the eastern Caliphate and "it is tempting to view the interminable plagues of the last years of the dynasty as an important factor in the victory of the Abbasid revolution". Modern historians concur that the actual circumstances of the plague of Amwas are not reconstructable and largely focus on the descriptions of the event in the 8th–10th-century Islamic histories and collections of hadith (traditions and sayings of Muhammad) in the context of theological debates on predestination , the status of Muslim sinners, and contagion. The plague of Amwas received more attention in medieval Arabic literature than any other epidemic until the 14th-century Black Death . Representations of the plague by the sources were "varied and contradictory", according to the historian Justin K. Stearns . The narratives of the response to the plague by Muhammad's companions Umar, Abu Ubayda, Amr and Mu'adh informed Muslim religious and legal interpretations of plague throughout the Middle Ages, including the response to the Black Death. Medieval Muslim scholars derived three principals from the contemporary reactions to the plague of Amwas: the first was that the plague was a form of divine mercy or martyrdom for the Muslim faithful and a punishment to non-believers; the second was the prohibition on Muslims entering or fleeing plague-stricken lands; and the third was the plague was not a contagion, rather it was directly imposed by God. The tenets consistently caused theological disagreements throughout the epidemic recurrences of the Middle Ages as a result of the difficulty in accepting plague as divine mercy or punishment and observable contagion. In the assessment of Dols, native Christian and Jewish attitudes and natural human anxieties likely influenced aspects of the first principle, namely that plague represented divine punishment or warnings. Muslims in this camp related the plague to lax morals among the Muslim troops in Syria, such as the consumption of wine, which supposedly led Umar to order the lashing of drinkers. On the other hand, the interpretation of plague as mercy or martyrdom is evident in Abu Ubayda's speeches to the troops at Amwas and in the council at Sargh. A poem about the plague of Amwas recorded by the Damascene historian Ibn Asakir (d. 1175) reflects the martyrdom belief: How many brave horsemen and how many beautiful, chaste women were killed in the valley of 'Amwas They had encountered the Lord, but He was not unjust to them When they died, they were among the non-aggrieved people in Paradise. We endure the plague as the Lord knows, and we were consoled in the hour of death. On the principle of predestination, the events of Amwas were used to argue that whether a person fled or remained in a plague-affected area their death had already been decreed by God. During an episode of plague in the Iraqi garrison city of Kufa , the prominent statesman and scholar Abu Musa al-Ash'ari (d. 662) turned away visitors to his home due to someone in his household having the plague, and he justified Muslims fleeing plague on the basis of Umar's actions at Sargh. According to Dols, this also implied a recognition of contagion despite the contradiction with the purported hadith rejecting contagion as a pre-Islamic theory. According to one of the main narratives of the Islamic traditional sources, Umar, intending to prevent the illness and death of his top commander Abu Ubayda, summoned the latter to Medina; Abu Ubayda, aware of Umar's intent, refused to abandon his men. Umar subsequently embarked for Syria to assess the situation, meeting with the army leaders at a desert way-stop called Sargh (thirteen days' march north of Medina). His first consultations were with leaders from the Muhajirun and Ansar factions, collectively the earliest Muslim converts and elite of the nascent Muslim state, who argued against fleeing the plague-affected areas. Disagreeing with their recommendations, he next consulted the leaders of the later converts from the Quraysh , the tribe to which the Islamic prophet Muhammad and the caliphs belonged, who proposed that the army should withdraw from the area of the epidemic, which Umar accepted. Abu Ubayda protested the army's withdrawal on the basis of a purported prohibition by Muhammad on Muslims fleeing or entering a plague-affected land. Umar retorted that a person would naturally choose the green side of a valley rather than the barren side, but regardless of the person's decision it would be God's will. This narrative was used by medieval Muslim scholars as a precedent justifying flight from an epidemic. The summit at Sargh concluded with Umar ordering Abu Ubdaya to lead the army to healthier grounds and the caliph's return to Medina. Abu Ubayda moved to encamp the army at the old Ghassanid capital of Jabiya in the highland region of the Hauran . Due to its healthy climate, Jabiya effectively acted as a sanatorium for plague-stricken troops and the center for the distribution of war spoils. On the way there, in 639, Abu Ubayda succumbed to the plague. His successor Mu'adh ibn Jabal and two of Mu'adh's wives and son (or his entire family) died immediately after, followed by Mu'adh's successor Yazid ibn Abi Sufyan. Shurahbil also died from the plague. Among the other prominent Muslims and companions of Muhammad in the army to succumb were Suhayl ibn Amr , Suhayl's son Abu Jandal , al-Fadl ibn Abbas , al-Harith ibn Hisham , and many of al-Harith's seventy family members who had settled in Syria. Amr ibn al-As is credited for leading the surviving Muslim troops to Jabiya. In December 639, he embarked on the conquest of Egypt . The Islamic traditional accounts maintain between 20,000 and 25,000 Muslim soldiers in Syria and their family members died in the plague. By 639, 4,000 Muslim troops were left in Jabiya out of some 24,000 in 637, though the modern historian Fred Donner notes that it is unclear how many of the missing troops had died or had temporarily fled and returned to Syria eventually. The plague caused substantial loss of life among the local Christian population in Syria. It also resulted in price rises and hoarding, prompting Umar to prohibit hoarding. According to al-Tabari (d. 923), after returning to Medina from Sargh, Umar informed his advisers of his intention to visit his troops in Syria–Palestine and assess the chaos wrought by the plague. During his purported visit in 639, he gave directions on the disposition of the estates of the Muslims who died in the epidemic and settled suspicious claims by some of the troops. As a result of the deaths of his top commanders in Syria, Umar appointed Yazid's brother and deputy, Mu'awiya ibn Abi Sufyan , commander of the army there, ultimately laying the foundation for the establishment of the Syria-centered Umayyad Caliphate by Mu'awiya in 661. The historian Wilferd Madelung surmises that the plague in Syria had precluded Umar from deploying commanders more preferable to him from Medina and he thus appointed Mu'awiya in lieu of a suitable alternative. The losses among the Muslim troops in Syria caused by the Amwas plague contributed to Mu'awiya's heavy military reliance on older-established, formerly Byzantine-allied and Christian Arab tribes in Syria, particularly the Banu Kalb , who had largely stayed neutral during the fighting between the Muslims and the Byzantines. Amwas was replaced as the Arabs' headquarters in Palestine first by Lydda and/or Jerusalem , followed by Ramla , which was founded by the Umayyad caliph Sulayman ibn Abd al-Malik in the early 8th century. As late as the 1870s a well in the village of Amwas bore the name bir al-ta'un (well of the plague). Jabiya remained the Arabs' principal military camp in Syria until the reign of Sulayman. There were recurrences of the plague in Syria–Palestine about every decade between 688/89 and 744/45. "The Umaiyad [sic] dynasty was literally plagued by this disease", in the words of Dols. The deaths of the Umayyad caliphs Mu'awiya II ( r. 683–684 ), Marwan I ( r. 684–685 ), Abd al-Malik ( r. 685–705 ), Sulayman ( r. 715–717 ) and the Umayyad governors in Iraq al-Mughira ibn Shu'ba ( r. 661–671 ) and Ziyad ibn Abihi ( r. 685–673 ) may all possibly have been caused by the plague epidemics in Syria and Iraq. The caliphs routinely withdrew from the cities to their desert palaces when the plague emerged during the summer months. Notable among them was Caliph Hisham ( r. 724–743 ), who preferred his palace at Rusafa over Damascus because he viewed the latter to be unhealthy. Dols speculates that the frequent recurrences may have consistently undercut natural population growth in Syria–Palestine, the center of the Umayyad Caliphate, and weakened Umayyad power. Concurrently, Arab tribal migrations into the far eastern province of Khurasan , which was spared from the plague epidemics, led to the lopsided growth and predominance of the eastern half of the Caliphate and the rise of the Abbasid Movement there, which toppled the Umayyads in 750. In the view of Conrad, by the end of these plague cycles, the Umayyads had lost practical control of the eastern Caliphate and "it is tempting to view the interminable plagues of the last years of the dynasty as an important factor in the victory of the Abbasid revolution". There were recurrences of the plague in Syria–Palestine about every decade between 688/89 and 744/45. "The Umaiyad [sic] dynasty was literally plagued by this disease", in the words of Dols. The deaths of the Umayyad caliphs Mu'awiya II ( r. 683–684 ), Marwan I ( r. 684–685 ), Abd al-Malik ( r. 685–705 ), Sulayman ( r. 715–717 ) and the Umayyad governors in Iraq al-Mughira ibn Shu'ba ( r. 661–671 ) and Ziyad ibn Abihi ( r. 685–673 ) may all possibly have been caused by the plague epidemics in Syria and Iraq. The caliphs routinely withdrew from the cities to their desert palaces when the plague emerged during the summer months. Notable among them was Caliph Hisham ( r. 724–743 ), who preferred his palace at Rusafa over Damascus because he viewed the latter to be unhealthy. Dols speculates that the frequent recurrences may have consistently undercut natural population growth in Syria–Palestine, the center of the Umayyad Caliphate, and weakened Umayyad power. Concurrently, Arab tribal migrations into the far eastern province of Khurasan , which was spared from the plague epidemics, led to the lopsided growth and predominance of the eastern half of the Caliphate and the rise of the Abbasid Movement there, which toppled the Umayyads in 750. In the view of Conrad, by the end of these plague cycles, the Umayyads had lost practical control of the eastern Caliphate and "it is tempting to view the interminable plagues of the last years of the dynasty as an important factor in the victory of the Abbasid revolution". Modern historians concur that the actual circumstances of the plague of Amwas are not reconstructable and largely focus on the descriptions of