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Plague

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Hittite plague

The Hittite Plague or Hand of Nergal was an epidemic , possibly of tularemia , which occurred in the mid-to-late 14th century BC .The Hittite Empire stretched from Turkey to Syria. The plague was likely an outbreak of Francisella tularensis which occurred along the Arwad-Euphrates trading route in the 14th century BC. Much of the ancient Near East suffered from outbreaks; however, Egypt and Assyria initiated a quarantine along their border, and they did not experience the epidemic. Tularemia is a bacterial infection which is still a threat. It is also referred to as "rabbit fever" and it is a zoonotic disease which can easily pass from animals to humans. The most common way that it is spread is through various insects which hop between species, such as ticks. The symptoms of an infection range from skin lesions to respiratory failure. Without treatment the mortality rate is 15% of those infected. According to former microbiologist Siro Trevisanato, "Tularemia is rare in many countries today, but remains a problem in some countries including Bulgaria." According to author Philip Norrie ( How Disease Affected the End of the Bronze Age ), there are three diseases most likely to have caused a post- Bronze Age societal collapse: smallpox , bubonic plague and tularemia. The tularemia plague which struck the Hittites could have been spread by insects or infected dirt or plants, through open wounds, or by eating infected animals. Hittite texts from the mid-14th century BC refer to the plague causing disabilities and death. Hittite King Muršili II wrote prayers seeking relief from the epidemic, which had lasted two decades and killed many of his subjects. The two kings who preceded him, Šuppiluliuma I and Šuppiluliuma's immediate heir, Arnuwanda II , had also succumbed to tularemia. Muršili had ascended to the throne because he was the last surviving son of Šuppiluliuma. Muršili believed that the plague had been transmitted to the Hittites by Egyptian prisoners who had been paraded through the capital city, Hattusa . There is some evidence suggesting that the Egyptians suffered from tularemia in the years preceding 1322 BC. The Hittites apparently also suspected zoonotic transmission, because they banned the use of donkeys in caravans. Another theory of the plague's origin suggests that it originated with rams that the Hittites had taken as spoils of war, along with other animals, after the Hittites raided Simyra . Soon after the animals were brought into Hittite villages, the tularemia outbreak began. The plague is mentioned in Amarna letter EA 35 , a letter written in Akkadian from the ruler of Alashiya (Cyprus) to the Pharaoh of Egypt during the Amarna Period . It dates from between 1350 and 1325 BC. In it, the plague is specially named as The Hand of Nergal.The disease was intentionally brought to western Anatolia in what is described as the "first known record of biological warfare ". Shortly after the Hittites experienced the outbreak of disease, the Arzawans from western Anatolia believed the Hittites were weakened and attacked them. The Arzawans claimed that rams suddenly appeared (1320 and 1318 BC) and the Arzawans brought them into their villages. It is thought that the Hittites had sent rams diseased with tularemia to infect their enemies. The Arzawans became so weakened by the plague that they failed in their attempt to conquer the Hittites.

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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.

Wiki

Plague

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Plague of Madness

" Plague of Madness " is the seventh episode of the first season of the American animated action drama Primal . It premiered unannounced on Adult Swim on April 1, 2020, as part of Adult Swim's annual April Fools' Day stunt , as a joking reference to the COVID-19 pandemic , after " Rage of the Ape-Men ", before formerly airing in its chronological place in the series (between " Scent of Prey " and " Coven of the Damned ") on October 11, 2020. It was directed by Genndy Tartakovsky , and written by David Krentz from a story by Tartakovsky, Krentz, Darrick Bachman , and Bryan Andrews . In the episode, Spear and Fang flee in terror from a zombified Argentinosaurus . The episode received critical acclaim, winning both an Annie Award and two Emmy Awards . It was released to home media on June 1, 2021. In a tranquil valley, an herd of Argentinosaurus are living their lives when one of their number is bitten by an insane zombified Parasaurolophus which bites one Argentinosaurus before being killed by it. Shortly afterward, the Argentinosaurus becomes a zombie itself, going on a rampage and massacring its herd. Sometime later, Spear and Fang stumble across the aftermath of the slaughter, disturbed by the many corpses and how they are untouched by scavengers or flies; a curious Fang sniffs one body before recoiling in terror, before the Argentinosaurus rises up behind the duo. Horrified, the two immediately flee through the jungle into a ravine, where the Argentinosaurus knocks itself out, and Spear and Fang rest in a cave. That night, Spear has a nightmare of the Argentinosaurus reviving and infecting him and Fang, and on awakening, decides to convince Fang to leave for night, lest his nightmare come to pass. As they make their way across the ravine, the Argentinosaurus awakens and continues its pursuit of them. As Spear and Fang escape through a crevasse too narrow for the Argentinosaurus , they begin to make their way across a volcanic plain, doing so carefully until the Argentinosaurus tears its body apart to break free and pursue them again. On being burned by a lava geyser, the Argentinosaurus jumps towards them, breaking through the crust into the lava below, and allowing Spear and Fang to ride a wave to safer ground and resume running, as the Argentinosaurus repeatedly re-emerges and sinks, unable to climb out but still pursing them. As the Argentinosaurus is slowly incinerated to ash, Spear and Fang observe its final agonizing moments in shared grief and dismay. Bloody Disgusting called the episode "absolutely relentless [in] just how intense and impactful "Plague of Madness" is. The efficiency of storytelling here is flawless. These 30 minutes of animation hold everything that makes Primal such a compelling show. It's brutal, action packed, filled with incredible money shots, yet it still manages to resonate with heartbreaking emotion [that] is never not completely sincere", praising the episode's director Genndy Tartakovsky for "us[ing] everything in his arsenal to create something powerful and moving", Bubbleblabber noting "Genndy's directorial effort [as] one [that] dazzles". Comic Book Resources lauded the episode as "the scariest and saddest Genndy Tartakovsky 's series has been to date", in particular for how "frightening [and] unexpectedly topical" the episode's exploration of disease was in light of the COVID-19 pandemic , noting how " Primal ' s main theme of the brutality of nature has never before been so widely relatable to our own society" than in the episode, bringing particular attention to how what "makes this simple story meaningful is its sense of empathy to all its characters", in spite of their actions, The Observer similarly praising how "the episode brings the tragedy of it all front and center to make sure the audience understands there are no villains in this story", comparing it to Mad Max: Fury Road . Monkeys Fighting Robots complimented the episode for "succeed[ing] as a piece of horror by understanding how to layer multiple genres over each other to create something refreshing", in particular for exploring "an element of zombie horror that often gets overlooked [in] the rot of the infection and how it affects the victim before they start ripping the ones they care about to shreds", a "terror [that] is almost as psychological as it is physical", concluding to call the episode "a perfect 20 minutes of terror [and] one of the most memorable episodes of [the] series", a sentiment echoed by Geek Ireland , marking it 4/5 stars. Bloody Disgusting called the episode "absolutely relentless [in] just how intense and impactful "Plague of Madness" is. The efficiency of storytelling here is flawless. These 30 minutes of animation hold everything that makes Primal such a compelling show. It's brutal, action packed, filled with incredible money shots, yet it still manages to resonate with heartbreaking emotion [that] is never not completely sincere", praising the episode's director Genndy Tartakovsky for "us[ing] everything in his arsenal to create something powerful and moving", Bubbleblabber noting "Genndy's directorial effort [as] one [that] dazzles". Comic Book Resources lauded the episode as "the scariest and saddest Genndy Tartakovsky 's series has been to date", in particular for how "frightening [and] unexpectedly topical" the episode's exploration of disease was in light of the COVID-19 pandemic , noting how " Primal ' s main theme of the brutality of nature has never before been so widely relatable to our own society" than in the episode, bringing particular attention to how what "makes this simple story meaningful is its sense of empathy to all its characters", in spite of their actions, The Observer similarly praising how "the episode brings the tragedy of it all front and center to make sure the audience understands there are no villains in this story", comparing it to Mad Max: Fury Road . Monkeys Fighting Robots complimented the episode for "succeed[ing] as a piece of horror by understanding how to layer multiple genres over each other to create something refreshing", in particular for exploring "an element of zombie horror that often gets overlooked [in] the rot of the infection and how it affects the victim before they start ripping the ones they care about to shreds", a "terror [that] is almost as psychological as it is physical", concluding to call the episode "a perfect 20 minutes of terror [and] one of the most memorable episodes of [the] series", a sentiment echoed by Geek Ireland , marking it 4/5 stars.

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Plague

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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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The Plague Dogs (film)

21 October 1982 ( 1982-10-21 ) (United Kingdom) 9 January 1985 ( 1985-01-09 ) (United States) United Kingdom United States The Plague Dogs is a 1982 animated adventure drama film , based on the 1977 novel of the same name by Richard Adams . It was written, directed and produced by Martin Rosen , who also directed Watership Down , the film adaptation of another novel by Adams, with animation direction by Tony Guy. The Plague Dogs was produced by Nepenthe Productions ; it was released by Embassy Pictures in the United States and by United Artists in the United Kingdom. The film was originally released unrated in the United States, but for its DVD release, was later re-rated PG-13 by the MPAA for mature themes such as animal cruelty , violent imagery, and emotionally distressing scenes. The Plague Dogs is the first non-family-oriented MGM animated film, and the first adult animated feature by the studio. The film's story is centered on two dogs named Rowf and Snitter, who escape from a research laboratory in Great Britain . In the process of telling the story, the film highlights the cruelty of performing vivisection and animal research for its own sake (though Rosen said that this was not an anti-vivisection film, but an adventure).Rowf, a labrador - mix , and Snitter, a smooth fox terrier , are two of many dogs used for experimental purposes at an animal research facility in the Lake District of north-western England . Snitter has had his brain surgically experimented upon-(leaving the top of his head scarred and covered with bandages) while Rowf has been drowned and resuscitated repeatedly. One evening, Snitter squeezes under the netting of his cage and into Rowf's, where they discover his cage is unlatched. They explore the facility in order to escape until they sneak into the incinerator , where they are nearly killed before finally escaping. Initially relieved and eager to experience their new freedom, the dogs are soon faced not only with the realities of life in the wild but with another more terrifying realization—they are being hunted by their former captors. They come to befriend the Tod, a nameless Geordie -accented fox who goes by the local slang term for a wild fox. The Tod teaches them to hunt in the wild in exchange for a share of their kills. Snitter hopes for a new home as he once had a master, but after accidentally killing a man by stepping onto the trigger of his shotgun as he climbs up onto him, Snitter loses hope. As time passes the two dogs grow emaciated, having to steal more and more food while still avoiding capture. The Tod is also proven to be difficult for the dogs to understand and cooperate. When the Tod finds a nest of eggs, he eats them all himself, enraging Rowf. The Tod himself disapproves of their risky behaviour, like killing domestic sheep grazing on the local hills. They go their separate ways for a time, but the Tod eventually returns to assist them by distracting a lab-hired gunman who then falls to his death. The three reconcile and wander about aimlessly, with the 3rd Battalion Parachute Regiment and the media roped into the pursuit, driven by rumours of the two dogs carrying bubonic plague and killing humans and sheep. The Tod parts company with the two dogs after leading them to a train pulled by River Irt on the Ravenglass and Eskdale Railway . While the dogs escape on the train, the Tod sacrifices his life distracting the humans in order to allow Snitter and Rowf to escape. Thanks to the Tod's distraction, Snitter and Rowf arrive at the coastal village of Ravenglass , but upon departing the train, the two dogs are spotted by an RAF Sea King helicopter and are pursued by it until they reach the shoreline and can run no further. As armed troops approach and prepare to shoot the dogs, Snitter looks out over the water and claims to see an island—he jumps into the sea and begins to swim to it. Rowf is hesitant to follow due to his conditioned fear of water , but his greater fear of the gunmen drives him to jump in as well and catch up with Snitter. Two gunshots are fired at the dogs but seemingly miss; immediately a white mist envelops the pair, and the humans and the helicopter disappear. The dogs swim through the mist towards the island Snitter claims to see but Rowf can't spot, until, at last, Snitter begins to doubt that "there is any island" and he stops paddling, losing hope. Rowf, however, claims to finally spot the island and urges Snitter to continue. As the dogs elude the helicopters in the foggy sea, audio from a phone conversation reveals that the lab would need to cease all experiments and shut down. By causing such a local panic, Rowf and Snitter saved the other lab animals from their cruelty. The dogs venture forth heading further into the mist, en route to what maybe is an island possibly waiting for them on the other side of it. The fates of Rowf and Snitter are left on an ambiguous note, as the sea they are swimming through is engulfed in an even thicker layer of mist. The following moment segues to the reveal of an island visible in the distance on the horizon. It is left uncertain if the body of land shown actually exists and is really there or if it is just an illusion with symbolic meaning.The film was animated in both Britain and San Francisco , California between 1979 and 1982. British animators such as Arthur Humberstone, Alan Simpson, George Jackson , and Colin White came from the unit that had previously worked on Watership Down . The San Francisco crew included Brad Bird , Phil Robinson, and Retta Scott , a "Disney veteran who had animated the vicious hunting dogs in Bambi ." Goldcrest Films invested £900,000 in the film and earned £308,000, losing the company £595,000. Jake Eberts who helped finance this and Watership Down thought the filmmakers made two errors: the film was downbeat with an unhappy ending, unlike the book, and was made without a distributor (an arrangement was made with Embassy but then the filmmakers wanted to re-negotiate and Embassy pulled out while United Artists became the film's UK distributor). The theme song, "Time and Tide", was composed and sung by Alan Price . The song, as well as dialogue from the film, was sampled by the Canadian industrial group Skinny Puppy for their anti-vivisection single , " Testure ", from their 1988 album VIVIsectVI . The theme song, "Time and Tide", was composed and sung by Alan Price . The song, as well as dialogue from the film, was sampled by the Canadian industrial group Skinny Puppy for their anti-vivisection single , " Testure ", from their 1988 album VIVIsectVI . The film had a test screening in Seattle on 17 December 1983. Rosen had difficulty in finding distributors for the film, and it entered a limited release in the U.S. on 9 January 1985. On Rotten Tomatoes the film has an approval rating of 63% based on reviews from eight critics, with an average rating of 7.3/10 . Janet Maslin , in her 1985 New York Times review of the U.S. release, praised the visual style: "Martin Rosen treats his Plague Dogs almost as though it were live action. He varies the scenery and the camera angles imaginatively [...] Mr. Rosen's direction is quite ingenious, much more so than Mr. Adams's story." Two versions exist: the original UK theatrical release (103 minutes) and the edited US version (86 minutes). Most edits were made to reduce running time but one was for its shocking content: After hired gunman Ackland falls to his death from a steep crag from which he attempts to shoot the dogs, a military helicopter flies over the snow-covered crags and valleys and the soldiers in the helicopter find the body ripped to shreds, implying that the starving dogs had eaten the corpse. The full theatrical cut was first released on a UK rental-only, PG-certificate VHS by Thorn EMI in December 1983; only around 8,000 copies were issued. On 22 August 1988, it was commercially released on VHS in the UK by Warner Home Video . In 1986, the edit was released on US VHS by Charter Entertainment . In 2002, Anchor Bay released a Region 2 DVD, but contained the US recut. Soon afterwards, Dutch budget label Indies Home Entertainment released a Region 2 disc which also contained the US cut but includes forced Dutch subtitles. In 2004, a DVD was released by Hollywood DVD in the UK with the US cut. Trinity Home Entertainment released their DVD in the United States the same year; Trinity tried to get the full cut, but when they were unable to obtain it, they ended up settling with using the truncated US version. Trinity's DVD was re-released by Phase 4 Films in 2010. In 2005, Australian distributor Umbrella Entertainment released both cuts on Region 4 DVD (they also released the full theatrical cut of Watership Down ), sourced from Rosen's private print. The same print was later released on Region 2 DVD in the UK by Optimum Releasing in 2008. In 2017, Shout! Factory announced that they had acquired the rights to the film in the United States, and that they would release the film for the first time on Blu-ray on 24 February 2018 under their Shout Select line. In late 2017, Shout! Factory announced that they had delayed the film's Blu-ray release to work with director Rosen in hopes of releasing the original version instead of the edit. In September 2018, Shout! Factory announced that the original version would be released on Blu-ray on 15 January 2019. The 2019 release includes both a 2K restoration of the original cut and the edit, as well as an interview with director Rosen regarding production. Screenbound Films also released a Blu-ray in the UK on 10 August 2020, likewise containing both cuts. It was also featured on The Criterion Channel as part of their arthouse animation lineup.