the event in the 8th–10th-century Islamic histories and collections of hadith (traditions and sayings of Muhammad) in the context of theological debates on predestination , the status of Muslim sinners, and contagion. The plague of Amwas received more attention in medieval Arabic literature than any other epidemic until the 14th-century Black Death . Representations of the plague by the sources were "varied and contradictory", according to the historian Justin K. Stearns . The narratives of the response to the plague by Muhammad's companions Umar, Abu Ubayda, Amr and Mu'adh informed Muslim religious and legal interpretations of plague throughout the Middle Ages, including the response to the Black Death. Medieval Muslim scholars derived three principals from the contemporary reactions to the plague of Amwas: the first was that the plague was a form of divine mercy or martyrdom for the Muslim faithful and a punishment to non-believers; the second was the prohibition on Muslims entering or fleeing plague-stricken lands; and the third was the plague was not a contagion, rather it was directly imposed by God. The tenets consistently caused theological disagreements throughout the epidemic recurrences of the Middle Ages as a result of the difficulty in accepting plague as divine mercy or punishment and observable contagion. In the assessment of Dols, native Christian and Jewish attitudes and natural human anxieties likely influenced aspects of the first principle, namely that plague represented divine punishment or warnings. Muslims in this camp related the plague to lax morals among the Muslim troops in Syria, such as the consumption of wine, which supposedly led Umar to order the lashing of drinkers. On the other hand, the interpretation of plague as mercy or martyrdom is evident in Abu Ubayda's speeches to the troops at Amwas and in the council at Sargh. A poem about the plague of Amwas recorded by the Damascene historian Ibn Asakir (d. 1175) reflects the martyrdom belief: How many brave horsemen and how many beautiful, chaste women were killed in the valley of 'Amwas They had encountered the Lord, but He was not unjust to them When they died, they were among the non-aggrieved people in Paradise. We endure the plague as the Lord knows, and we were consoled in the hour of death. On the principle of predestination, the events of Amwas were used to argue that whether a person fled or remained in a plague-affected area their death had already been decreed by God. During an episode of plague in the Iraqi garrison city of Kufa , the prominent statesman and scholar Abu Musa al-Ash'ari (d. 662) turned away visitors to his home due to someone in his household having the plague, and he justified Muslims fleeing plague on the basis of Umar's actions at Sargh. According to Dols, this also implied a recognition of contagion despite the contradiction with the purported hadith rejecting contagion as a pre-Islamic theory.

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Bubonic plague

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Black Death in England

The Black Death was a bubonic plague pandemic, which reached England in June 1348. It was the first and most severe manifestation of the second pandemic , caused by Yersinia pestis bacteria . The term Black Death was not used until the late 17th century. Originating in Asia, it spread west along the trade routes across Europe and arrived on the British Isles from the English province of Gascony . The plague was spread by flea-infected rats, as well as individuals who had been infected on the continent. Rats were the reservoir hosts of the Y. pestis bacteria and the Oriental rat flea was the primary vector. The first-known case in England was a seaman who arrived at Weymouth , Dorset, from Gascony in June 1348. By autumn, the plague had reached London, and by summer 1349 it covered the entire country, before dying down by December. Low estimates of mortality in the early 20th century have been revised upwards due to re-examination of data and new information, and a figure of 40–60% of the population is widely accepted. The most immediate consequence was a halt to the campaigns of the Hundred Years' War . In the long term, the decrease in population caused a shortage of labour, with subsequent rise in wages, resisted by the landowners, which caused deep resentment among the lower classes. The Peasants' Revolt of 1381 was largely a result of this resentment, and even though the rebellion was suppressed, in the long term serfdom was ended in England. The Black Death also affected artistic and cultural efforts, and may have helped advance the use of the vernacular. In 1361–1362 the plague returned to England, this time causing the death of around 20% of the population. After this the plague continued to return intermittently throughout the 14th and 15th centuries, in local or national outbreaks. From this point its effect became less severe, and one of the last outbreaks of the plague in England was the Great Plague of London in 1665–1666.It is impossible to establish with any certainty the exact number of inhabitants in England at the eve of the Black Death , and estimates range from 3 to 7 million. The number is probably at the higher end, and an estimate of around 6 million inhabitants seems plausible. Earlier demographic crises—in particular the Great Famine of 1315–1317 —had resulted in great numbers of deaths, but there is no evidence of any significant decrease in the population prior to 1348. England was still a predominantly rural and agrarian society; close to 90 per cent of the population lived in the countryside. Of the major cities, London was in a class of its own, with perhaps as many as 70,000 inhabitants. Further down the scale were Norwich , with around 12,000 people, and York with around 10,000. The main export, and the source of the nation's wealth, was wool. Until the middle of the century the export had consisted primarily of raw wool to cloth makers in Flanders . Gradually though, the technology for cloth making used on the Continent was appropriated by English manufacturers, who started an export of cloths around mid-century that would boom over the following decades. Politically, the kingdom was evolving into a major European power, through the youthful and energetic kingship of Edward III . In 1346, the English had won a decisive battle over the Scots at the Battle of Neville's Cross , and it seemed that Edward III would realise his grandfather Edward I 's ambition of bringing the Scots under the suzerainty of the English crown. The English were also achieving military success on the Continent. Less than two months before the Battle of Neville's Cross, a numerically inferior English army led by the king himself won a spectacular victory over the French royal forces at the Battle of Crécy . The victory was immediately followed by Edward laying siege to the port city of Calais . When the city fell the next year, this provided the English with a strategically important enclave that would remain in their possession for over two centuries. The term "Black Death"—which refers to the first and most serious outbreak of the second pandemic—was not used by contemporaries, who preferred such names as the "Great Pestilence" or the "Great Mortality". It was not until the 17th century that the term under which we know the outbreak today became common, probably derived from Scandinavian languages. It is generally agreed today that the disease in question was plague , caused by Yersinia pestis bacteria . These bacteria are carried by fleas , which can be transferred to humans through contact with rats . Flea bites carry the disease into the lymphatic system , through which it makes its way to the lymph nodes . Here the bacteria multiply and form swellings called buboes , from which the term bubonic plague is derived. After three or four days the bacteria enter the bloodstream, and infect organs such as the spleen and the lungs . The patient will then normally die after a few days. A different strain of the disease is pneumonic plague , where the bacteria become airborne and enter directly into the patient's lungs. This strain is far more virulent, as it spreads directly from person to person. These types of infection probably both played a significant part in the Black Death, while a third strain was more rare. This is the septicaemic plague, where the flea bite carries the bacteria directly into the blood stream, and death occurs very rapidly. A study reported in 2011 of skeletons exhumed from the Black Death cemetery in East Smithfield , London , found Yersinia pestis DNA. An archaeological dig in the vicinity of Thornton Abbey in Lincolnshire was reported in the science section of The Guardian for 30 November 2016, not only confirming evidence of the Y. pestis DNA in the human remains exhumed there but also dating the remains to mid-1349. Genotyping showed that it was [at that time] a newly evolved strain, ancestor of all modern strains and proved the Black Death was bubonic plague. Modern medical knowledge suggests that because it was a new strain, the human immune system would have had little or no defence against it, helping to explain the plague's virulence and high death rates. The Black Death seems to have originated in Central Asia , where the Y. pestis bacterium is endemic in the rodent population. It is unknown exactly what caused the outbreak, but a series of natural occurrences likely brought humans into contact with the infected rodents. The epidemic reached Constantinople in the late spring of 1347, through Genoese merchants trading in the Black Sea . From here it reached Sicily in October that same year, and by early 1348 it had spread over the entire Italian mainland. It spread rapidly through France, and had reached as far north as Paris by June 1348. Moving simultaneously westward, it arrived in the English province of Gascony around the same time. It is impossible to establish with any certainty the exact number of inhabitants in England at the eve of the Black Death , and estimates range from 3 to 7 million. The number is probably at the higher end, and an estimate of around 6 million inhabitants seems plausible. Earlier demographic crises—in particular the Great Famine of 1315–1317 —had resulted in great numbers of deaths, but there is no evidence of any significant decrease in the population prior to 1348. England was still a predominantly rural and agrarian society; close to 90 per cent of the population lived in the countryside. Of the major cities, London was in a class of its own, with perhaps as many as 70,000 inhabitants. Further down the scale were Norwich , with around 12,000 people, and York with around 10,000. The main export, and the source of the nation's wealth, was wool. Until the middle of the century the export had consisted primarily of raw wool to cloth makers in Flanders . Gradually though, the technology for cloth making used on the Continent was appropriated by English manufacturers, who started an export of cloths around mid-century that would boom over the following decades. Politically, the kingdom was evolving into a major European power, through the youthful and energetic kingship of Edward III . In 1346, the English had won a decisive battle over the Scots at the Battle of Neville's Cross , and it seemed that Edward III would realise his grandfather Edward I 's ambition of bringing the Scots under the suzerainty of the English crown. The English were also achieving military success on the Continent. Less than two months before the Battle of Neville's Cross, a numerically inferior English army led by the king himself won a spectacular victory over the French royal forces at the Battle of Crécy . The victory was immediately followed by Edward laying siege to the port city of Calais . When the city fell the next year, this provided the English with a strategically important enclave that would remain in their possession for over two centuries. The term "Black Death"—which refers to the first and most serious outbreak of the second pandemic—was not used by contemporaries, who preferred such names as the "Great Pestilence" or the "Great Mortality". It was not until the 17th century that the term under which we know the outbreak today became common, probably derived from Scandinavian languages. It is generally agreed today that the disease in question was plague , caused by Yersinia pestis bacteria . These bacteria are carried by fleas , which can be transferred to humans through contact with rats . Flea bites carry the disease into the lymphatic system , through which it makes its way to the lymph nodes . Here the bacteria multiply and form swellings called buboes , from which the term bubonic plague is derived. After three or four days the bacteria enter the bloodstream, and infect organs such as the spleen and the lungs . The patient will then normally die after a few days. A different strain of the disease is pneumonic plague , where the bacteria become airborne and enter directly into the patient's lungs. This strain is far more virulent, as it spreads directly from person to person. These types of infection probably both played a significant part in the Black Death, while a third strain was more rare. This is the septicaemic plague, where the flea bite carries the bacteria directly into the blood stream, and death occurs very rapidly. A study reported in 2011 of skeletons exhumed from the Black Death cemetery in East Smithfield , London , found Yersinia pestis DNA. An archaeological dig in the vicinity of Thornton Abbey in Lincolnshire was reported in the science section of The Guardian for 30 November 2016, not only confirming evidence of the Y. pestis DNA in the human remains exhumed there but also dating the remains to mid-1349. Genotyping showed that it was [at that time] a newly evolved strain, ancestor of all modern strains and proved the Black Death was bubonic plague. Modern medical knowledge suggests that because it was a new strain, the human immune system would have had little or no defence against it, helping to explain the plague's virulence and high death rates. The Black Death seems to have originated in Central Asia , where the Y. pestis bacterium is endemic in the rodent population. It is unknown exactly what caused the outbreak, but a series of natural occurrences likely brought humans into contact with the infected rodents. The epidemic reached Constantinople in the late spring of 1347, through Genoese merchants trading in the Black Sea . From here it reached Sicily in October that same year, and by early 1348 it had spread over the entire Italian mainland. It spread rapidly through France, and had reached as far north as Paris by June 1348. Moving simultaneously westward, it arrived in the English province of Gascony around the same time. In this year, in Melcombe, in the county of Dorset, a little before the Feast of St. John the Baptist, two ships, one of them from Bristol, came alongside. One of the sailors had brought with him from Gascony the seeds of the terrible pestilence and through him the men of the town of Melcombe were the first in England to be infected. Grey Friars' Chronicle According to the chronicle of the grey friars at King's Lynn , the plague arrived by ship from Gascony to Melcombe ( Weymouth ) shortly before the Feast of St. John the Baptist on 24 June 1348. Other sources mention different points of arrival, including Bristol and Southampton . Though the plague might have arrived independently at Bristol later, the Grey Friars' Chronicle is considered the most authoritative account. If it is assumed that the chronicle reports the first outbreak of the plague, rather than its actual arrival , then the arrival most likely happened around 8 May. From Weymouth the disease spread rapidly across the south-west. The first major city to be struck was Bristol. The disease reached London in the autumn of 1348, before most of the surrounding countryside. This had certainly happened by November, though according to some accounts as early as 29 September (Michaelmas). It travelled to London by three principal routes: overland from Weymouth, through Salisbury and Winchester ; overland from Gloucester ; and along the coast by ship. The full effect of the plague was felt in the capital early the next year. Conditions in London were ideal for the plague: the streets were narrow and flowing with sewage, and houses were overcrowded and poorly ventilated. By March 1349 the disease was spreading haphazardly across all of southern England. During the first half of 1349 the Black Death spread northwards. A second front opened up when the plague arrived by ship at the Humber , after which it spread both south and north. In May it reached York , and during the summer months of June, July and August, it ravaged the north. Certain northern counties, like Durham and Cumberland , had been the victim of violent incursions from the Scots, and were therefore left particularly vulnerable to the devastations of the plague. Pestilence is less virulent during the winter months, and spreads less rapidly. The Black Death in England had survived the winter of 1348–49, but during the following winter it subsided, and by December 1349 conditions were returning to relative normality. It had taken the disease around 500 days to traverse the entire country. Various methods of treatment were used, including sweating , bloodletting , and forced vomiting and urinating. Symptoms of the illness included blotches, hardening of the glands under the groin and underarms, and dementia. During the initial phase of the disease, bloodletting was performed on the same side where the physical manifestations of the buboes or risings appeared. For instance, if a rising appeared on the right side of the groin the physician would bleed a vein in the ankle on the same side. To provoke sweating , medicines such as Mithridate , Venice-Treacle , Matthiolus , Bezoar-Water , Serpentary Roots and Electuarium de Ovo were used. Sweating was used when measures were desperate; if a patient had tokens , a severe version of risings , the physician would wrap the naked patient in a blanket drenched in cold water. This was only done while the patient still had natural heat in his system. The desired effect was to make the patient sweat violently and thus purge all corruption from the blood which was caused by the disease. Another practice was the use of pigeons when treating swellings. Swellings which were white in appearance and deep were unlikely to break, and were anointed with Oil of Lillies or Camomil . Once the swelling rose to a head and was red in appearance and not deep in the flesh, it was broken with the use of a feather from a young pigeon's tail. The feather's fundament [ clarification needed ] was held to the swelling to try to draw out the venom. However, if the swelling dropped and became black in appearance, the physician had to be cautious when drawing the cold from the swelling. If it was too late to prevent, the physician would take the young pigeon, cut it open from breast to back, break it open and apply the pigeon (while still alive) over the cold swelling. The cupping therapy was an alternative method which was heated and then placed over the swellings. Once the sore was broken, the physician would apply Mellilot Plaister with Linimentum Arcei and heal the sore with digence [ clarification needed ] . Although historical records for England were more extensive than those of any other European country, it is still extremely difficult to establish the death toll with any degree of certainty. Difficulties include uncertainty about the size of the total population, as described above, but also uncertainty about the proportion of the population that died from the plague. Contemporary accounts are often grossly inflated, stating numbers as high as 90%. Modern historians give estimates of death rates ranging from around 25% to more than 60% of the total population. The pioneering work in the field was made by Josiah William Russell in his 1948 British Medieval Population . Russell looked at inquisitions post mortem (IPMs)—taken by the Crown to assess the wealth of the greatest landowners after their death—to assess the mortality caused by the Black Death, and from this he arrived at an estimate of 23.6% of the entire population. He also looked at episcopal registers for the death toll among the clergy, where the result was between 30 and 40%. Russell believed the clergy was at particular risk of contagion, and eventually arrived at an overall mortality rate of "only" 20 per cent. Several of Russell's assumptions have been challenged, and the tendency since has been to adjust the assessment upwards. Philip Ziegler , in 1969, estimated the death rate to have been around one third of the population. Jeremy Goldberg , in 1996, believed a number closer to 45 per cent would be more realistic. A 2004 study by Ole Jørgen Benedictow suggests the exceptionally high mortality level of 62.5 per cent. Assuming a population of 6 million, this estimate would correspond to 3,750,000 deaths. Such a high percentage would place England above the average that Benedictow estimates for Western Europe as a whole, of 60 per cent. Many historians have not accepted such a high death rate. In 2016, Carenza Lewis reported the results of a new method of assessing the death toll. She argued that pottery before and after the Black Death is datable because there was a change at that time from the high medieval to the late medieval style, and that counts of pottery of each type therefore provide a useful proxy for long term changes in population. She and her colleagues analysed pottery sherds from test pits in more than 50 continuously occupied rural settlements in eastern England, and found a decline