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Crayfish plague

Crayfish plague ( Aphanomyces astaci ) is a water mold that infects crayfish , most notably the European Astacus which dies within a few weeks of being infected. When experimentally tested, species from Australia , New Guinea and Japan were also found to be susceptible to the infection. Crayfish plague first arrived in Europe in Italy in 1859, either with imported crayfish from North America, or in ballast water discharge . After its original introduction in Italy in 1860, it spread quickly through Europe and was discovered in Sweden in 1907, in Spain in 1972, in Norway in 1971, in Great Britain in 1981, in Turkey in 1984 and in Ireland in 1987. In 1959, to bolster dwindling stocks of native crayfish, the signal crayfish was introduced to Sweden . The signal crayfish was known to be resistant, and it was not recognised at that time that it was a carrier of the disease. After 150 years of contact, no resistance has been discovered in native European crayfish. This species was studied and named by the German Mycologist Friedrich Schikora (1859 – 1932), from a type specimen in Germany in 1906.Transport of signal crayfish, red swamp crayfish and infected native European freshwater crayfish between waters is the main cause of contamination, though the disease can also be spread via items that have been in contact with contaminated water, such as a fishing tackle or footwear. The spores are sensitive to high or low temperatures. Most authorities have local rules and regulations to minimize the movement of water between different waterbodies (in for example a boat), and recommend that crayfish used as bait should come from the same water as that being fished, or should be frozen to at least −10 °C (14 °F) for one day before use, if there is a risk of contamination. The spores of crayfish plague disappear from an infected water system (connected lakes and rivers) within a few weeks once the last infected crayfish is removed. Reintroduction is then possible, as long as no infected waters are in contact with the lake.Infection with Aphanomyces astaci is accompanied by few signs in its early stages, and the first indication of infection may be mortality. In the later stages, the muscles of the tail may appear whitened, or brownish-red where blood cells have encapsulated the hyphae. The effects of the neurotoxins in the oomycete can include appearing in daytime (crayfish are typically nocturnal) and a lack of coordination.

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The Golden Plague

The Golden Plague (German: Die goldene Pest ) may refer to:

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The Scarlet Plague

The Scarlet Plague is a post-apocalyptic fiction novel by American writer Jack London , originally published in The London Magazine in 1912. The book was noted in 2020 as having been very similar to the COVID-19 pandemic , especially given London wrote it at a time when the world was not as quickly connected by travel as it is today. However unlike COVID-19, in this story, victims died within an hour and mortality was practically 100%. The story takes place in 2073, sixty years after an uncontrollable epidemic, the Red Death, has depopulated the planet. James Smith is one of the survivors of the era before the scarlet plague hit and is still left alive in the San Francisco area, and he travels with his grandsons Edwin, Hoo-Hoo, and Hare-Lip. His grandsons are young and live as primeval hunter-gatherers in a heavily depopulated world. Their intellect is limited, as are their language abilities. Edwin asks Smith, whom they call "Granser", to tell them of the disease alternately referred to as scarlet plague, scarlet death, or red death. Smith recounts the story of his life before the plague, when he was an English professor. The then future year of 2013 is described as a plutocratic society reminiscent of London's other books such as the Iron Heel with Smith recalling "Morgan the Fifth was appointed President of the United States by the Board of Magnates". The Scarlet Plague came about and spread rapidly across the globe. Sufferers would turn scarlet, particularly on the face, and become numb in their lower extremities. Victims usually died within 30 minutes of first seeing symptoms. Despite their efforts doctors and scientists can find no cure, and those who attempted to do so were also killed by the disease. The grandsons question Smith's belief in "germs" causing the illness because they cannot be seen. Smith witnesses his first victim of the scarlet plague while teaching when a young woman's face turns scarlet. She dies quickly, and a panic soon overtakes the campus. He returns home, but his family refuses to join him because they fear he is infected. Soon, an epidemic overtakes the area and residents begin rioting and killing one another. Smith meets with colleagues at his college's chemistry building, where they hope to wait out the problem. They soon realize they must move elsewhere for safety and begin trekking northward. Shortly, Smith's entire party dies out and he is left as the sole survivor. He lives for three years on his own with the company of a pony and two dogs. Eventually, his need for social interaction compels him back to the San Francisco area in search of other people. He finally discovers a sort of new society has been created with a few survivors, who have broken into tribes. Smith worries that he is the last to remember the times before the plague. He reminisces about the quality of food, social classes, his job, and technology. As he realizes his time grows short, he tries to impart the value of knowledge and wisdom to his grandsons. His efforts are in vain, however, as the children ridicule his recollections of the past, which sound totally unbelievable to them.The Scarlet Plague was written in 1910 but not serialized until the May–June 1912 issue of London Magazine . It was published as a book in 1915 by Macmillan . London published The Scarlet Plague in book form at a point in his career that biographers and critics have called a "professional decline", from September 1912 to May 1916. In this period, he stopped writing short works and shifted to longer works including The Abysmal Brute (1913), John Barleycorn (1913), The Mutiny of the Elsinore (1914), The Star Rover (1915), among others. The Scarlet Plague was later reprinted in the February 1949 issue of Famous Fantastic Mysteries . Readers were impressed that London seemed to have anticipated the anxieties of the Atomic Age. Jack London was inspired in part by Edgar Allan Poe 's 1842 short story " The Masque of the Red Death ", though the virus itself has different symptoms. Both Poe's story and London's fall into a genre of apocalyptic fiction featuring a universal plague that nearly wipes out humanity. Other examples include Mary Shelley 's The Last Man (1826), George R. Stewart 's Earth Abides (1949), Michael Crichton 's The Andromeda Strain (1969), Stephen King 's The Stand (1978). , and René Barjavel 's Ravage (1943)

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An American Plague

An American Plague: The True and Terrifying Story of the Yellow Fever Epidemic of 1793 is a 2003 nonfiction adolescent history by author Jim Murphy published by Clarion Books . An American Plague was one of the finalists in the 2003 National Book Award and was a 2004 Newbery Honor Book . It portrays the agony and pain this disease brought upon the American people marking its place in history in order to never be forgotten.The book takes place during the 1793 Philadelphia yellow fever epidemic . At this point Philadelphia is considered to be the largest city located in North America . The city is hit with an incurable and unknown disease which kills about 50% of the people affected. The author Jim Murphy describes a disease called the yellow fever and how it affected the residents of Philadelphia. In the novel he highlights the heroic roles and actions that the Philadelphia free blacks took in order to fight this deadly disease, and how it causes a constitutional crisis that leads president George Washington to leave the city of Philadelphia. The cure for the disease was not found until centuries later.Dr. Benjamin Rush : Developed a radical treatment process for the yellow fever disease which involved withdrawing blood from patients and giving patients mercury and the root of a poisonous plant. Mayor Matthew Clarkson : The only government leader who stayed to deal with the issues that were going on in Philadelphia when the plague was taking place. President George Washington : Was involved with foreign affairs when the plague struck and was out of touch with the government affairs for the time length of six weeks while the plague was taking over Philadelphia. Thomas Jefferson : Was the Secretary of State when the plague struck Philadelphia. Edmond-Charles Genêt : Was the French Ambassador who wanted the Americans to help France with their revolution . The Reverend J. Henry c. Helmuth : Believed that the plague was a punishment sent by god because there was an increase in gambling as well as in drinking among the people of Philadelphia. Absalom Jones : Was involved in the building of the St. George's United Methodist Church and, after participating and helping build the church, was told to sit in the back of the church by the church leaders. Mathew Carey : Wrote a book that was pronounced to be a best seller titled " A Short Account of the Malignant Fever " Dr. William Currie : Believed that the fever came from a shipment that came from the West Indies and claimed that it was not the yellow fever.Critics that were able to engage with the book found it to be very intriguing. It has been stated that Jim Murphy created an impeccable book that draws the reader in while at the same time creating fear. He is able to describe how horrid this period of time was for history with solid research and amazing facts. "In a lavishly illustrated book, containing maps, newspaper columns and period illustrations, Jim Murphy unflinchingly presents the horrors of the event as well as its heroes" states Anita Silvey. Kirkus Reviews named it Starred Review and found the book to be "A mesmerizing, macabre account...powerful evocative prose... compelling subject matter...fascinating discussion...valuable lesson in reading and writing history. Stellar." "Leisurely, lyrical tone...Murphy injects the events with immediacy...archival photographs...bring the story to life...comprehensive history." was Publishers Weekly' s opinion about the work. Murphy spotlights the heroic role of Philadelphia's free blacks in combating the disease, and the Constitutional crisis that President Washington faced when he was forced to leave the city — and all his papers — while escaping the deadly contagion. [ citation needed ]

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The Plague That Makes Your Booty Move... It's the Infectious Grooves

The Plague That Makes Your Booty Move... It's the Infectious Grooves is the debut album by Infectious Grooves , released in 1991. The song "Therapy" featured vocals from Ozzy Osbourne . The album introduces the character Sarsippius.Some of the songs received airplay on MTV , including "Therapy" and "Punk It Up". Steve Huey from AllMusic praised the album, calling it "an unabashed good-time party record". The album charted at 198 on the Billboard 200 and 6 on the Billboard Heatseekers ."Punk It Up" (Muir/Trujillo) – 3:51 "Therapy" (Muir/Trujillo) – 3:25 "I Look Funny?" (Muir/Sarsippius) – 0:26 "Stop Funk'n with My Head" (Dunn/Muir/Trujillo) – 3:23 "I'm Gonna Be My King" (Dunn/Muir/Trujillo) – 5:23 "Closed Session" (Muir/Sarsippius) – 1:19 "Infectious Grooves" (Dunn/Muir/Trujillo) – 4:13 "Infectious Blues" (Muir/Trujillo) – 0:43 "Monster Skank" (Muir/Trujillo) – 3:42 "Back to the People" (Infectious Grooves) – 2:46 "Turn Your Head" (Muir/Sarsippius) – 1:19 "You Lie...And Yo Breath Stank" (Muir/Trujillo) – 2:55 "Do the Sinister" (Muir/Trujillo) – 4:15 "Mandatory Love Song" (Muir) – 0:09 "Infecto Groovalistic" (Muir/Trujillo) – 5:05 "Thanx But No Thanx" (Muir/Sarsippius) – 1:54

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Plague

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Plague Mass

Blaise Dupuy Kurt Munkacsi Plague Mass is a live album by American avant-garde artist Diamanda Galás . It was recorded on October 12 and 13, 1990 at the Cathedral of St. John the Divine , New York City and released on April 1, 1991 by record label Mute .AllMusic described the performance as a "heart-wrenching cry about the physical suffering caused by the AIDS plague being compounded by the shameful arrogance of self-appointed moralists." Trouser Press described it as "sepulchral, breathtakingly dramatic and, in the best possible sense, appalling". It was placed on Terrorizer ' s list of the "100 Most Important Albums of the Nineties". Diamanda Galás – vocals David Linton - percussion Kurt Munkacsi – production Blaise Dupuy – production Rory Johnson – executive production