in the number of pottery producing pits of 45 per cent. Norfolk had the greatest drop of 65 per cent, while there was no drop in 10 per cent of settlements, mostly commercial centres. Archbishop Zouche of York issued a warning throughout the diocese in July 1348 (when the epidemic was raging further south) of "great mortalities, pestilences and infections of the air". The Great Mortality, as it was then known, entered Yorkshire around February 1349 and quickly spread through the diocese. The clergy were on the front line of the disease, bringing comfort to the dying, hearing final confessions and organising burials. This, almost by necessity, put them at a greater risk of infection. Estimates suggest that the death rate of clergy in some parts of the archdiocese could have been as high as 48 per cent. This is reflected in the Ordination Register, which shows a massive rise in ordained clergy over the period—some being recruited before the arrival of plague in a clerical recruitment drive, but many once plague had arrived, replacing those who had been killed. In 1346, 111 priests and 337 acolytes were recruited. In 1349, 299 priests and 683 acolytes are named, with 166 priests being ordained in one session alone in February 1350." Russell had trusted the IPMs to give a true picture of the national average, because he assumed death rates to be relatively equal across the social spectrum. This assumption has been proven wrong, and studies of peasant plague mortality from manor rolls have returned much higher rates. This could be a consequence of the elite's ability to avoid infection by escaping plague-infected areas. It could also result from lower post-infection mortality among those more affluent, due to better access to care and nursing. If so, this would also mean that the mortality rates for the clergy—who were normally better off than the general population—were no higher than the average. ...destructive Death (who seizes young and old alike, sparing no one and reducing rich and poor to the same level) has lamentably snatched from both of us our dearest daughter, (whom we loved best of all, as her virtues demanded). Edward III in a letter to King Alfonso of Castile The manorial records offer a good opportunity to study the geographical distribution of the plague. Its effect seems to have been about the same all over England, though areas like East Anglia , which had frequent contact with the Continent, were severely affected. On a local level, however, there were great variations. A study of the Bishop of Worcester 's estates reveals that, while his manors of Hartlebury and Hanbury had a mortality rate of only 19 per cent, the manor of Aston lost as much as 80 per cent of its population. The manor rolls are less useful for studying the demographic distribution of the mortality, since the rolls only record the heads of households, normally an adult male. Here the IPMs show us that the most vulnerable to the disease were infants and the elderly. There seem to have been relatively few deaths from the Black Death at higher levels of society. The only member of the royal family who can be said with any certainty to have died from the Black Death was in France at the time of her infection. Edward III's daughter Joan was residing in Bordeaux on her way to marry Pedro of Castile in the summer of 1348. When the plague broke out in her household she was moved to a small village nearby, but she could not avoid infection, and died there on 2 September. It is possible that the popular religious author Richard Rolle , who died on 30 September 1349, was another victim of the Black Death. The English philosopher William of Ockham has been mentioned as a plague victim. This, however, is an impossibility. Ockham was living in Munich at the time of his death, on 10 April 1347, two years before the Black Death reached that city. Although historical records for England were more extensive than those of any other European country, it is still extremely difficult to establish the death toll with any degree of certainty. Difficulties include uncertainty about the size of the total population, as described above, but also uncertainty about the proportion of the population that died from the plague. Contemporary accounts are often grossly inflated, stating numbers as high as 90%. Modern historians give estimates of death rates ranging from around 25% to more than 60% of the total population. The pioneering work in the field was made by Josiah William Russell in his 1948 British Medieval Population . Russell looked at inquisitions post mortem (IPMs)—taken by the Crown to assess the wealth of the greatest landowners after their death—to assess the mortality caused by the Black Death, and from this he arrived at an estimate of 23.6% of the entire population. He also looked at episcopal registers for the death toll among the clergy, where the result was between 30 and 40%. Russell believed the clergy was at particular risk of contagion, and eventually arrived at an overall mortality rate of "only" 20 per cent. Several of Russell's assumptions have been challenged, and the tendency since has been to adjust the assessment upwards. Philip Ziegler , in 1969, estimated the death rate to have been around one third of the population. Jeremy Goldberg , in 1996, believed a number closer to 45 per cent would be more realistic. A 2004 study by Ole Jørgen Benedictow suggests the exceptionally high mortality level of 62.5 per cent. Assuming a population of 6 million, this estimate would correspond to 3,750,000 deaths. Such a high percentage would place England above the average that Benedictow estimates for Western Europe as a whole, of 60 per cent. Many historians have not accepted such a high death rate. In 2016, Carenza Lewis reported the results of a new method of assessing the death toll. She argued that pottery before and after the Black Death is datable because there was a change at that time from the high medieval to the late medieval style, and that counts of pottery of each type therefore provide a useful proxy for long term changes in population. She and her colleagues analysed pottery sherds from test pits in more than 50 continuously occupied rural settlements in eastern England, and found a decline in the number of pottery producing pits of 45 per cent. Norfolk had the greatest drop of 65 per cent, while there was no drop in 10 per cent of settlements, mostly commercial centres. Archbishop Zouche of York issued a warning throughout the diocese in July 1348 (when the epidemic was raging further south) of "great mortalities, pestilences and infections of the air". The Great Mortality, as it was then known, entered Yorkshire around February 1349 and quickly spread through the diocese. The clergy were on the front line of the disease, bringing comfort to the dying, hearing final confessions and organising burials. This, almost by necessity, put them at a greater risk of infection. Estimates suggest that the death rate of clergy in some parts of the archdiocese could have been as high as 48 per cent. This is reflected in the Ordination Register, which shows a massive rise in ordained clergy over the period—some being recruited before the arrival of plague in a clerical recruitment drive, but many once plague had arrived, replacing those who had been killed. In 1346, 111 priests and 337 acolytes were recruited. In 1349, 299 priests and 683 acolytes are named, with 166 priests being ordained in one session alone in February 1350." Archbishop Zouche of York issued a warning throughout the diocese in July 1348 (when the epidemic was raging further south) of "great mortalities, pestilences and infections of the air". The Great Mortality, as it was then known, entered Yorkshire around February 1349 and quickly spread through the diocese. The clergy were on the front line of the disease, bringing comfort to the dying, hearing final confessions and organising burials. This, almost by necessity, put them at a greater risk of infection. Estimates suggest that the death rate of clergy in some parts of the archdiocese could have been as high as 48 per cent. This is reflected in the Ordination Register, which shows a massive rise in ordained clergy over the period—some being recruited before the arrival of plague in a clerical recruitment drive, but many once plague had arrived, replacing those who had been killed. In 1346, 111 priests and 337 acolytes were recruited. In 1349, 299 priests and 683 acolytes are named, with 166 priests being ordained in one session alone in February 1350." Russell had trusted the IPMs to give a true picture of the national average, because he assumed death rates to be relatively equal across the social spectrum. This assumption has been proven wrong, and studies of peasant plague mortality from manor rolls have returned much higher rates. This could be a consequence of the elite's ability to avoid infection by escaping plague-infected areas. It could also result from lower post-infection mortality among those more affluent, due to better access to care and nursing. If so, this would also mean that the mortality rates for the clergy—who were normally better off than the general population—were no higher than the average. ...destructive Death (who seizes young and old alike, sparing no one and reducing rich and poor to the same level) has lamentably snatched from both of us our dearest daughter, (whom we loved best of all, as her virtues demanded). Edward III in a letter to King Alfonso of Castile The manorial records offer a good opportunity to study the geographical distribution of the plague. Its effect seems to have been about the same all over England, though areas like East Anglia , which had frequent contact with the Continent, were severely affected. On a local level, however, there were great variations. A study of the Bishop of Worcester 's estates reveals that, while his manors of Hartlebury and Hanbury had a mortality rate of only 19 per cent, the manor of Aston lost as much as 80 per cent of its population. The manor rolls are less useful for studying the demographic distribution of the mortality, since the rolls only record the heads of households, normally an adult male. Here the IPMs show us that the most vulnerable to the disease were infants and the elderly. There seem to have been relatively few deaths from the Black Death at higher levels of society. The only member of the royal family who can be said with any certainty to have died from the Black Death was in France at the time of her infection. Edward III's daughter Joan was residing in Bordeaux on her way to marry Pedro of Castile in the summer of 1348. When the plague broke out in her household she was moved to a small village nearby, but she could not avoid infection, and died there on 2 September. It is possible that the popular religious author Richard Rolle , who died on 30 September 1349, was another victim of the Black Death. The English philosopher William of Ockham has been mentioned as a plague victim. This, however, is an impossibility. Ockham was living in Munich at the time of his death, on 10 April 1347, two years before the Black Death reached that city. Among the most immediate consequences of the Black Death in England was a shortage of farm labour, and a corresponding rise in wages. The medieval world-view was unable to interpret these changes in terms of socio-economic development, and it became common to blame degrading morals instead. The landowning classes saw the rise in wage levels as a sign of social upheaval and insubordination, and reacted with coercion. In 1349, King Edward III passed the Ordinance of Labourers , fixing wages at pre-plague levels. The ordinance was reinforced by Parliament's passing of the Statute of Labourers in 1351. The labour laws were enforced with ruthless determination over the following decades. These legislative measures proved largely inefficient at regulating the market, but the government's repressive measures to enforce them caused public resentment. These conditions were contributing factors to the Peasants' Revolt in 1381. The revolt started in Kent and Essex in late May, and once the rebels reached London they burnt down John of Gaunt 's Savoy Palace , and killed both the Chancellor and the Treasurer . They then demanded the complete abolition of serfdom , and were not pacified until the young King Richard II personally intervened. The rebellion was eventually suppressed, but the social changes it promoted were already irreversible. By around 1400 serfdom was virtually extinct in England, replaced by the form of tenure called copyhold . It is conspicuous how well the English government handled the crisis of the mid-fourteenth century, without descending into chaos and total collapse in the manner of the Valois government of France. To a large extent this was the accomplishment of administrators such as Treasurer William de Shareshull and Chief Justice William Edington , whose highly competent leadership guided the governance of the nation through the crisis. The plague's greatest effect on the government was probably in the field of war, where no major campaigns were launched in France until 1355. Another notable consequence of the Black Death was the raising of the real wage of England (due to the shortage of labour as a result of the reduction in population), a trait shared across Western Europe, which in general led to a real wage in 1450 that was unmatched in most countries until the 19th or 20th century. The higher wages for workers combined with sinking prices on grain products led to a problematic economic situation for the gentry . As a result, they started to show an increased interest for offices like justice of the peace , sheriff and member of parliament . The gentry took advantage of their new positions and a more systematic corruption than before spread. A result of this was that the gentry as a group became highly disliked by commoners. The omnipresence of death also inspired greater piety in the upper classes, which can be seen in the fact that three Cambridge colleges were founded during or shortly after the Black Death. England did not experience the same trend of roving bands of flagellants , common on the continent. Neither were there any pogroms against the Jews , since the Jews had been expelled by Edward I in 1290. The high rate of mortality among the clergy naturally led to a shortage of priests in many parts of the country. The clergy were seen to have an elevated status among ordinary people and this was partly due to their purported closeness with God, being his envoys on earth. However, as the church itself had given the cause of the Black Death to be the impropriety of the behaviour of men, the higher death rate among the clergy led the people to lose faith in the Church as an institution—it had proved as ineffectual against the horror of Y. pestis as every other medieval institution. The corruption within the Catholic priesthood also angered the English people. Many priests abandoned the terrified people. Others sought benefits from the rich families who needed burials. The dissatisfaction led to anti-clericalism and the rise of John Wycliffe , an English priest. His ideas paved a path for the Christian reformation in England. Some people did not lose their Christian faith, if anything it was renewed; they began to long for a more personal relationship with God—around the time after the Black Death many chantries (private chapels) began to spread in use from not just the nobility, but to among the well-to-do. This change in the power of the papacy in England is demonstrated by the statutes of Praemunire . The Black Death also affected arts and culture significantly. It was inevitable that a catastrophe of such proportions would affect some of the greater building projects, as the amount of available labour fell sharply. The building of the cathedrals of Ely and Exeter was temporarily halted in the years immediately following the first outbreak of the plague. The shortage of labour also helped advance the transition from the Decorated style of building to the less elaborate Perpendicular style . The Black Death may also have promoted the use of vernacular English, as the number of teachers proficient in French dwindled, contributing to the late-14th-century flowering of English literature, represented by writers such as Geoffrey Chaucer and John Gower . Among the most immediate consequences of the Black Death in England was a shortage of farm labour, and a corresponding rise in wages. The medieval world-view was unable to interpret these changes in terms of socio-economic development, and it became common to blame degrading morals instead. The landowning classes saw the rise in wage levels as a sign of social upheaval and insubordination, and reacted with coercion. In 1349, King Edward III passed the Ordinance of Labourers , fixing wages at pre-plague levels. The ordinance was reinforced by Parliament's passing of the Statute of Labourers in 1351. The labour laws were enforced with ruthless determination over the following decades. These legislative measures proved largely inefficient at regulating the market, but the government's repressive measures to enforce them caused public resentment. These conditions were contributing factors to the Peasants' Revolt in 1381. The revolt started in Kent and Essex in late May, and once the rebels reached London they burnt down John of Gaunt 's Savoy Palace , and killed both the Chancellor and the Treasurer . They then demanded the complete abolition of serfdom , and were not pacified until the young King Richard II personally intervened. The rebellion was eventually suppressed, but the social changes it promoted were already irreversible. By around 1400 serfdom was virtually extinct in England, replaced by the form of tenure called copyhold . It is conspicuous how well the English government handled the crisis of the mid-fourteenth century, without descending into chaos and total collapse in the manner of the Valois government of France. To a large extent this was the accomplishment of administrators such as Treasurer William de Shareshull and Chief Justice William Edington , whose highly competent leadership guided the governance of the nation through the crisis. The plague's greatest effect on the government was probably in the field of war, where no major campaigns were launched in France until 1355. Another notable consequence of the Black Death was the raising of the real wage of England (due to the shortage of labour as a result of the reduction in population), a trait shared across Western Europe, which in general led to a real wage in 1450 that was unmatched in most countries until the 19th or 20th century. The higher wages for workers combined with sinking prices on grain products led to a problematic economic situation for the gentry . As a result, they started to show an increased interest for offices like justice of the peace , sheriff and member of parliament . The gentry took advantage of their new positions and a more systematic corruption than before spread. A result of this was that the gentry as a group became highly disliked by commoners. The omnipresence of death also inspired greater piety in the upper classes, which can be seen in the fact that three Cambridge colleges were founded during or shortly after the Black Death. England did not experience the same trend of roving bands of flagellants , common on the continent. Neither were there any pogroms against the Jews , since the Jews had been expelled by Edward I in 1290. The high rate of mortality among the clergy naturally led to a shortage of priests in many parts of the country. The clergy were seen to have an elevated status among ordinary people and this was partly due to their purported closeness with God, being his envoys on earth. However, as the church itself had given the cause of the Black Death to be the impropriety of the behaviour of men, the higher death rate among the clergy led the people to lose faith in the Church as an institution—it had proved as ineffectual against the horror of Y. pestis as every other medieval institution. The corruption within the Catholic priesthood also angered the English people. Many priests abandoned the terrified people. Others sought benefits from the rich families who needed burials. The dissatisfaction led to anti-clericalism and the rise of John Wycliffe , an English priest. His ideas paved a path for the Christian reformation in England. Some people did not lose their Christian faith, if anything it was renewed; they began to long for a more personal relationship with God—around the time after the Black Death many chantries (private chapels) began to spread in use from not just the nobility, but to among the well-to-do. This change in the power of the papacy in England is demonstrated by the statutes of Praemunire . The Black Death also affected arts and culture significantly. It was inevitable that a catastrophe of such proportions would affect some of the greater building projects, as the amount of available labour fell sharply. The building of the cathedrals of Ely and Exeter was temporarily halted in the years immediately following the first outbreak of the plague. The shortage of labour also helped advance the transition from the Decorated style of building to the less elaborate Perpendicular style . The Black Death may also have promoted the use of vernacular English, as the number of teachers proficient in French dwindled, contributing to the late-14th-century flowering of English literature, represented by writers such as Geoffrey Chaucer and John Gower . The Black Death was the first occurrence of the second pandemic , which continued to strike England and the rest of Europe more or less regularly until the 18th century. The