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Plague

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Capacitor plague

The capacitor plague was a problem related to a higher-than-expected failure rate of non-solid aluminium electrolytic capacitors between 1999 and 2007, especially those from some Taiwanese manufacturers, due to faulty electrolyte composition that caused corrosion accompanied by gas generation; this often resulted in rupturing of the case of the capacitor from the build-up of pressure . High failure rates occurred in many well-known brands of electronics, and were particularly evident in motherboards , video cards , and power supplies of personal computers . A 2003 article in The Independent claimed that the cause of the faulty capacitors was due to a mis-copied formula. In 2001, a scientist working in the Rubycon Corporation in Japan stole a mis-copied formula for capacitors' electrolytes. He then took the faulty formula to the Luminous Town Electric company in China, where he had previously been employed. In the same year, the scientist's staff left China, stealing again the mis-copied formula and moving to Taiwan, where they created their own company, producing capacitors and propagating even more of this faulty formula of capacitor electrolytes. The first flawed capacitors linked to Taiwanese raw material problems were reported by the specialist magazine Passive Component Industry in September 2002. Shortly thereafter, two mainstream electronics journals reported the discovery of widespread prematurely failing capacitors, from Taiwanese manufacturers, in motherboards. These publications informed engineers and other technically interested specialists, but the issue did not receive widespread public exposure until Carey Holzman published his experiences about "leaking capacitors" in the overclocking performance community. The news from the Holzman publication spread quickly on the Internet and in newspapers, partly due to the spectacular images of the failures – bulging or burst capacitors, expelled sealing rubber and leaking electrolyte on countless circuit boards. Many PC users were affected, and caused an avalanche of reports and comments on thousands of blogs and other web communities. The quick spread of the news also resulted in many misinformed users and blogs posting pictures of capacitors that had failed due to reasons other than faulty electrolyte. Most of the affected capacitors were produced from 1999 to 2003 and failed between 2002 and 2005. Problems with capacitors produced with an incorrectly formulated electrolyte have affected equipment manufactured up to at least 2007. Major vendors of motherboards such as Abit , IBM , Dell , Apple , HP , and Intel were affected by capacitors with faulty electrolytes. In 2005, Dell spent some US$420 million replacing motherboards outright and on the logistics of determining whether a system was in need of replacement. Many other equipment manufacturers unknowingly assembled and sold boards with faulty capacitors, and as a result the effect of the capacitor plague could be seen in all kinds of devices worldwide. Because not all manufacturers had offered recalls or repairs, do it yourself repair instructions were written and published on the Internet. In the November/December 2002 issue of Passive Component Industry , following its initial story about defective electrolyte, reported that some large Taiwanese manufacturers of electrolytic capacitors were denying responsibility for defective products. While industrial customers confirmed the failures, they were not able to trace the source of the faulty components. The defective capacitors were marked with previously unknown brands such as "Tayeh", "Choyo", or "Chhsi". The marks were not easily linked to familiar companies or product brands. The motherboard manufacturer ABIT Computer Corp. was the only affected manufacturer that publicly admitted to defective capacitors obtained from Taiwan capacitor makers being used in its products. However, the company would not reveal the name of the capacitor maker that supplied the faulty products.The first flawed capacitors linked to Taiwanese raw material problems were reported by the specialist magazine Passive Component Industry in September 2002. Shortly thereafter, two mainstream electronics journals reported the discovery of widespread prematurely failing capacitors, from Taiwanese manufacturers, in motherboards. These publications informed engineers and other technically interested specialists, but the issue did not receive widespread public exposure until Carey Holzman published his experiences about "leaking capacitors" in the overclocking performance community. The news from the Holzman publication spread quickly on the Internet and in newspapers, partly due to the spectacular images of the failures – bulging or burst capacitors, expelled sealing rubber and leaking electrolyte on countless circuit boards. Many PC users were affected, and caused an avalanche of reports and comments on thousands of blogs and other web communities. The quick spread of the news also resulted in many misinformed users and blogs posting pictures of capacitors that had failed due to reasons other than faulty electrolyte. Most of the affected capacitors were produced from 1999 to 2003 and failed between 2002 and 2005. Problems with capacitors produced with an incorrectly formulated electrolyte have affected equipment manufactured up to at least 2007. Major vendors of motherboards such as Abit , IBM , Dell , Apple , HP , and Intel were affected by capacitors with faulty electrolytes. In 2005, Dell spent some US$420 million replacing motherboards outright and on the logistics of determining whether a system was in need of replacement. Many other equipment manufacturers unknowingly assembled and sold boards with faulty capacitors, and as a result the effect of the capacitor plague could be seen in all kinds of devices worldwide. Because not all manufacturers had offered recalls or repairs, do it yourself repair instructions were written and published on the Internet. In the November/December 2002 issue of Passive Component Industry , following its initial story about defective electrolyte, reported that some large Taiwanese manufacturers of electrolytic capacitors were denying responsibility for defective products. While industrial customers confirmed the failures, they were not able to trace the source of the faulty components. The defective capacitors were marked with previously unknown brands such as "Tayeh", "Choyo", or "Chhsi". The marks were not easily linked to familiar companies or product brands. The motherboard manufacturer ABIT Computer Corp. was the only affected manufacturer that publicly admitted to defective capacitors obtained from Taiwan capacitor makers being used in its products. However, the company would not reveal the name of the capacitor maker that supplied the faulty products.The non-solid aluminium electrolytic capacitors with improperly formulated electrolyte mostly belonged to the so-called "low equivalent series resistance (ESR)", "low impedance ", or "high ripple current" e-cap series. The advantage of e-caps using an electrolyte composed of 70% water or more is, in particular, a low ESR, which allows a higher ripple current , and decreased production costs, water being the least costly material in a capacitor. All electrolytic capacitors with non-solid electrolyte age over time, due to evaporation of the electrolyte. The capacitance usually decreases and the ESR usually increases. The normal lifespan of a non-solid electrolytic capacitor of consumer quality, typically rated at 2000 h/85 °C and operating at 40 °C, is roughly 6 years. It can be more than 10 years for a 1000 h/105 °C capacitor operating at 40 °C. Electrolytic capacitors that operate at a lower temperature can have a considerably longer lifespan. The capacitance should normally degrade to as low as 70% of the rated value, and the ESR increase to twice the rated value, over the normal life span of the component, before it should be considered as a "degradation failure". The life of an electrolytic capacitor with defective electrolyte can be as little as two years. The capacitor may fail prematurely after reaching approximately 30% to 50% of its expected lifetime. The electrical characteristics of a failed electrolytic capacitor with an open vent are the following: capacitance value decreases to below the rated value ESR increases to very high values. Electrolytic capacitors with an open vent are in the process of drying out, regardless of whether they have good or bad electrolyte. They always show low capacitance values and very high ohmic ESR values. Dry e-caps are therefore electrically useless. E-caps can fail without any visible symptoms. Since the electrical characteristics of electrolytic capacitors are the reason for their use, these parameters must be tested with instruments to definitively decide if the devices have failed. But even if the electrical parameters are out of their specifications, the assignment of failure to the electrolyte problem is not a certainty. Non-solid aluminium electrolytic capacitors without visible symptoms, which have improperly formulated electrolyte, typically show two electrical symptoms: When examining a failed electronic device, the failed capacitors can easily be recognized by clearly visible symptoms that include the following: Bulging of the vent on top of the capacitor. (The "vent" is stamped into the top of the casing of a can-shaped capacitor, forming a seam that is meant to split to relieve pressure build-up inside, preventing an explosion.) Ruptured or cracked vent, often accompanied by visible crusty rust-like brown or red dried electrolyte deposits. Capacitor casing sitting crooked on the circuit board, caused by the bottom rubber plug being pushed out, sometimes with electrolyte having leaked onto the motherboard from the base of the capacitor, visible as dark-brown or black surface deposits on the PCB. The leaked electrolyte can be confused with thick elastic glue sometimes used to secure the capacitors against shock. A dark brown or black crust up the side of a capacitor is invariably glue, not electrolyte. The glue itself is harmless.The non-solid aluminium electrolytic capacitors with improperly formulated electrolyte mostly belonged to the so-called "low equivalent series resistance (ESR)", "low impedance ", or "high ripple current" e-cap series. The advantage of e-caps using an electrolyte composed of 70% water or more is, in particular, a low ESR, which allows a higher ripple current , and decreased production costs, water being the least costly material in a capacitor. All electrolytic capacitors with non-solid electrolyte age over time, due to evaporation of the electrolyte. The capacitance usually decreases and the ESR usually increases. The normal lifespan of a non-solid electrolytic capacitor of consumer quality, typically rated at 2000 h/85 °C and operating at 40 °C, is roughly 6 years. It can be more than 10 years for a 1000 h/105 °C capacitor operating at 40 °C. Electrolytic capacitors that operate at a lower temperature can have a considerably longer lifespan. The capacitance should normally degrade to as low as 70% of the rated value, and the ESR increase to twice the rated value, over the normal life span of the component, before it should be considered as a "degradation failure". The life of an electrolytic capacitor with defective electrolyte can be as little as two years. The capacitor may fail prematurely after reaching approximately 30% to 50% of its expected lifetime.The electrical characteristics of a failed electrolytic capacitor with an open vent are the following: capacitance value decreases to below the rated value ESR increases to very high values. Electrolytic capacitors with an open vent are in the process of drying out, regardless of whether they have good or bad electrolyte. They always show low capacitance values and very high ohmic ESR values. Dry e-caps are therefore electrically useless. E-caps can fail without any visible symptoms. Since the electrical characteristics of electrolytic capacitors are the reason for their use, these parameters must be tested with instruments to definitively decide if the devices have failed. But even if the electrical parameters are out of their specifications, the assignment of failure to the electrolyte problem is not a certainty. Non-solid aluminium electrolytic capacitors without visible symptoms, which have improperly formulated electrolyte, typically show two electrical symptoms:When examining a failed electronic device, the failed capacitors can easily be recognized by clearly visible symptoms that include the following: Bulging of the vent on top of the capacitor. (The "vent" is stamped into the top of the casing of a can-shaped capacitor, forming a seam that is meant to split to relieve pressure build-up inside, preventing an explosion.) Ruptured or cracked vent, often accompanied by visible crusty rust-like brown or red dried electrolyte deposits. Capacitor casing sitting crooked on the circuit board, caused by the bottom rubber plug being pushed out, sometimes with electrolyte having leaked onto the motherboard from the base of the capacitor, visible as dark-brown or black surface deposits on the PCB. The leaked electrolyte can be confused with thick elastic glue sometimes used to secure the capacitors against shock. A dark brown or black crust up the side of a capacitor is invariably glue, not electrolyte. The glue itself is harmless.Industrial espionage was implicated in the capacitor plague, in connection with the theft of an electrolyte formula. A materials scientist working for Rubycon in Japan left the company, taking the secret water-based electrolyte formula for Rubycon's ZA and ZL series capacitors, and began working for a Chinese company. The scientist then developed a copy of this electrolyte. Then, some staff members who defected from the Chinese company copied an incomplete version of the formula and began to market it to many of the aluminium electrolytic manufacturers in Taiwan, undercutting the prices of the Japanese manufacturers. This incomplete electrolyte lacked important proprietary ingredients which were essential to the long-term stability of the capacitors and was unstable when packaged in a finished aluminium capacitor. This faulty electrolyte allowed the unimpeded formation of hydroxide and produced hydrogen gas. There are no public court proceedings related to the alleged theft, as Rubycon's complete electrolyte formula remained secure. However, independent laboratory analysis of defective capacitors has shown that many of the premature failures appear to be associated with high water content and missing inhibitors in the electrolyte, as described below. Unimpeded formation of hydroxide (hydration) and associated hydrogen gas production, occurring during "capacitor plague" or "bad capacitors" incidents involving the failure of large numbers of aluminium electrolytic capacitors, has been demonstrated by two researchers at the Center for Advanced Life Cycle Engineering of the University of Maryland who analyzed the failed capacitors. The two scientists initially determined, by ion chromatography and mass spectrometry , that there was hydrogen gas present in failed capacitors, leading to bulging of the capacitor's case or bursting of the vent. Thus it was proved that the oxidation takes place in accordance with the first step of aluminium oxide formation. Because it has been customary in electrolytic capacitors to bind the excess hydrogen by using reducing or depolarizing compounds, such as aromatic nitrogen compounds or amines , to relieve the resulting pressure, the researchers then searched for compounds of this type. Although the analysis methods were very sensitive in detecting such pressure-relieving compounds, no traces of such agents were found within the failed capacitors. In capacitors in which the internal pressure build-up was so great that the capacitor case was already bulging but the vent had not opened yet, the pH value of the electrolyte could be measured. The electrolyte of the faulty Taiwanese capacitors was alkaline, with a pH of between 7 and 8. Good comparable Japanese capacitors had an electrolyte that was acidic, with a pH of around 4. As it is known that aluminium can be dissolved by alkaline liquids, but not that which is mildly acidic, an energy dispersive X-ray spectroscopy (EDX or EDS) fingerprint analysis of the electrolyte of the faulty capacitors was made, which detected dissolved aluminium in the electrolyte. To protect the metallic aluminium against the aggressiveness of the water, some phosphate compounds, known as inhibitors or passivators , can be used to produce long-term stable capacitors with high-aqueous electrolytes. Phosphate compounds are mentioned in patents regarding electrolytic capacitors with aqueous electrolytic systems. Since phosphate ions were missing and the electrolyte was also alkaline in the investigated Taiwanese electrolytes, the capacitor evidently lacked any protection against water damage, and the formation of more-stable alumina oxides was inhibited. Therefore, only aluminium hydroxide was generated. The results of chemical analysis were confirmed by measuring electrical capacitance and leakage current in a long-term test lasting 56 days. Due to the chemical corrosion, the oxide layer of these capacitors had been weakened, so after a short time the capacitance and the leakage current increased briefly, before dropping abruptly when gas pressure opened the vent. The report of Hillman and Helmold proved that the cause of the failed capacitors was a faulty electrolyte mixture used by the Taiwanese manufacturers, which lacked the necessary chemical ingredients to ensure the correct pH of the electrolyte over time, for long-term stability of the electrolytic capacitors. Their further conclusion, that the electrolyte with its alkaline pH value had the fatal flaw of a continual buildup of hydroxide without its being converted into the stable oxide, was verified on the surface of the anode foil both photographically and with an EDX-fingerprint analysis of the chemical components.Industrial espionage was implicated in the capacitor plague, in connection with the theft of an electrolyte formula. A materials scientist working for Rubycon in Japan left the company, taking the secret water-based electrolyte formula for Rubycon's ZA and ZL series capacitors, and began working for a Chinese company. The scientist then developed a copy of this electrolyte. Then, some staff members who defected from the Chinese company copied an incomplete version of the formula and began to market it to many of the aluminium electrolytic manufacturers in Taiwan, undercutting the prices of the Japanese manufacturers. This incomplete electrolyte lacked important proprietary ingredients which were essential to the long-term stability of the capacitors and was unstable when packaged in a finished aluminium capacitor. This faulty electrolyte allowed the unimpeded formation of hydroxide and produced hydrogen gas. There are no public court proceedings related to the alleged theft, as Rubycon's complete electrolyte formula remained secure. However, independent laboratory analysis of defective capacitors has shown that many of the premature failures appear to be associated with high water content and missing inhibitors in the electrolyte, as described below. Unimpeded formation of hydroxide (hydration) and associated hydrogen gas production, occurring during "capacitor plague" or "bad capacitors" incidents involving the failure of large numbers of aluminium electrolytic capacitors, has been demonstrated by two researchers at the Center for Advanced Life Cycle Engineering of the University of Maryland who analyzed the failed capacitors. The two scientists initially determined, by ion chromatography and mass spectrometry , that there was hydrogen gas present in failed capacitors, leading to bulging of the capacitor's case or bursting of the vent. Thus it was proved that the oxidation takes place in accordance with the first step of aluminium oxide formation. Because it has been customary in electrolytic capacitors to bind the excess hydrogen by using reducing or depolarizing compounds, such as aromatic nitrogen compounds or amines , to relieve the resulting pressure, the researchers then searched for compounds of this type. Although the analysis methods were very sensitive in detecting such pressure-relieving compounds, no traces of such agents were found within the failed capacitors. In capacitors in which the internal pressure build-up was so great that the capacitor case was already bulging but the vent had not opened yet, the pH value of the electrolyte could be measured. The electrolyte of the faulty Taiwanese capacitors was alkaline, with a pH of between 7 and 8. Good comparable Japanese capacitors had an electrolyte that was acidic, with a pH of around 4. As it is known that aluminium can be dissolved by alkaline liquids, but not that which is mildly acidic, an energy dispersive X-ray spectroscopy (EDX or EDS) fingerprint analysis of the electrolyte of the faulty capacitors was made, which detected dissolved aluminium in the electrolyte. To protect the metallic aluminium against the aggressiveness of the water, some phosphate compounds, known as inhibitors or passivators , can be used to produce long-term stable capacitors with high-aqueous electrolytes. Phosphate compounds are mentioned in patents regarding electrolytic capacitors with aqueous electrolytic systems. Since phosphate ions were missing and the electrolyte was also alkaline in the investigated Taiwanese electrolytes, the capacitor evidently lacked any protection against water damage, and the formation of more-stable alumina oxides was inhibited. Therefore, only aluminium hydroxide was generated. The results of chemical analysis were confirmed by measuring electrical capacitance and leakage current in a long-term test lasting 56 days. Due to the chemical corrosion, the oxide layer of these capacitors had been weakened, so after a short time the capacitance and the leakage current increased briefly, before dropping abruptly when gas pressure opened the vent. The report of Hillman and Helmold proved that the cause of the failed capacitors was a faulty electrolyte mixture used by the Taiwanese manufacturers, which lacked the necessary chemical ingredients to ensure the correct pH of the electrolyte over time, for long-term stability of the electrolytic capacitors. Their further conclusion, that the electrolyte with its alkaline pH value had the fatal flaw of a continual buildup of hydroxide without its being converted into the stable oxide, was verified on the surface of the anode foil both photographically and with an EDX-fingerprint analysis of the chemical components.

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Plague

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Plague Inc: Evolved

Xbox One 18 September 2015 Windows , macOS , Linux 18 February 2016 PlayStation 4 31 May 2016 Nintendo Switch 2 August 2019 Plague Inc: Evolved is a real-time strategy simulation video game , developed and published by UK-based independent games studio Ndemic Creations. The game is a remake of the developer's previous game, Plague Inc. , adapted for PC and consoles. In the game, the player creates and evolves a pathogen in an effort to destroy the world with a deadly plague . The game uses an epidemic model with a complex and realistic set of variables to simulate the spread and severity of the plague, and has attracted the attention of the CDC . The core game of Plague Inc: Evolved is the same as Plague Inc. – the player controls a plague which has infected patient zero . The player must infect and kill the whole world population by evolving the plague and adapting to various environments. However, there is a time pressure to complete the game before humans, the opponent, develop a cure for the plague. The developer has said that the game was inspired by Pandemic 2 , a browser-based Flash game released in 2008 by Dark Realm Studios. The game series has been praised by the Centers for Disease Control and Prevention who said "it uses a non-traditional route to raise public awareness on epidemiology, disease transmission, and diseases/pandemic information. The game creates a compelling world that engages the public on serious public health topics". The developer of the game was invited to give a talk at the CDC. It also includes all of the expansion packs from the original Plague Inc. game. On 28 January 2021 Plague Inc: The Cure a free DLC (now paid) was released wherein the player attempts to eradicate a rapidly spreading plague by creating a cure before they lose all of their "authority" due to too many people getting panicked about disease spread. The player can slow the spread of the plague by imposing health guidelines, public awareness schemes and continental lockdowns. [ non-primary source needed ]On 28 January 2021 Plague Inc: The Cure a free DLC (now paid) was released wherein the player attempts to eradicate a rapidly spreading plague by creating a cure before they lose all of their "authority" due to too many people getting panicked about disease spread. The player can slow the spread of the plague by imposing health guidelines, public awareness schemes and continental lockdowns. [ non-primary source needed ]Plague Inc: Evolved went live on Steam Early Access on 20 February 2014. In 2014, the developer used "almost half a million pieces of feedback and feature requests from players" to help him understand what players wanted from the game and said he was "only 50 percent of the way through the original Plague Inc. design document". A multiplayer mode, titled "VS. mode" was added to the game on 1 December 2015. In this mode, two players compete to spread their own plague across the world, while preventing in-game humans from inventing a cure and trying to eradicate the other player's disease. The mode adds new genes, evolution and abilities to the game. The 1.0 release took place on 18 February 2016. On August 9, 2019, Ndemic Creations released Plague Inc. Evolved for the Nintendo Switch ; gameplay is operated through the Switch's Joy-Con , or the touchscreen. The Xbox One version of Plague Inc. Evolved has received "generally favorable reviews" from review aggregator Metacritic . Critics gave the game an average score of 80 out of 100. In March 2016, the Italian edition of Eurogamer gave the game a 7 out of 10 score, praising the game for its relatively complex gameplay but mildly criticising it for a lack of depth caused by its origins as a mobile game. In October 2015, GamesRadar+ rated the game a 4 out of 5, stating that the game is a "delicate balancing act". There was some controversy due to the nature of the game during the COVID-19 pandemic , due to this Plague Inc. The Cure was given out for free on some platforms until it ended.

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Plague

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Red plague

Red plague can refer to the following diseases: It can also have the following meanings:

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Plague

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Chauliognathus lugubris

Chauliognathus lugubris , the plague soldier beetle , green soldier beetle or banana bug , is a species of soldier beetle (Cantharidae) native to Australia. It has a flattened body to 15 millimetres (0.59 in) long with a prominent yellow-orange stripe behind the black prothorax . The abdomen is yellow-orange but is mostly obscured by the metallic olive green elytra . Plague soldier beetles are most common in spring and early summer, and have an adult lifespan of 2-3 months. They are most commonly found in the temperate region of southeast Australia, and are occasionally found in parts of the southwest. The beetles often swarm in large, localised groups around flora such as shrubs and trees, primarily to mate and eat. These swarms can include hundreds of thousands of beetles. As adults, plague soldier beetles are thought to feed on pollen and nectar. While in their larval stage, plague soldier beetles live in soil and are thought to feed on smaller, soft-shelled invertebrates.

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Plague

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Locust Plague of 1874

The Locust Plague of 1874 , or the Grasshopper Plague of 1874 , occurred when hordes of Rocky Mountain locusts invaded the Great Plains in the United States and Canada . The locust hordes covered about 2,000,000 square miles (5,200,000 km 2 ) and caused millions of dollars' worth of damage. The swarms were so thick that they could cover the sun for up to six hours. Efforts were made to stop the infestation, including eating the locusts. Following the plague, the population of Rocky Mountain locusts continued to decline each year after 1874 and in spring 1875, many of the hatched locust eggs died due to frost, contributing to their eventual extinction.The locust plague encompassed the Dakota Territory , the Montana Territory , the Wyoming Territory , the Colorado Territory , Iowa , Minnesota , Missouri , Nebraska , Kansas , the Indian Territory , and Texas . The locust plague also reached the Northwest Territories and Manitoba ; one 1877 observer theorized that a range of coniferous timber prevented them from overtaking some parts of Saskatchewan . While the exact mechanism behind why locust movement is inhibited by coniferous ranges is not known, the locusts were never observed to be able to cross these regions. The locusts spread out across about 2,000,000 square miles (5,200,000 km 2 ) , while a locust infestation named Albert's swarm in 1875 covered 198,000 square miles (510,000 km 2 ) . The United States Entomological Commission wrote in 1880 that the infestation "covered a swath equal to the combined areas of Connecticut , Delaware , Maine , Maryland , Massachusetts , New Hampshire , New Jersey , New York , Pennsylvania , Rhode Island , and Vermont ." Compared to previous infestations in the region, the 1874 plague was significantly more damaging. In some cases, the locusts blocked the sun for up to six hours. The locusts were able to breed quickly due to it being hot and dry during the spring and summer. The locusts swarms would pile up to over a foot high and ate crops, trees, leaves, grass, wool off sheep, harnesses on horses, paint from wagons, and pitchfork handles. Drinking water was often all that the farmers could protect. The locusts ate for several days by eating from the fields and trees, and moved to eating food from inside the farmers' homes. Carpets and clothes were torn apart by the locusts in the process. The excrement from the locusts infected the ponds and streams. Despite livestock eating the locusts and bonfires killing many of them, the estimated 120 billion to 12.5 trillion locusts were not stopped by any of these interventions. Crop damage caused by the locusts cost over $200 million. Migration to the Midwest stopped as a result, causing many travelers to return to their homes in the east or move further to the west. Trains had trouble moving due to the "slippery, gooey mess" of dead locusts. The tracks were "slick with grasshopper guts" which caused the trains to lose traction, according to the book It Happened in Nebraska . A Kansas pioneer was quoted as saying, "They looked like a great, white glistening cloud, for their wings caught the sunshine on them and made them look like a cloud of white vapor". Another Kansas settler said, "I never saw such a sight before. This morning, as we looked up toward the sun, we could see millions in the air. They looked like snowflakes." Farmers tried killing the locusts with fire and exploding gunpowder, and one case resulted in the locusts smothering out the flames. A device called a hopperdozer was used to attempt to stop the infestation. The hopperdozer had a scraper with coal tar that was pulled by horses on fields, but it only worked on flat ground. This device would be dragged against the wind, and young locusts would be blown into the tar, killing them. In Kansas, Governor Thomas A. Osborn convinced the legislature to approve $73,000 in bonds for aid and railroads carried supplies for free to Kansas farmers. Other Americans donated barley and corn to the Kansas farmers. In Nebraska, it was required that farmers have no leftover money and nothing left to sell in order to receive assistance from the Nebraska Relief and Aid Association. Entomologist Charles Valentine Riley suggested eating the locusts to get rid of them, including locusts fried in butter and in a soup. Farmers would attempt to make meals out of the locusts. The federal government eased residency requirements for homesteaders and Congress supplied $30,000 in seeds to the area. From 1874 to 1875, the U.S. Army handed out thousands of pieces of clothing and other items, including rations. In spring 1875, many of the hatched locust eggs from the 1874 infestation died due to the frost . The population of Rocky Mountain locusts continued to decline each year after 1874, leading to their extinction. Many farmers left Nebraska due to the crop damage. Riley wrote in the 1877 book The Locust Plague in the United States that the 1874 locust plague was worse than any of its predecessors. He also said that famine and death in the affected regions would have been possible if it were not for the aid received. Riley surmised that Kansas ultimately suffered the most out of the affected regions. Locusts continued to cause more infestations, including Albert's swarm , until insecticides were created during World War II . Laura Ingalls Wilder wrote about the locust devastation of her family's Minnesota farm in one of her memoir books for children, On the Banks of Plum Creek .