first serious recurrence in England came in the years 1361−62. Little is known about the death rates caused by these later outbreaks, but the so-called pestis secunda may have had a mortality of around 20 per cent. Genetic analysis performed on remains recovered from the abbey of St. Mary's Graces dating between 1353 and 1364 found the pPCP1 plasmid, a plasmid only found in Yersinia pestis and not the related environmental agent Yersinia pseudotuberculosis , revealing that this outbreak was also caused by Yersinia pestis just as the initial outbreak had been. This epidemic was also particularly devastating for the population's ability to recover, since it disproportionately affected infants and young men. This was also the case with the next occurrence, in 1369, where the death rate was around 10−15 per cent. Over the following decades the plague would return—on a national or a regional level—at intervals of five to 12 years, with gradually dwindling death tolls. Then, in the decades from 1430 to 1480, the disease returned in force. An outbreak in 1471 took as much as 10–15 per cent of the population, while the death rate of the plague of 1479–1480 could have been as high as 20 per cent. From that point outbreaks became fewer and more manageable, due largely to conscious efforts by central and local governments—from the late 15th century onward—to curtail the disease. This included quarantines on people and goods coming from infected places, bans on public gatherings (such as fairs), enforced household quarantine for the infected (known as 'locking up') and quarantines on ships and crews coming from ports where Plague outbreaks had occurred. From the early seventeenth century there was also greater use of quarantine facilities, called pesthouses , in preference to household quarantine. Some of these, such as the Forlorn Hope Pesthouse established by Bristol in 1665–6, appear to have been proper quarantine hospitals, staffed by doctors. The establishment of such a hospital may help to explain why the death rate in Bristol in the 1665–66 outbreak was "only" c.0.6 percent. This was much lower than the mortality rate of 10–20 percent witnessed in Bristol's Plague epidemics of 1565, 1575, 1603–1604 and 1645. The Great Plague of 1665–66 was the last major outbreak in England. It is best known for the famous Great Plague of London , which killed 100,000 people (20 per cent of the population) in the capital. Other places hit hard included Eyam in Derbyshire, Derby itself and Norwich .

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Bubonic plague

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Tularemia

Tularemia , also known as rabbit fever , is an infectious disease caused by the bacterium Francisella tularensis . Symptoms may include fever , skin ulcers , and enlarged lymph nodes . Occasionally, a form that results in pneumonia or a throat infection may occur. The bacterium is typically spread by ticks , deer flies , or contact with infected animals. It may also be spread by drinking contaminated water or breathing in contaminated dust. It does not spread directly between people. Diagnosis is by blood tests or cultures of the infected site. Prevention is by using insect repellent , wearing long pants, rapidly removing ticks, and not disturbing dead animals. Treatment is typically with the antibiotic streptomycin . Gentamicin , doxycycline , or ciprofloxacin may also be used. Between the 1970s and 2015, around 200 cases were reported in the United States a year. Males are affected more often than females. It occurs most frequently in the young and the middle aged. In the United States, most cases occur in the summer. The disease is named after Tulare County, California , where the disease was discovered in 1911. A number of other animals, such as rabbits , may also be infected. Depending on the site of infection, tularemia has six characteristic clinical variants: ulceroglandular (the most common type representing 75% of all forms), glandular, oropharyngeal, pneumonic, oculoglandular, and typhoidal. The incubation period for tularemia is 1 to 14 days; most human infections become apparent after three to five days. In most susceptible mammals, the clinical signs include fever , lethargy, loss of appetite , signs of sepsis , and possibly death. Nonhuman mammals rarely develop the skin lesions seen in people. Subclinical infections are common, and animals often develop specific antibodies to the organism. Fever is moderate or very high, and tularemia bacilli can be isolated from blood cultures at this stage. The face and eyes redden and become inflamed. Inflammation spreads to the lymph nodes , which enlarge and may suppurate (mimicking bubonic plague ). Lymph node involvement is accompanied by a high fever. Tularemia is caused by the bacteria Francisella tularensis which is typically spread by ticks , deer flies , and contact with infected animals. The bacteria can penetrate into the body through damaged skin, mucous membranes, and inhalation. Humans are most often infected by tick/deer fly bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. Hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. It has been contracted from inhaling particles from an infected rabbit ground up in a lawnmower ( see below ). Tularemia is not spread directly from person to person. Humans can also be infected through bioterrorism attempts. Francisella tularensis can live both within and outside the cells of the animal it infects, meaning it is a facultative intracellular bacterium . It primarily infects macrophages , a type of white blood cell , and thus is able to evade the immune system. The course of disease involves the spread of the organism to multiple organ systems, including the lungs , liver , spleen , and lymphatic system . The course of disease is different depending on the route of exposure. Mortality in untreated (before the antibiotic era) patients has been as high as 50% in the pneumoniac and typhoidal forms of the disease, which however account for less than 10% of cases. The most common way the disease is spread is via arthropod vectors . Ticks involved include Amblyomma , Dermacentor , Haemaphysalis , and Ixodes . Rodents , rabbits, and hares often serve as reservoir hosts , but waterborne infection accounts for 5–10% of all tularemia in the United States. Tularemia can also be transmitted by biting flies, particularly the deer fly Chrysops discalis . Individual flies can remain infectious for 14 days and ticks for over two years. [ citation needed ] Tularemia may also be spread by direct contact with contaminated animals or material, by ingestion of poorly cooked flesh of infected animals or contaminated water, or by inhalation of contaminated dust. The bacteria can penetrate into the body through damaged skin, mucous membranes, and inhalation. Humans are most often infected by tick/deer fly bite or through handling an infected animal. Ingesting infected water, soil, or food can also cause infection. Hunters are at a higher risk for this disease because of the potential of inhaling the bacteria during the skinning process. It has been contracted from inhaling particles from an infected rabbit ground up in a lawnmower ( see below ). Tularemia is not spread directly from person to person. Humans can also be infected through bioterrorism attempts. Francisella tularensis can live both within and outside the cells of the animal it infects, meaning it is a facultative intracellular bacterium . It primarily infects macrophages , a type of white blood cell , and thus is able to evade the immune system. The course of disease involves the spread of the organism to multiple organ systems, including the lungs , liver , spleen , and lymphatic system . The course of disease is different depending on the route of exposure. Mortality in untreated (before the antibiotic era) patients has been as high as 50% in the pneumoniac and typhoidal forms of the disease, which however account for less than 10% of cases. The most common way the disease is spread is via arthropod vectors . Ticks involved include Amblyomma , Dermacentor , Haemaphysalis , and Ixodes . Rodents , rabbits, and hares often serve as reservoir hosts , but waterborne infection accounts for 5–10% of all tularemia in the United States. Tularemia can also be transmitted by biting flies, particularly the deer fly Chrysops discalis . Individual flies can remain infectious for 14 days and ticks for over two years. [ citation needed ] Tularemia may also be spread by direct contact with contaminated animals or material, by ingestion of poorly cooked flesh of infected animals or contaminated water, or by inhalation of contaminated dust. In lymph node biopsies, the typical histopathologic pattern is characterized by geographic areas of necrosis with neutrophils and necrotizing granulomas. The pattern is non specific and similar to other infectious lymphadenopathies. The laboratorial isolation of F. tularensis requires special media such as buffered charcoal yeast extract agar . It cannot be isolated in the routine culture media because of the need for sulfhydryl group donors (such as cysteine). The microbiologist must be informed when tularemia is suspected not only to include the special media for appropriate isolation, but also to ensure that safety precautions are taken to avoid contamination of laboratory personnel. Serological tests (detection of antibodies in the serum of the patients) are available and widely used. Cross reactivity with Brucella can confuse interpretation of the results, so diagnosis should not rely only on serology. Molecular methods such as PCR are available in reference laboratories. [ citation needed ]In lymph node biopsies, the typical histopathologic pattern is characterized by geographic areas of necrosis with neutrophils and necrotizing granulomas. The pattern is non specific and similar to other infectious lymphadenopathies. The laboratorial isolation of F. tularensis requires special media such as buffered charcoal yeast extract agar . It cannot be isolated in the routine culture media because of the need for sulfhydryl group donors (such as cysteine). The microbiologist must be informed when tularemia is suspected not only to include the special media for appropriate isolation, but also to ensure that safety precautions are taken to avoid contamination of laboratory personnel. Serological tests (detection of antibodies in the serum of the patients) are available and widely used. Cross reactivity with Brucella can confuse interpretation of the results, so diagnosis should not rely only on serology. Molecular methods such as PCR are available in reference laboratories. [ citation needed ]There are no safe, available, approved vaccines against tularemia. However, vaccination research and development continues, with live attenuated vaccines being the most thoroughly researched and most likely candidate for