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The Plague of the Zombies

The Plague of the Zombies is a 1966 British horror film directed by John Gilling and starring André Morell , John Carson , Jacqueline Pearce , Brook Williams , and Michael Ripper . The film's imagery influenced many later films in the zombie genre. [ citation needed ]In a Cornish village in August 1860, the inhabitants of the town are dying from a mysterious plague that seems to be spreading at an accelerated rate. Even the local doctor, Peter Tompson, cannot combat the disease. Alarmed, Tompson sends for outside help from his friend and former mentor, Sir James Forbes. Accompanying Sir James is his daughter Sylvia, a childhood friend of Peter's wife, Alice. As Sir James and Sylvia arrive in the village, Sylvia deters a group of rowdy fox hunters from killing a fox. Shortly after, Sir James and Sylvia encounter a funeral procession in town, which is interrupted by the fox hunters, who come to harass Sylvia for intentionally misleading them. In the melee, the pallbearers drop the casket over the side of a bridge, revealing the corpse of John Martinus, a recently deceased man. In an attempt to learn more about the disease, Sir James and Peter attempt to disinter the corpses that were recently buried, and are frightened upon finding the coffins empty. Meanwhile, Sylvia is harassed by the fox hunters while walking through the woods, and chased into a manor house owned by Squire Clive Hamilton. The hunters humiliate Sylvia in what appears to be pre-emptory rape, but are stopped by Squire Hamilton, who chastises them for harassing her. As Sylvia departs the house, she encounters a grey-skinned man near an abandoned tin mine headframe, and watches in horror as he throws Alice's lifeless body onto the ground. The following morning, Sylvia leads her father and Peter to the location, where they locate Alice's corpse. Police accuse Tom, the brother of John Martinus, of killing Alice, as he was found sleeping in a drunken stupor near her body. Tom denies involvement, and claims he witnessed his deceased brother walking near the mine. An autopsy on Alice shows no signs of rigor mortis, and, even stranger, blood smeared on her face is determined to be of animal origin. Sir James notices a bandaged slash wound on her wrist, which Peter says she sustained on a piece of broken glass days before. Later that evening, Squire Hamilton pays Sylvia a visit. Purposely, Hamilton manages to shatter a wine glass, and Sylvia happens to cut her finger on one of the sharp edges of the glass. Secretly, the Squire conceals a piece of the blood-stained glass into his coat pocket and departs. The next day, at Alice's funeral, Sylvia begins to feel faint. Through further investigation, Sir James and Peter learn that the squire lived in Haiti for several years and practised Haitian voodoo rituals, as well as black magic. Meanwhile, Squire Hamilton, now with a vestige of Sylvia's blood, has begun using his voodoo magic to lure Sylvia into the dark woods. She is led to the abandoned tin mine by an army of walking zombies for a voodoo ceremony that will transform her into one of the walking dead. It is revealed that Squire Hamilton has been turning the locals into the walking dead, in order to create workers to mine the tin and make money off of it. While Peter follows Sylvia to the mines, Sir James investigates the Squire's house and finds some small figures in coffins the Squire uses for his voodoo. After a struggle with one of the Squire's henchmen the room is accidentally set ablaze, Sir James barely manages to escape after threatening a servant who notices the inferno for information on the mine. He races to the mines to join Peter, while in the mansion the figures in the coffins catch fire, causing their zombie counterparts to do the same and go crazy. Using the distraction caused by the burning crazed zombies, Sir James and Peter rescue Sylvia and flee from the burning flames as they listen to the anguished screams of Hamilton and his zombies; thus the plague is ended.David Pirie compares it to The Reptile in that "[b]oth concern small Cornish communities threatened by a kind of alien and inexplicable plague which has been imported from the East via a corrupt aristocracy: both are, by implication at least, violently anti-colonial". Scholar Ruth Heholt notes in an article in Hellebore magazine that both The Reptile and The Plague of the Zombies are part of a tradition that associates Cornwall with the exotic and the foreign. Cornwall represents "the non-English within England; the foreign at home."Production on the film began on 28 July 1965 at Bray Studios . It was shot back-to-back with The Reptile using the same sets, a Cornish village created on the backlot by Bernard Robinson . Pearce and Ripper appeared in both films. The film was released in some markets on a double feature with Dracula: Prince of Darkness . The film needed to earn $1.5 million in rentals to break even. It earned $2.34 million in rentals, thus making a profit. The Plague of the Zombies has been well received by critics. A contemporary review in Variety called it "a well-made horror programmer" with "formula scripting," and The Monthly Film Bulletin declared, "The best Hammer Horror for quite some time, with remarkably few of the lapses into crudity which are usually part and parcel of this company's work," adding, "Visually the film is splendid, with elegantly designed sets, and both interiors and exteriors shot in pleasantly muted colours; and the script manages quite a few offbeat strokes." Among more recent assessments, AllMovie called it a "spooky, atmospheric horror opus that ranks among Hammer Films' finest." Time Out London wrote "perhaps a little tame these days, compared with modern gore-shock, but Gilling's Hammer chiller [...] is highly atmospheric." The Hammer Story: The Authorised History of Hammer Films wrote, "much has been said of The Plague of the Zombies ' influence on genre landmark Night of the Living Dead , made in 1968. A unique and shocking experiment in pushing the parameters of Hammer horror, The Plague of the Zombies deserves greater recognition in its own right." Writing in The Zombie Movie Encyclopedia , academic Peter Dendle called it a "well-acted and capably-produced" zombie film that would go on to influence the depiction of zombies in many other films. Radio Times gave the film four stars and called it "John Gilling's best work" It currently holds an 83% approval rating on Rotten Tomatoes, based on 12 reviews. Shout Factory released a Blu-ray of the film on 15 January 2019 with brand new commentaries from filmmakers Constantine Nasr, Ted Newsom and film historian Steve Haberman. The film needed to earn $1.5 million in rentals to break even. It earned $2.34 million in rentals, thus making a profit. The Plague of the Zombies has been well received by critics. A contemporary review in Variety called it "a well-made horror programmer" with "formula scripting," and The Monthly Film Bulletin declared, "The best Hammer Horror for quite some time, with remarkably few of the lapses into crudity which are usually part and parcel of this company's work," adding, "Visually the film is splendid, with elegantly designed sets, and both interiors and exteriors shot in pleasantly muted colours; and the script manages quite a few offbeat strokes." Among more recent assessments, AllMovie called it a "spooky, atmospheric horror opus that ranks among Hammer Films' finest." Time Out London wrote "perhaps a little tame these days, compared with modern gore-shock, but Gilling's Hammer chiller [...] is highly atmospheric." The Hammer Story: The Authorised History of Hammer Films wrote, "much has been said of The Plague of the Zombies ' influence on genre landmark Night of the Living Dead , made in 1968. A unique and shocking experiment in pushing the parameters of Hammer horror, The Plague of the Zombies deserves greater recognition in its own right." Writing in The Zombie Movie Encyclopedia , academic Peter Dendle called it a "well-acted and capably-produced" zombie film that would go on to influence the depiction of zombies in many other films. Radio Times gave the film four stars and called it "John Gilling's best work" It currently holds an 83% approval rating on Rotten Tomatoes, based on 12 reviews. Shout Factory released a Blu-ray of the film on 15 January 2019 with brand new commentaries from filmmakers Constantine Nasr, Ted Newsom and film historian Steve Haberman. A novelization of the film was written by John Burke as part of his 1967 book The Second Hammer Horror Film Omnibus . The film was adapted into a 13-page comic strip for the October 1977 issue of the magazine House of Hammer (volume 1, # 13, published by Top Sellers Limited ). It was drawn by Trevor Goring and Brian Bolland from a script by Steve Moore . The cover of the issue featured a painting by Brian Lewis of a famous scene from the film. In the first season Amazing Stories television show episode "Mirror, Mirror", the cemetery scene film is used to portray a clip of Sam Waterston 's character's horror film being shown by Dick Cavett . [ citation needed ]

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Plague

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Plaguers

September 8, 2008 ( 2008-09-08 ) (Semana) Plaguers is a 2008 American science-fiction horror film written and directed by Brad Sykes and featuring Steve Railsback . Tarver ( Steve Railsback ) is a crew member on board Pandora , a freight transport carrier headed toward Earth with a desperately needed new energy supply, a strange substance called "Thanatos". Pandora ' s captain, Darian Holoway (Alexis Zibolis) was recently promoted after the death of former captain Rubini (David P. Johnson). Some of the crew are suspicious of the Thanatos. Approaching Earth, the ship diverts to respond to a distress call from the spacecraft Diana . The Diana appears abandoned until the discovery of four nurses from the Diana ' s medical facility who claim to have survived a pirate attack. The nurses are actually the pirates and they attempt a takeover of the Pandora . During the struggles, the Thanatos container is ruptured and fluid spills onto one of the pirates. She mutates and becomes a "plaguer". One by one, the pirates and the Pandora crew become infected, as the Thanatos becomes strong enough to take control of the ship and head it straight toward Earth.Writer/director Brad Sykes included certain elements that were reminiscent of Alien . His reference points in writing the film were Aliens , Prince of Darkness , and The Thing . He said he "liked how the characters didn't die, but were transformed into something alien or inhuman as the story progressed." Sykes also said that Italian film director Lamberto Bava 's Dèmoni (also known as Demons ) influenced the actions of the plaguers themselves and that he loves "the wild energy of Italian horror films and tried to bring that into the film whenever possible." He even told his cast to watch Dèmoni for inspiration. Quiet Earth wrote that Plaguers is a "scifi horror film that wants to be Alien but comes off feeling like another in a long line of Alien 'homages'." In its review of the film, DVD Talk said there "are a lot of problems with Plaguers , though it does have some merit", offering that there were "occasional scattered moments of actual tension, and a few effective jump scares", and that "makeup effects are for the most part lots of fun..." DVD Verdict said, " Plaguers is a 'so bad it's bad' film that explores the space zombie territory with little regard for common sense or science fiction", concluding that the film "doesn't qualify for camp or cult classic, it's just flat out terrible and would be embarrassing for even a public access channel to put on their schedule." Larry Stanley "B-Movie" Award Best Actor ( Steve Railsback ) Honorable Mention as Best Actress (Alexis Zibolis) Science Fiction Genre Award – Honorable Mention as Best Picture – Feature Best Special Effects Best One-Liner ("There's only one captain on this ship, and today it ain't you.")Larry Stanley "B-Movie" Award Best Actor ( Steve Railsback ) Honorable Mention as Best Actress (Alexis Zibolis) Science Fiction Genre Award – Honorable Mention as Best Picture – FeatureBest Special Effects Best One-Liner ("There's only one captain on this ship, and today it ain't you.")

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Plague

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Plague!

Plague! is a board game first published by B&B Productions in 1991, and was designed by Steven Barsky.Plague! is about the arrival of the Black Plague in Weymouth, England, in 1348.Richard H. Berg comments: " Plague! is not a game to play to see who wins, mostly because it is so chaotic and random at times. It is a game that delightfully highlights the fact that, as with many trips, it's not where you're going but how you get there."

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Plague

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Plague Recordings

Plague Recordings (also known as Plague) is an independent record label formerly operating from Belgium specialising in ambient, industrial and experimental electronic music. Plague Recordings was founded in 2007 and released albums from 2tokiislands (France), Audela (N/A), Ambient Temple of Imagination (USA), Manifesto (Sweden), Nathan Siter (Finland), Pump (UK), Sid Redlin (USA) and Wicked Messenger (Germany/Australia). Over the years, two compilations saw the light of day. Artists included Maarten van der Vleuten (Netherlands), Scanner (UK), The Caretaker (UK/Germany), vidnaObmana (Belgium), Moljebka Pvlse (Sweden), Ondo (Sweden), Machinist & Mendel Kaelen (Netherlands). The label's lift-off album May The Plague Be With You , an anonymous work featuring 3 tracks ( Black Box Warning I, II, III), each 23 minutes long, has ever since intrigued drone faddists worldwide. Offered as free MP3 in 2009-2010, MTPBWY was legally downloaded > 7.000 times. Over the years several other albums were offered free of charge. In 2010 the label went into hiatus focusing on transcendental activities. According to several online sources, Plague has planned 2 new releases by Wicked Messenger, scheduled in 2011.