approval. Sub-unit vaccine candidates, such as killed-whole cell vaccines, are also under investigation, however research has not reached a state of public use. Optimal preventative practices include limiting direct exposure when handling potentially infected animals by wearing gloves and face masks (importantly when skinning deceased animals). If infection occurs or is suspected, treatment is generally with the antibiotics streptomycin or gentamicin . Doxycycline was previously used. Gentamicin may be easier to obtain than streptomycin. There is also tentative evidence to support the use of quinolone antibiotics . Since the discovery of antibiotics, the rate of death associated with tularemia has decreased from 60% to less than 4%. Tularemia is most common in the Northern Hemisphere , including North America and parts of Europe and Asia. It occurs between 30° and 71° north latitude . In the United States, although records show that tularemia was never particularly common, incidence rates continued to drop over the course of the 20th century. Between 1990 and 2000, the rate dropped to less than 1 per one million, meaning the disease is extremely rare in the United States today. In Europe, tularemia is generally rare, though outbreaks with hundreds of cases occur every few years in neighboring Finland and Sweden . In Sweden over a period from 1984 to 2012 a total of 4,830 cases of tularemia occurred (most of the infections were acquired within the country). About 1.86 cases per 100,000 persons occur each year with higher rates in those between 55 and 70. In the 14th century BC , Tularemia spread throughout the Hittite Empire , known as the Hittite plague , and was the first recorded use of biological warfare . From May to October 2000, an outbreak of tularemia in Martha's Vineyard , Massachusetts , resulted in one fatality, and brought the interest of the United States Centers for Disease Control and Prevention (CDC) as a potential investigative ground for aerosolised Francisella tularensis . For a time, Martha's Vineyard was identified as the only place in the world where documented cases of tularemia resulted from lawn mowing . However, in May 2015 a resident of Lafayette, Colorado , died from aerosolised F. tularensis , which was also connected to lawn mowing, highlighting this new vector of risk. An outbreak of tularemia occurred in Kosovo in 1999–2000. In 2004, three researchers at Boston Medical Center , in Massachusetts, were accidentally infected with F. tularensis , after apparently failing to follow safety procedures. In 2005, small amounts of F. tularensis were detected in the National Mall area of Washington, D.C. , the morning after an antiwar demonstration on September 24, 2005. Biohazard sensors were triggered at six locations surrounding the Mall. While thousands of people were potentially exposed, no infections were reported. The detected bacteria likely originated from a natural source, not from a bioterror attempt . In 2005, an outbreak occurred in Germany amongst participants in a hare hunt. About 27 people came into contact with contaminated blood and meat after the hunt. Ten of the exposed, aged 11 to 73, developed tularemia. One of these died due to complications caused by chronic heart disease. Tularemia is endemic in the Gori region of the Eurasian country of Georgia . The last outbreak was in 2006. The disease is also endemic on the uninhabited Pakri Islands off the northern coast of Estonia . Used for bombing practice by Soviet forces, chemical and bacteriological weapons may have been dropped on these islands. In July 2007, an outbreak was reported in the Spanish autonomous region of Castile and León and traced to the plague of voles infesting the region. Another outbreak had taken place ten years before in the same area. In January 2011, researchers searching for brucellosis among feral pig populations in Texas discovered widespread tularemia infection or evidence of past infection in feral hog populations of at least two Texas counties, even though tularemia is not normally associated with pigs at all. Precautions were recommended for those who hunt, dress, or prepare feral hogs. Since feral hogs roam over large distances, concern exists that tularemia may spread or already be present in feral hogs over a wide geographic area. In November 2011, it was found in Tasmania . Reports claimed it to be the first in the Southern Hemisphere . However, the causative organism was documented to have been isolated from a foot wound in the Northern Territory in 2003. In 2014, at least five cases of tularemia were reported in Colorado and at least three more cases in early 2015, including one death as a result of lawn mowing, as noted above. In the summer of 2015, a popular hiking area just north of Boulder was identified as a site of animal infection and signs were posted to warn hikers. [ citation needed ]In the 14th century BC , Tularemia spread throughout the Hittite Empire , known as the Hittite plague , and was the first recorded use of biological warfare . From May to October 2000, an outbreak of tularemia in Martha's Vineyard , Massachusetts , resulted in one fatality, and brought the interest of the United States Centers for Disease Control and Prevention (CDC) as a potential investigative ground for aerosolised Francisella tularensis . For a time, Martha's Vineyard was identified as the only place in the world where documented cases of tularemia resulted from lawn mowing . However, in May 2015 a resident of Lafayette, Colorado , died from aerosolised F. tularensis , which was also connected to lawn mowing, highlighting this new vector of risk. An outbreak of tularemia occurred in Kosovo in 1999–2000. In 2004, three researchers at Boston Medical Center , in Massachusetts, were accidentally infected with F. tularensis , after apparently failing to follow safety procedures. In 2005, small amounts of F. tularensis were detected in the National Mall area of Washington, D.C. , the morning after an antiwar demonstration on September 24, 2005. Biohazard sensors were triggered at six locations surrounding the Mall. While thousands of people were potentially exposed, no infections were reported. The detected bacteria likely originated from a natural source, not from a bioterror attempt . In 2005, an outbreak occurred in Germany amongst participants in a hare hunt. About 27 people came into contact with contaminated blood and meat after the hunt. Ten of the exposed, aged 11 to 73, developed tularemia. One of these died due to complications caused by chronic heart disease. Tularemia is endemic in the Gori region of the Eurasian country of Georgia . The last outbreak was in 2006. The disease is also endemic on the uninhabited Pakri Islands off the northern coast of Estonia . Used for bombing practice by Soviet forces, chemical and bacteriological weapons may have been dropped on these islands. In July 2007, an outbreak was reported in the Spanish autonomous region of Castile and León and traced to the plague of voles infesting the region. Another outbreak had taken place ten years before in the same area. In January 2011, researchers searching for brucellosis among feral pig populations in Texas discovered widespread tularemia infection or evidence of past infection in feral hog populations of at least two Texas counties, even though tularemia is not normally associated with pigs at all. Precautions were recommended for those who hunt, dress, or prepare feral hogs. Since feral hogs roam over large distances, concern exists that tularemia may spread or already be present in feral hogs over a wide geographic area. In November 2011, it was found in Tasmania . Reports claimed it to be the first in the Southern Hemisphere . However, the causative organism was documented to have been isolated from a foot wound in the Northern Territory in 2003. In 2014, at least five cases of tularemia were reported in Colorado and at least three more cases in early 2015, including one death as a result of lawn mowing, as noted above. In the summer of 2015, a popular hiking area just north of Boulder was identified as a site of animal infection and signs were posted to warn hikers. [ citation needed ]The tularemia bacterium was first isolated by G.W. McCoy of the United States Public Health Service plague lab and reported in 1912. Scientists determined tularemia could be dangerous to humans; a human being may catch the infection after contacting an infected animal. The ailment soon became associated with hunters, cooks and agricultural workers. The Centers for Disease Control and Prevention (CDC) regard F. tularensis as a viable biological warfare agent, and it has been included in the biological warfare programs of the United States, Soviet Union and Japan at various times. A former Soviet biological weapons scientist, Ken Alibek , has alleged that an outbreak of tularemia among German soldiers shortly before the Battle of Stalingrad was due to the release of F. tularensis by Soviet forces. Others who have studied the pathogen "propose that an outbreak resulting from natural causes is more likely". In the United States, practical research into using rabbit fever as a biological warfare agent took place in 1954 at Pine Bluff Arsenal , Arkansas , an extension of the Fort Detrick program. It was viewed as an attractive agent because: [ citation needed ] it is easy to aerosolize it is highly infective; between 10 and 50 bacteria are sufficient to infect victims it is nonpersistent and easy to decontaminate (unlike anthrax ) it is highly incapacitating to infected persons it has comparatively low lethality, which is useful where enemy soldiers are in proximity to noncombatants, e.g. civilians The Schu S4 strain was standardized as "Agent UL" for use in the United States M143 bursting spherical bomblet . It was a lethal biological warfare agent with an anticipated fatality rate of 40–60%. The rate-of-action was around three days, with a duration-of-action of one to three weeks (treated) and two to three months (untreated), with frequent relapses. UL was streptomycin resistant. The aerobiological stability of UL was a major concern, being sensitive to sunlight, and losing virulence over time after release. When the 425 strain was standardized as "agent JT" (an incapacitant rather than lethal agent), the Schu S4 strain's symbol was changed again to SR. [ citation needed ] Both wet and dry types of F. tularensis (identified by the codes TT and ZZ) were examined during the "Red Cloud" tests , which took place from November 1966 to February 1967 in the Tanana Valley , Alaska. Cats and dogs can acquire the disease from the bite of a tick or flea that has fed on an infected host, such as a rabbit or rodent. For treatment of infected cats, antibiotics are the preferred treatment, including tetracycline, chloramphenicol or streptomycin. Long treatment courses may be necessary as relapses are common.