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Plague

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Major Grom: Plague Doctor

Artyom Gabrelyanov Roman Kotkov Evgeniy Eronin Vladimir Besedin Aleksandr Kim Valentina Tronova Nikolay Titov Artyom Gabrelyanov Evgeny Fedotov Artyom Gabrelyanov Michael Kitaev Olga Filipuk Roman Kotkov Evgeniy Eronin Tikhon Zhiznevsky Lyubov Aksyonova Aleksei Maklakov Aleksandr Seteykin Sergei Goroshko Dmitry Chebotaryov Mikhail Evlanov Oleg Chugunov Yuriy Karikh Aleksandr Puzyryov Russian English ₽640 million Major Grom: Plague Doctor ( Russian : Майор Гром: Чумной Доктор , romanized : Mayor Grom: Chumnoy Doktor ) is a 2021 Russian action film directed by Oleg Trofim, based on the comic book series of the same name by the Russian publisher Bubble Comics , created by Artyom Gabrelyanov . It is the second film adapted from Bubble Comics , as well as the first feature-length film based on a Russian comic. Prior to that, the studio had released the short film Major Grom . It stars Tikhon Zhiznevsky in the lead role, alongside Lyubov Aksyonova , Aleksei Maklakov , Aleksandr Seteykin, Sergei Goroshko, and Dmitry Chebotaryov. The film is set in Saint Petersburg and tells the story of police major Igor Grom, an honest and skilled cop with unconventional methods, who pursues a vigilante murderer in the mask of a plague doctor . A teaser for the film was first screened on 30 September 2017 at IgroMir / Comic-Con Russia 2017, after which the project faced difficulties in production for some time, with the team being disbanded and reassembled, and the concept of the film redone from scratch. Three years later, a full trailer was shown at Comic Con Russia 2020 , with a tentative release date. Major Grom: Plague Doctor premiered on 25 March 2021 in St. Petersburg . The online premiere took place on 5 May 2021 on KinoPoisk HD and Netflix . Major Grom: Plague Doctor received a moderately positive reception from critics: the overall quality of the work was noted, but the clichéd and unoriginal plot was also criticised. Some observers have claimed that the film denounces the Russian opposition and praises the police, but not all reviewers agreed with this opinion; the authors themselves have denied these allegations in several interviews. The film failed at the box office, collecting only 328 million rubles in the CIS , with a budget of 640 million rubles, but it proved popular on Netflix and Kinopoisk HD. Saint Petersburg police major Igor Grom is chasing three bank robbers dressed in red sports suits and disguised as villainous hockey players from the popular Soviet cartoon Puck! Puck! He catches them, while causing significant property damage, and gets reprimanded by his superior, colonel General Fedor Prokopenko. Soon after, the trial of "rich boy" Kirill Grechkin begins; he is accused of fatally hitting a girl with his car. Despite the evidence against him, Grechkin is acquitted and the brother of the deceased, Lyosha Makarov, suspects the court of corruption. IT millionaire Sergei Razumovsky, founder of the social network Vmeste, and his friend Oleg Volkov, who grew up in the same orphanage as the deceased girl, are also outraged by the court's decision. At the same time, videos of the Plague Doctor appear on the internet—an avenger in a mask and a combat suit, armed with bombs and flamethrowers, who promises to "cleanse" the city of scoundrels. The Doctor burns Kirill Grechkin to death in his car. After the murder, Oleg comes to Razumovsky and confesses that he was the Doctor. Razumovsky is upset by this, but hesitates to turn his friend in to the authorities. Grom, who witnessed the murder, is trying to investigate it and find the Doctor, who is now considered by many to be a hero. FSB officer Evgeny Strelkov, who arrives from Moscow to capture the Doctor, removes the major from the case. Instead, Grom and his new trainee, Dima Dubin, are sent to deal with the theft of twelve refrigerators. However, contrary to their official assignment, the two continue to investigate the Doctor's case, having received a tip from Grom's informant and unsuccessfully trying to knock information out of people associated with the criminal underworld. In the meantime, Grom saves a young woman from thugs, but she turns out to be journalist and blogger Yulia Pchyolkina, who staged the attack in order to get close to Grom and obtain information about the Plague Doctor case for her blog. Meanwhile, the Doctor accumulates new victims: the head of a bank that defrauded depositors and the owner of a polluting landfill, along with the latter's entire family. Dubin speculates that the Doctor's next appearance will be at the opening of a casino, where the crème de la crème of St. Petersburg society will gather. Grom infiltrates the opening party, where he meets Pchyolkina and Razumovsky. Instead of the real Doctor, however, only his followers appear, wanting to rob the rich. Sergei Razumovsky tries to prevent the violence and dissuade them with money, but a fight ensues, in which Grom and a number of FSB officers capture the bandits. Grom is subsequently forced to resign from the police by Strelkov. Despite his dismissal, he continues his investigation and learns about Razumovsky's childhood in the orphanage, and that he used to draw birds that looked like the Doctor's mask. Back at the casino, Pchyolkina had told Grom about Razumovsky's contract with Holt International, a company engaged in high-tech weapons development. It was Holt International that created the Plague Doctor's costume and equipment. Grom directly accuses Razumovsky of being the Plague Doctor. By this point, Sergei has realized that the accusation is true: "Oleg" was his secondary personality (Grom points out that according to official documents, the real Oleg Volkov died in the war in Syria a year before). His dark side takes over; he knocks Grom out with a blow to the head, puts the Doctor's suit on him, and tosses him near the site of his next murder. The police grab Grom, and Strelkov now believes that Igor is the Doctor. Dubin and Pchyolkina help Grom escape from custody, and he goes on the hunt for the Doctor. Meanwhile, the vigilante publishes a new video: he calls on all his followers to fill the streets and lynch anyone they consider to be a villain. Spontaneous pogroms begin in the city. Razumovsky confesses to Igor that in this way, he wants to get rid of not only corrupt officials and rich people, but also his followers, whom he considers to be immoral imitators and misfits; in his opinion, the state will be forced to send troops and kill them, and Razumovsky will subsequently be able to create a "new Petersburg". A fight breaks out between Grom and Razumovsky, in which the Doctor almost wins, but Dubin and Pchyolkina come to Grom's rescue. Razumovsky is neutralized, and Pchyolkina reveals that she recorded his boasting speech, including his nefarious plans. Grom declares to the Doctor that he also sees problems in the country, but considers it unacceptable to solve them by means of murder. Meanwhile, the pogroms quickly subside when a gang led by one of Grom's informants acts against the rioters. Lyosha Makarov, who participated in them, is planning to kill the corrupt judge who released Grechkin. When his grandchildren visit him, however, Lyosha realizes that he is incapable of committing the murder, and spares him. FSB officer Strelkov claims all credit for the apprehension of the Plague Doctor, while Grom is content to spend time with his new friends, Dubin and Pchyolkina. In a mid-credits scene, Razumovsky is shown in a mental institution. His "dark side" speaks to him, telling him that "they" will soon be free. In a post-credits scene, Oleg Volkov is shown in a militant camp in Syria: it turns out that he is still alive, and he watches his friend Razumovsky's capture on television.The filmmakers tried to use less famous actors as they were dissatisfied with the same few actors playing in many different films. Bubble had difficulties with the casting—in particular, with the selection of a lead actor to portray Igor Grom. Alexander Gorbatov, who played Grom in the short film , did not return to the role due to lack of interest in the project. The search for a new actor took a whole year. According to screenwriter and producer Roman Kotkov, "...we could not even imagine that it was so difficult to find a tall handsome man with intelligence in his eyes in Russia". Eventually, Tikhon Zhiznevsky was selected for the role. Zhiznevsky had to lose ten kilograms for the part, as well as undergo serious physical training in order to look more athletic. For this, he worked with coaches in Moscow and St. Petersburg . Dmitry Chebotaryov, another actor who took part in the film and who had known Zhiznevsky for a long time, recalls that he and many of Zhiznevsky's other acquaintances would never have thought that their friend would fit the part he was about to play, as he was mainly known for playing romantic roles. For the role of Sergei Razumovsky, theatre actor Sergei Goroshko was chosen. In order to convincingly play the character, Goroshko compiled a complete biography of the character, from his birth until the events after the film, partly sourcing this from the comics as well as from the film's scriptwriters. Goroshko also had to lose weight for the role, in his case fifteen kilograms. The voice of the Plague Doctor in the mask is an overlap of the voices of Goroshko and Dmitry Chebotaryov. Actor Dmitry Chebotaryov auditioned for both the roles of Igor Grom and Oleg, and, according to the producers, both auditions were successful, but he was eventually selected to play Oleg Volkov. Chebotaryov was the only actor among the main cast who did not have to change his appearance in any way for filming. Ukrainian rapper Kyivstoner was approved for the role of Booster Ignat, Grom's informant, due to his flamboyant personality. Almost all of his lines were improvised. Politician Vitaly Milonov was invited to appear in a cameo as himself, since the studio needed a character who would condemn the actions of the Plague Doctor on the in-film television. Director Oleg Trofim was opposed to Milonov becoming this character since he did not want the film to have unnecessary allusions to real life, but Gabrelyanov insisted, and Milonov appeared in a short scene in which he committed to a ban of the Plague Doctor masks. The filmmakers tried to use less famous actors as they were dissatisfied with the same few actors playing in many different films. Bubble had difficulties with the casting—in particular, with the selection of a lead actor to portray Igor Grom. Alexander Gorbatov, who played Grom in the short film , did not return to the role due to lack of interest in the project. The search for a new actor took a whole year. According to screenwriter and producer Roman Kotkov, "...we could not even imagine that it was so difficult to find a tall handsome man with intelligence in his eyes in Russia". Eventually, Tikhon Zhiznevsky was selected for the role. Zhiznevsky had to lose ten kilograms for the part, as well as undergo serious physical training in order to look more athletic. For this, he worked with coaches in Moscow and St. Petersburg . Dmitry Chebotaryov, another actor who took part in the film and who had known Zhiznevsky for a long time, recalls that he and many of Zhiznevsky's other acquaintances would never have thought that their friend would fit the part he was about to play, as he was mainly known for playing romantic roles. For the role of Sergei Razumovsky, theatre actor Sergei Goroshko was chosen. In order to convincingly play the character, Goroshko compiled a complete biography of the character, from his birth until the events after the film, partly sourcing this from the comics as well as from the film's scriptwriters. Goroshko also had to lose weight for the role, in his case fifteen kilograms. The voice of the Plague Doctor in the mask is an overlap of the voices of Goroshko and Dmitry Chebotaryov. Actor Dmitry Chebotaryov auditioned for both the roles of Igor Grom and Oleg, and, according to the producers, both auditions were successful, but he was eventually selected to play Oleg Volkov. Chebotaryov was the only actor among the main cast who did not have to change his appearance in any way for filming. Ukrainian rapper Kyivstoner was approved for the role of Booster Ignat, Grom's informant, due to his flamboyant personality. Almost all of his lines were improvised. Politician Vitaly Milonov was invited to appear in a cameo as himself, since the studio needed a character who would condemn the actions of the Plague Doctor on the in-film television. Director Oleg Trofim was opposed to Milonov becoming this character since he did not want the film to have unnecessary allusions to real life, but Gabrelyanov insisted, and Milonov appeared in a short scene in which he committed to a ban of the Plague Doctor masks. Representatives of Bubble Studios repeatedly stated that the short film Major Grom would be a test project before filming a full-length movie, which, if successful, would be followed by adaptations of other Bubble comics. It was also stated that Bubble Studios plans to attract American actors to the project, film it in English, and launch it internationally, with a focus on Western markets. The full-length Major Grom was to be produced by the same team as the short one. The planned budget at that time was at least five million US dollars . The filmmakers also said that the look of Saint Petersburg in the film would differ from the real one, and, in addition, the geography of the city would undergo changes. Bubble Studios director and Major Grom screenwriter, Artyom Gabrelyanov, commented, "There are certain things that make the character look organic. If you take a camera and just shoot what is outside the window, then any superhero in a Russian context will look funny". The filmmakers planned to stick to a 12+ rating, although they did not deny that scenes of violence could increase the rating to 16+. According to Gabrelyanov, the studio did not set itself the goal of giving "a [Russian] answer" to Hollywood , and that it is more important for it to prove its merits by deeds, not by words. In November 2017, Bubble Studios announced an open casting for the film. Vladimir Besedin, who was the director at the time, mentioned that there would be several after-credits scenes related to the story. A teaser for the film was first shown on 30 September 2017 at IgroMir / Comic-Con Russia 2017 . The clip shows a young restless skateboarder, played by Oleg Chugunov , who watches a video of the Plague Doctor and begins to believe in his ideas, before joining a flash mob in which everyone who wants to protest against government corruption must release a paper airplane from a window. Igor Grom himself appears in the video only from the back, in passing, at a shawarma kiosk. The scenery of Saint Petersburg is made to look like New York City , and the actors speak English; the audio was later dubbed into Russian. Responses to the teaser included accusations by Alexander Strepetilov, editor of Mir Fantastiki magazine, that the Plague Doctor was a satire on popular Russian opposition politician Alexei Navalny (while in the comics he was an allusion to Pavel Durov , a creator of the Russian social network VKontakte ). Popular video blogger and film reviewer Evgeny Bazhenov, known as BadComedian , to the contrary, stated that any parallels in the film with existing reality were the right move on the studio's part: "In their first film, I did not relate myself to anyone. Here at least it is clear that this is a modern world, modern people". According to the filmmakers, the short film was well received by Western audiences, and therefore the teaser was filmed in English. Artyom Gabrelyanov stated that Hollywood producers were very interested in the project. One of these was Harvey Weinstein , but the meeting with him was cancelled at the very last moment due to allegations of sexual harassment against him. Foreign producers insisted on the participation of English-speaking actors and an Americanization of the film, so as to better cater to English-speaking audiences. Examples of this included changing Saint Petersburg to New York City and renaming Igor Grom to Harry Thunder. However, Bubble felt that this contradicted their concept for the project. As a result, they decided to refuse the help of foreign producers and shoot the film primarily for a Russian-speaking audience. Subsequently, the first teaser, as well as the original 2017 short film, were deemed non-canonical to the events of Major Grom: Plague Doctor . During development, the production team had creative disagreements that prevented the work from continuing. The creative team wanted the film to be more story-driven, while the director of the short film, Vladimir Besedin, as well as the crew, wanted it to be more action-packed. This changed when Artyom Gabrelyanov met producer Mikhail Kitaev, who became interested in the film and at the same time had experience in grand-scale projects, such as Invasion , Sputnik , Chernobyl , and T-34 . He helped make connections, select actors, and create scenery. Kitaev saw the Major Grom short film while on the set of the 2018 film Ice , together with Oleg Trofim, and both liked it. According to the plan, filming was supposed to begin a month and a half after Kitaev joined the project, but in fact, Bubble only had a script and concept art , and they were not ready for filming. Kitaev immediately noted the inexperience of the team and the lack of skillful management, and he felt that the script was decent but needed improvement. The first weeks of working on the film were extremely difficult, as the team did not understand what to do. In the end, the project was frozen, all deadlines were cancelled, and Gabrelyanov and Kitaev turned to Artyom's father, Aram Gabrelyanov [ ru ] , founder of Life news agency , who had invested in the movie, for approval of a further work plan. A personnel reshuffle occurred, the new team worked for three weeks, but conflicts continued to arise, and the project was frozen again—this time for a week and a half, resulting in the entire team being disbanded. Vladimir Besedin, director of the short film, resigned, and Gabrelyanov, Kitaev, and Kotkov made a list of directors who could cope with the project, eventually selecting Oleg Trofim. The film's plot is based on the first story arc of the original comic series , which recounts the struggle of Major Grom with a serial killer hiding under the mask of a plague doctor . In the scenario itself, Bubble Studios planned to leave about 80% of the plot of the original story and add 20% of new content. After the teaser was released, the filmmakers received many unflattering comments related to its political content, both from Russian pro-government structures and from members of the public opposed to the government. As a result, it was decided to remove all the politics that were present in the original comic, leaving only the problem of "uncontrolled crimes of rich people who can get away from the law with their money" and focusing on social inequality instead. Gabrelyanov noted that the problem of inequality would also be more understandable to foreign viewers than allusions to Russian politics. Initial drafts of the script had scenes with helicopters and skyscrapers, but when producer Maxim Kitaev joined the project, he advised the scriptwriters to remove them, as they would require too much money, due to their scale. The plot before the restart of production was too large, and it would have been impossible to film, even if the team had a budget 2–3 times bigger, so the writers had to shorten it. When asked why the plot of Major Grom is so unoriginal and clichéd, Oleg Trofim replied that comics adaptations hadn't previously been filmed in Russia, and local filmmakers needed to master the genre and its basics first. Only once this happened would it be possible to deconstruct the genre and create something more original. During adaptation, the plot of the original comic underwent significant changes. For example, in the film, the character of Yulia Pchyolkina is not only the protagonist's love interest and damsel in distress , but also a full-fledged participant in the story line. Oleg Trofim commented: "It is not relevant anymore to show the heroine as a girl who does not want to decide anything, but wants a dress". In the film, the personality of Igor Grom also changed: in the comics, he is very noble and strictly follows a moral code, whereas in the film, he is more antiheroic and less scrupulous. The writers deliberately didn't show Grom's origin story , opting to only offer hints throughout the film. Roman Kotkov explained this by saying that superhero origin stories have become boring to audiences. The character of Razumovsky also underwent some changes, especially his motivation: in the film, the Plague Doctor sincerely, albeit using radical methods, wants to make the world a better place, whereas in the comics, he only uses justice as an excuse, while committing murders for his personal gain. The film contains a number of references to other Bubble comics, which are considered to be a setup for a potential Bubble cinematic universe. There is mention of a "hitman with rat" in the film—the nickname of Demonslayer, one of the key characters in the Bubble comic universe and the protagonist of the comic series of the same name. Holt International, a corporation that designed the Plague Doctor's suit, appears in the Red Fury comic series as a main antagonist. If Besedin wanted St. Petersburg to appear Americanized, Oleg Trofim made the city look closer to reality. Trofim lived in St. Petersburg for five years, and art director Dmitry Onishchenko is from there and knows the city well, and this helped when choosing locations. For over two months, Trofim and Onishchenko explored St. Petersburg to find streets that would best be suited for specific moments of the film. Oleg Trofim explained: "We know classical Petersburg, which is full of Baroque architecture and Art Nouveau . This is the city in which there was a revolution , and Soviet architecture has strongly settled there. We are also familiar with the gangster Petersburg from the 1990s, with its endless networks of courtyards . We were faced with the task of determining which Petersburg to show. As a result, we completely abandoned the Soviet legacy and that of the 1990s and concentrated on the historical part, the one that is timeless, the one that creates the image of St. Petersburg as a majestic palace city". In addition, the filmmakers decided to alter the layout of the city, as compared to the real St. Petersburg. To do this, they sketched a rough plan, marking the main locations in the film: the poor neighborhoods Grom visits, a police station, Razumovsky's office, and Grom's apartment. As a result, it turned out that Bolshaya Morskaya Street leads to Radishchev Street , Zhukov Street becomes Galernaya Street , and Nevsky Prospect does not seem to exist at all. Oleg Trofim complained that the logistics in St. Petersburg were inconvenient for filming, and that was why they had to create their own scenery. After the initial publicity in 2017, there was no new information about the film for two years. On 5 October 2019, continuation of work on the project was announced at IgroMir / Comic-Con Russia . It was announced that the director had been replaced, and instead of Vladimir Besedin, Oleg Trofim was at the helm of the production. The role of Major Grom also changed from Aleksander Gorbatov ( ru ) to Tikhon Zhiznevsky ( ru ). Additionally, significant changes had been made to the script. Filming resumed in Saint Petersburg and the film was initially planned to go on screen in 2019. However, in October of that year, it was announced that it would not be released on the due date. Filming was completed in December 2019. The official first trailer was released on 27 May 2020, a day after Saint Petersburg's anniversary celebrations. Representatives of Bubble Studios repeatedly stated that the short film Major Grom would be a test project before filming a full-length movie, which, if successful, would be followed by adaptations of other Bubble comics. It was also stated that Bubble Studios plans to attract American actors to the project, film it in English, and launch it internationally, with a focus on Western markets. The full-length Major Grom was to be produced by the same team as the short one. The planned budget at that time was at least five million US dollars . The filmmakers also said that the look of Saint Petersburg in the film would differ from the real one, and, in addition, the geography of the city would undergo changes. Bubble Studios director and Major Grom screenwriter, Artyom Gabrelyanov, commented, "There are certain things that make the character look organic. If you take a camera and just shoot what is outside the window, then any superhero in a Russian context will look funny". The filmmakers planned to stick to a 12+ rating, although they did not deny that scenes of violence could increase the rating to 16+. According to Gabrelyanov, the studio did not set itself the goal of giving "a [Russian] answer" to Hollywood , and that it is more important for it to prove its merits by deeds, not by words. In November 2017, Bubble Studios announced an open casting for the film. Vladimir Besedin, who was the director at the time, mentioned that there would be several after-credits scenes related to the story. A teaser for the film was first shown on 30 September 2017 at IgroMir / Comic-Con Russia 2017 . The clip shows a young restless skateboarder, played by Oleg Chugunov , who watches a video of the Plague Doctor and begins to believe in his ideas, before joining a flash mob in which everyone who wants to protest against government corruption must release a paper airplane from a window. Igor Grom himself appears in the video only from the back, in passing, at a shawarma kiosk. The scenery of Saint Petersburg is made to look like New York City , and the actors speak English; the audio was later dubbed into Russian. Responses to the teaser included accusations by Alexander Strepetilov, editor of Mir Fantastiki magazine, that the Plague Doctor was a satire on popular Russian opposition politician Alexei Navalny (while in the comics he was an allusion to Pavel Durov , a creator of the Russian social network VKontakte ). Popular video blogger and film reviewer Evgeny Bazhenov, known as BadComedian , to the contrary, stated that any parallels in the film with existing reality were the right move on the studio's part: "In their first film, I did not relate myself to anyone. Here at least it is clear that this is a modern world, modern people". According to the filmmakers, the short film was well received by Western audiences, and therefore the teaser was filmed in English. Artyom Gabrelyanov stated that Hollywood producers were very interested in the project. One of these was Harvey Weinstein , but the meeting with him was cancelled at the very last moment due to allegations of sexual harassment against him. Foreign producers insisted on the participation of English-speaking actors and an Americanization of the film, so as to better cater to English-speaking audiences. Examples of this included changing Saint Petersburg to New York City and renaming Igor Grom to Harry Thunder. However, Bubble felt that this contradicted their concept for the project. As a result, they decided to refuse the help of foreign producers and shoot the film primarily for a Russian-speaking audience. Subsequently, the first teaser, as well as the original 2017 short film, were deemed non-canonical to the events of Major Grom: Plague Doctor . During development, the production team had creative disagreements that prevented the work from continuing. The creative team wanted the film to be more story-driven, while the director of the short film, Vladimir Besedin, as well as the crew, wanted it to be more action-packed. This changed when Artyom Gabrelyanov met producer Mikhail Kitaev, who became interested in the film and at the same time had experience in grand-scale projects, such as Invasion , Sputnik , Chernobyl , and T-34 . He helped make connections, select actors, and create scenery. Kitaev saw the Major Grom short film while on the set of the 2018 film Ice , together with Oleg Trofim, and both liked it. According to the plan, filming was supposed to begin a month and a half after Kitaev joined the project, but in fact, Bubble only had a script and concept art , and they were not ready for filming. Kitaev immediately noted the inexperience of the team and the lack of skillful management, and he felt that the script was decent but needed improvement. The first weeks of working on the film were extremely difficult, as the team did not understand what to do. In the end, the project was frozen, all deadlines were cancelled, and Gabrelyanov and Kitaev turned to Artyom's father, Aram Gabrelyanov [ ru ] , founder of Life news agency , who had invested in the movie, for approval of a further work plan. A personnel reshuffle occurred, the new team worked for three weeks, but conflicts continued to arise, and the project was frozen again—this time for a week and a half, resulting in the entire team being disbanded. Vladimir Besedin, director of the short film, resigned, and Gabrelyanov, Kitaev, and Kotkov made a list of directors who could cope with the project, eventually selecting Oleg Trofim. The film's plot is based on the first story arc of the original comic series , which recounts the struggle of Major Grom with a serial killer hiding under the mask of a plague doctor . In the scenario itself, Bubble Studios planned to leave about 80% of the plot of the original story and add 20% of new content. After the teaser was released, the filmmakers received many unflattering comments related to its political content, both from Russian pro-government structures and from members of the public opposed to the government. As a result, it was decided to remove all the politics that were present in the original comic, leaving only the problem of "uncontrolled crimes of rich people who can get away from the law with their money" and focusing on social inequality instead. Gabrelyanov noted that the problem of inequality would also be more understandable to foreign viewers than allusions to Russian politics. Initial drafts of the script had scenes with helicopters and skyscrapers, but when producer Maxim Kitaev joined the project, he advised the scriptwriters to remove them, as they would require too much money, due to their scale. The plot before the restart of production was too large, and it would have been impossible to film, even if the team had a budget 2–3 times bigger, so the writers had to shorten it. When asked why the plot of Major Grom is so unoriginal and clichéd, Oleg Trofim replied that comics adaptations hadn't previously been filmed in Russia, and local filmmakers needed to master the genre and its basics first. Only once this happened would it be possible to deconstruct the genre and create something more original. During adaptation, the plot of the original comic underwent significant changes. For example, in the film, the character of Yulia Pchyolkina is not only the protagonist's love interest and damsel in distress , but also a full-fledged participant in the story line. Oleg Trofim commented: "It is not relevant anymore to show the heroine as a girl who does not want to decide anything, but wants a dress". In the film, the personality of Igor Grom also changed: in the comics, he is very noble and strictly follows a moral code, whereas in the film, he is more antiheroic and less scrupulous. The writers deliberately didn't show Grom's origin story , opting to only offer hints throughout the film. Roman Kotkov explained this by saying that superhero origin stories have become boring to audiences. The character of Razumovsky also underwent some changes, especially his motivation: in the film, the Plague Doctor sincerely, albeit using radical methods, wants to make the world a better place, whereas in the comics, he only uses justice as an excuse, while committing murders for his personal gain. The film contains a number of references to other Bubble comics, which are considered to be a setup for a potential Bubble cinematic universe. There is mention of a "hitman with rat" in the film—the nickname of Demonslayer, one of the key characters in the Bubble comic universe and the protagonist of the comic series of the same name. Holt International, a corporation that designed the Plague Doctor's suit, appears in the Red Fury comic series as a main antagonist. If Besedin wanted St. Petersburg to appear Americanized, Oleg Trofim made the city look closer to reality. Trofim lived in St. Petersburg for five years, and art director Dmitry Onishchenko is from there and knows the city well, and this helped when choosing locations. For over two months, Trofim and Onishchenko explored St. Petersburg to find streets that would best be suited for specific moments of the film. Oleg Trofim explained: "We know classical Petersburg, which is full of Baroque architecture and Art Nouveau . This is the city in which there was a revolution , and Soviet architecture has strongly settled there. We are also familiar with the gangster Petersburg from the 1990s, with its endless networks of courtyards . We were faced with the task of determining which Petersburg to show. As a result, we completely abandoned the Soviet legacy and that of the 1990s and concentrated on the historical part, the one that is timeless, the one that creates the image of St. Petersburg as a majestic palace city". In addition, the filmmakers decided to alter the layout of the city, as compared to the real St. Petersburg. To do this, they sketched a rough plan, marking the main locations in the film: the poor neighborhoods Grom visits, a police station, Razumovsky's office, and Grom's apartment. As a result, it turned out that Bolshaya Morskaya Street leads to Radishchev Street , Zhukov Street becomes Galernaya Street , and Nevsky Prospect does not seem to exist at all. Oleg Trofim complained that the logistics in St. Petersburg were inconvenient for filming, and that was why they had to create their own scenery. After the initial publicity in 2017, there was no new information about the film for two years. On 5 October 2019, continuation of work on the project was announced at IgroMir / Comic-Con Russia . It was announced that the director had been replaced, and instead of Vladimir Besedin, Oleg Trofim was at the helm of the production. The role of Major Grom also changed from Aleksander Gorbatov ( ru ) to Tikhon Zhiznevsky ( ru ). Additionally, significant changes had been made to the script. Filming resumed in Saint Petersburg and the film was initially planned to go on screen in 2019. However, in October of that year, it was announced that it would not be released on the due date. Filming was completed in December 2019. The official first trailer was released on 27 May 2020, a day after Saint Petersburg's anniversary celebrations. The music for the film was written by composer Roman Seliverstov. The film features symphonic music themes written by Seliverstov specifically for the production, as well as additional licensed songs. The symphonic portion of the soundtrack was recorded by the London Symphony Orchestra at Abbey Road Studios , in the United Kingdom. Seliverstov insisted that the music be recorded in this particular studio, since, in his opinion, audiences were accustomed to the sound of Hollywood films, and something similar had to be achieved in Major Grom . For the Plague Doctor's theme song, a special musical instrument was created, the "space cello", which resembles a cello but has only two strings, attached to sound boxes by long steel springs. This musical instrument produces an aggressive, metallic sound, which, according to the composer's plan, should emphasize the fearsome character of the antagonist. The creators decided to use only Russian-language songs for the soundtrack. Oleg Trofim tried to use songs that were "not yet spoiled by their popularity", to help audiences discover new music. During the opening credits of the film, a cover of the song " Peremen! " plays, performed by 15-year-old Taisia Ashmarova. The song heard during the end credits, " Poezd v ogne [ ru ] ", is performed by Levan Gorozia . List of tracks used in Major Grom: Plague Doctor , published by Yandex Music : At the 2020 Comic-Con Russia on 4 October, an official trailer was presented and it was announced that the film would be released in April 2021. Major Grom: Plague Doctor had a special screening on 26 March at the Aurora cinema in St. Petersburg. Its world premiere took place on 29 March at the Karo 11 October cinema centre in Moscow . Major Grom: Plague Doctor received mixed to positive reviews from Russian critics with review aggregator Kritikanstvo rating it 6,4/10 based on 39 reviews, while KinoPoisk reported a 71% critical approval rating based on 34 reviews. The movie was praised by Kanobu , Mir Fantastiki , Igromania , Rossiyskaya Gazeta , TASS , TJournal , DTF.ru, Elle Girl , and RBK Daily . Others, like Afisha , Film.ru , and TimeOut Russia published mixed reviews, while Nezavisimaya Gazeta , Kino Mail.ru , InterMedia , and Meduza were critical of the movie, and Kommersant published two conflicting reviews. Many critics praised the film for impressive visuals and the portrayal of a fictionalized version of Saint Petersburg, with an emphasis on the city's atmosphere. The acting, especially by Zhiznevsky and Aksyonova, was also met positively. However, many authors were uncomfortable with the movie's underlying message, which some believed to be anti-liberal and pro-police.After Roskomnadzor , Russia's media oversight agency, blocked the Telegram messaging service nationwide in 2018, Pavel Durov organized a flash mob , urging protesters to release paper airplanes on the streets on 22 April 2018 at 19:00. A very similar flash mob, including a mass release of paper airplanes, was organized in the first Major Grom teaser by the Plague Doctor, whose character in the comic is loosely based on Durov. Before the premiere, the website Byulleten Kinoprokatchika predicted that first-weekend box office receipts would amount to 200 million rubles. However, the film received half the box office and earned only 105 million in the first weekend. In the second weekend, about 66 million rubles were collected, and the total amount reached, taking into account the day of the premiere, rose to 222 million. The media suggested that the film could hardly recoup the announced budget of 640 million rubles by the end of its run. As a result, box office receipts amounted to only 317 million rubles in Russia and about 11 million in the CIS . To support Major Grom by word of mouth , Bubble comics fans organized a series of flash mobs on social media to draw attention to the film. Some fans bought up all the seats in cinemas to increase ticket sales, and an unknown person even rented a billboard on New Arbat Avenue , in the center of Moscow, where Major Grom fan tweets were shown. Nevertheless, despite low box office returns, the film gained popularity on streaming services: in May, it topped views on Kinopoisk HD , second only to Zack Snyder's Justice League . On Netflix , the film reached the top in a day, an extremely rare outcome for Russian cinema on this platform. By 8 July, the film entered the top ten on Netflix in 64 countries around the world, and took first place in fourteen countries.