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Bubonic plague

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Nights of Plague

Nights of Plague ( Turkish : Veba Geceleri ) is a 2021 novel by Orhan Pamuk . Its Pamuk's 11th and longest novel. Inspired by historical events, it is set on a fictitious island, Mingheria, in the eastern Mediterranean between Crete and Cyprus . A number of early reviewers observed that Nights of Plague 's plot resembles that of Albert Camus 's novel The Plague . Its English translation, by Ekin Oklap, was published by Knopf Doubleday in the United States and Faber and Faber in the United Kingdom . In 2016, Pamuk began writing a historical novel about a bubonic plague epidemic on a fictitious island. He was particularly interested in the way plagues are Orientalized in such books as Defoe 's A Journal of the Plague Year , Manzoni 's The Betrothed , and Camus 's The Plague . In a 2020 article, he wrote that Western observers such as Defoe saw a fatalistic tendency in the Muslim worldview—the religious concept of "Every Man's end being determined", as Defoe put it. In 1901, a ship from Istanbul arrives on the island of Mingheria, where bubonic plague has broken out. Mingheria serves as a microcosm of the declining Ottoman Empire , where diverse groups coexist but are on the brink of disintegration. The plague reflects the empire's metaphorical characterization as "the sick man of Europe". To combat it, Sultan Abdul Hamid II dispatches Bonkowski Pasha, the empire's chief inspector of public health, and a Muslim epidemiologist, Prince Consort Doctor Nuri, and his wife, the sultan's niece Princess Pakize. When Bonkowski is murdered, it falls upon Pakize and Nuri to employ methods reminiscent of Sherlock Holmes to identify the culprit. Simultaneously, Western approaches to controlling the plague are attempted. But the islanders resist quarantine measures, resulting in an increasing number of infectious bodies. Amid this chaos, gruesome discoveries like two corpses fused together are made, leaving questions about their relationship unanswered. Matt A. Hanson of World Literature Today noted that the motifs of Nights of Plague are prevalent in the latter years of Ottoman collapse , notably during Abdul Hamid's disastrous reign. Pamuk fictionalizes the formation of the fragmented political identities that sparked World War I and eventually strengthened the foundations of the Turkish republic. In The Atlantic , Judith Shulevitz wrote that Nights of Plague is plainly satire and metaphor, mordantly riffing on Ottoman, revolutionary, and nationalist leadership styles in a critique of Atatürk , Kemalism , and even President Erdoğan 's government—but not in a single sentence. In his review for The New Yorker , James Wood noted that Pamuk, though aware how plague has historically been unfairly Orientalized, seems to relish Orientalizing Mingheria, imbuing it with swirls of Ottoman magic and mythology. Toward the end of the book, its narrator mentions the "negatively inflected sense" of Edward Said 's term " Orientalism ". In his review for The Times , Peter Kemp wrote that Nights of Plague masterfully weaves a tale of intrigue and disease.

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Bubonic plague

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Roman Plague of 590

The Roman Plague of 590 was an epidemic of plague that affected the city of Rome in the year 590. Probably bubonic plague , it was part of the first plague pandemic that followed the great plague of Justinian , which began in the 540s and may have killed more than 100 million Europeans before spreading to other parts of the world and which lasted until the end of Late Antiquity . The plague was described by the bishop and chronicler Gregory of Tours and later chronicler Paul the Deacon . The winter before the plague broke out, many of Rome's granaries were damaged when the Tiber flooded in November 589. Gregory of Tours recounts that portentous serpents and dragons were seen in the waters. The epidemic began in early 590; Gregory's narrative is not specific but death came rapidly to infected patients and the chronicler describes the disease as a 'plague of the groin' ( Latin : lues inguinaria ), factors which aid its identification as bubonic plague. Bishop of Rome Pelagius II died of plague in February 590 and Pope Gregory I , then a deacon , was elected his successor. Gregory was previously praefectus urbi before becoming a monk . Gregory had previously served as an apocrisiarius , a kind of papal ambassador to the East Roman Empire , where he had likely been influenced by Byzantine practices. The imperial capital of Constantinople , consecrated to the protection of the Mother of God (the Theotokos ), had a practice whereby processions of the faithful through the city streets chanting psalms and kyrie eleison to allay God's wrath. Gregory had likely witnessed these processions during his stay in Constantinople. When the plague was in Rome in 590 and Gregory was still a deacon, he organized such a procession to take place in Rome wherein seven groups would hold processions through the streets of the city and ending at the basilica of Mary Major to ask for the Virgin Mary 's protection. The processions took place on April 25, 590. The Marian aspect of the procession was perhaps unusual at the time, since Rome was traditionally associated with St Peter's protection, but it may have been a result of Byzantine influence, since Constantinople was often put under the Theotokos's protection during times of crisis. The seven processional groups were: 1) clergy, 2) abbots and monks, 3) abbesses and nuns, 4) men 5) married women 6) widows and 7) children (also perhaps including the poor of Rome). The reason for the processions was because plagues and other national disasters were typically interpreted at the time as being the chastisement of God for sinfulness, and therefore to appease God's wrath, these measures were taken. [ citation needed ] Eighty people collapsed during the procession as a result of being infected by plague. According to later legend, Pope Gregory saw a vision as the procession approached the mausoleum of the Roman emperor Hadrian , on the right bank of the Tiber near the Vatican Hill . The pope beheld St Michael the Archangel brandishing and then sheathing his sword atop the monument, which was interpreted to signify that God's wrath had been turned back, and the plague supposedly stopped at that moment, following which the faithful thanked the Mother of God . The 2nd century AD imperial tomb, which became a fortress in late Antiquity, subsequently became known as Castel Sant'Angelo , ' Castle of the Holy Angel ' . In the 18th century, a bronze sculpture was set on the summit of Castel Sant'Angelo to commemorate the legend, portraying the winged archangel in Roman armour and designed by Peter Anton von Verschaffelt in 1753. [ citation needed ]

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