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Contagious bovine pleuropneumonia

Contagious bovine pleuropneumonia ( CBPP – also known as lung plague ), is a contagious bacterial disease that afflicts the lungs of cattle , buffalo , zebu , and yaks . It is caused by the bacterium Mycoplasma mycoides , and the symptoms are pneumonia and inflammation of the lung membranes. The incubation period is 20 to 123 days. It was particularly widespread in the United States in 1879, affecting herds from several states. The outbreak was so severe that it resulted in a trade embargo by the British government, blocking U.S. cattle exports to Britain and Canada. This prompted the United States to establish the Bureau of Animal Industry , set up in 1884 to eradicate the disease, which it succeeded in doing by 1892. Louis Willems , a Belgian doctor, began pioneering work in the 1850s on animal inoculation against the disease. The bacteria are widespread in Africa, the Middle East, Southern Europe, as well as parts of Asia. It is an airborne species, and can travel up to several kilometres in the right conditions.Contagious bovine pleuropneumonia came to Australia on a shipment of five head of cattle from England in 1858, imported by one of Melbourne 's earliest settlers Mr Boadle. Three weeks later, a heifer named St Bees fell ill. Boadle called in a veterinarian who diagnosed it with the disease. The heifer died three weeks later. Whilst Boadle destroyed the herd, St Bees had already infected a bullock team grazing on a neighbouring property. Pleuropneumonia spread up the overland route to New South Wales , into Queensland and across northern Australia. It later arrived in Western Australia via a shipload of cattle. Only Tasmania was to remain free of the epidemic in Australia. A national management strategy was implemented in 1959, inspired by the work of chief veterinary officer of the Northern Territory Colonel Lionel Rose . A National Committee for the Control and Eradication of Pleuropneumonia was established, under the Chief of the CSIRO Division of Animal Health and Production, D A Gill. It defined infected, protected and disease-free areas. Once these were established, there were restrictions on the movement of cattle between zones. The national programme was empowered to employ veterinary officers, stock inspectors and police across Australia. Pleuropneumonia was announced to be eradicated in Australia by 1973.

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Plague

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Journal for Plague Lovers

Journal for Plague Lovers is the ninth studio album by Welsh alternative rock band Manic Street Preachers , released on 18 May 2009 by record label Columbia . Recorded between October 2008 and February 2009 and produced by Steve Albini and Dave Eringa , it features exclusively posthumously published lyrics by Richey Edwards , who disappeared on 1 February 1995 and was presumed deceased in 2008. It is the only Manic Street Preachers album in which the lyrics for every song were written solely by Edwards. The album received critical acclaim upon release and debuted at number 3 on the UK Albums Chart .The Manics posted the following message on their official website: All thirteen songs on the new record feature lyrics left to us by Richey. The brilliance and intelligence of the lyrics dictated that we had to finally use them. Topics include The Grande Odalisque by Ingres , Marlon Brando , Giant Haystacks , celebrity , consumerism and dysmorphia ; all reiterating the genius and intellect of Richard James Edwards. Wire, the band's de facto lyricist, had begun contributing musically to the songwriting process on the album, stating "I did write quite a bit of music. [...] I wrote all of 'William's Last Words', I wrote pretty much all of 'Marlon JD', I wrote the chorus for ' Peeled Apples ', the verse for 'She Bathed Herself in a Bath of Bleach'". The lyrics are taken from a folder of songs, haikus , collages and drawings Edwards gave to bassist-lyricist Nicky Wire a few weeks before he disappeared. Edwards also gave photocopies of the folder to singer-guitarist James Dean Bradfield and drummer Sean Moore . The band have described the Rymans folder as having a picture of Bugs Bunny drawn on the front emblazoned with the word ' opulence ' in capital letters. In promotional interviews for the album, Bradfield and Wire have revealed that the folder contains around twenty-eight songs. Four of these appeared on the 1996 album Everything Must Go : "Elvis Impersonator: Blackpool Pier", " Kevin Carter ", "Removables" and "Small Black Flowers that Grow in the Sky". Of the rest of the folder, Wire stated: There's probably between eight and ten maybe that were too impossible. Some of them are little haikus, four lines. "Dolphin-Friendly Tuna Wars", that's one; "Alien Orders/Invisible Armies", that's one [the band have recorded an instrumental that takes its title from this lyric]; "Young Men", which is quite Joy Division . They just didn't feel right. We'll probably put them all out in a book one day. There's not gonna be a Journal for Plague Lovers Two . The special version of the record does come with the original version of the tracks on there. So you can see the editing process, if there is any. The album was released with a Deluxe edition that included pages from Richey's journal. The table of contents page for Richey's journal is reproduced within the liner notes. Eighteen of the twenty-eight listings there, however, are removed using black felt-tip. There are only a limited number of pages from the journal that are reproduced in the liner notes. Several tracks refer to Edwards' time in a couple of hospitals in 1994. Among them is "She Bathed Herself in a Bath of Bleach", of which James Dean Bradfield said to the NME : "There're some people he met when he was in one of the two places having treatment and I think he just digested other people's stories and experiences." The final track, "William's Last Words", has been compared to a suicide note , and although Nicky Wire rejects this suggestion Bradfield observes, "you can draw some pretty obvious conclusions from the lyrics." Wire, who admitted finding the task of editing this song "pretty choking", eventually composed the music and sang lead vocals after Bradfield found himself unsuited to the task. The album features several cultural references, including a passage from the film The Machinist , which features in the song " Peeled Apples " and a passage taken from the film The Virgin Suicides , which features in the song "Doors Closing Slowly". Bradfield commented that Journal for Plague Lovers was an attempt to finally secure the legacy of their former member Richey Edwards and the result was that, during the recording process, it was as close to feeling his presence since his disappearance: "There was a sense of responsibility to do his words justice. That was part of the whole thing of letting enough time lapse. Once we actually got into the studio, it almost felt as if we were a full band; it [was] as close to him being in the room again as possible." Stylistically, the album features a post-punk and alternative rock sound reminiscent of The Holy Bible . Cam Lindsay of Exclaim! proclaimed the record to be a "relentlessly exploratory piece of art rock ". The album's opening track " Peeled Apples " was played for the first time on Zane Lowe 's BBC Radio 1 show on 25 March 2009. During an interview with Lowe, Wire said there would be no singles released from the album. "Jackie Collins Existential Question Time" was aired on XFM and Kerrang! Radio on 30 March. It was also embedded on the band's official website. In 2020, an in-depth analysis of Edwards' lyrics on the album, by Guy Mankowski (with input from Edwards' sister, Rachel) was published in the journal 'Punk & Post-Punk'. Mankowski concluded that 'in Edwards' lyrics, a number of metaphors reconfigure the malleability of the physical body and expand the concept of how self-fashioning can be applied in relation to it'. The album was released on 18 May 2009 on CD , a two-disc CD edition, download and LP . The album entered the UK Album Chart at number 3, selling 34,707 copies in the first week. It charted within the Top 20 in Ireland and in Norway. So far the album has been certified Silver in the UK. A Deluxe Edition CD was released, includes a second disc with demo versions of all thirteen album songs and a hardback 36-page booklet featuring Edwards' original lyrics and artwork. These lyrics, in the process of adaptation to the album, had often been substantially edited and rearranged. This version of the album is missing the hidden track "Bag Lady", whose lyrics are however not included on the single disc edition. The Japanese edition of the album was released on 13 May 2009, and features two exclusive bonus tracks. The download version includes a bonus remix by the NYPC and an acoustic version of the title track. The album cover art uses an original painting, Stare (2005), by Jenny Saville , who also contributed artwork for The Holy Bible . The top four UK supermarkets stocked the CD in a plain slipcase, after the cover was deemed "inappropriate" due to the belief that the red on the boy's face was blood. Bradfield said the decision was "utterly bizarre", and commented: You can have lovely shiny buttocks and guns everywhere in the supermarket on covers of magazines and CDs, but you show a piece of art and people just freak out. The album cover art placed second in a 2009 poll for Best Art Vinyl . The album cover art uses an original painting, Stare (2005), by Jenny Saville , who also contributed artwork for The Holy Bible . The top four UK supermarkets stocked the CD in a plain slipcase, after the cover was deemed "inappropriate" due to the belief that the red on the boy's face was blood. Bradfield said the decision was "utterly bizarre", and commented: You can have lovely shiny buttocks and guns everywhere in the supermarket on covers of magazines and CDs, but you show a piece of art and people just freak out. The album cover art placed second in a 2009 poll for Best Art Vinyl . Contrary to worries on the part of Nicky Wire that Journal for Plague Lovers "could seriously damage" the band, and in spite of initial suspicions that the album constituted "a blatant attempt to recapture the glory days of an album [they] released 15 years ago ", reviews were ultimately highly favourable. At Metacritic , which assigns a normalized rating out of 100 to reviews from mainstream critics, the album received an average score of 85 out of 100 based on eighteen reviews, which indicates "universal acclaim". Journal for Plague Lovers scored a rare five-star review in Q magazine, which argued that by "breathing life into Richey Edwards's own last words", the band "crafted not a memorial but a celebration". Retrospectively, the publication named the album the fifth best record of 2009, declaring it one of the band's "finest and most heartfelt moments". John Doran from NME awarded the record an 8/10 grade, arguing that Journal for Plague Lovers should not be burdened with expectations of becoming " The Holy Bible Mark II" but was simply "an outstanding album in its own right". The magazine named the album the 14th best of the year. Uncut , meanwhile, argued that the record brought a "sense of closure" to the legacy of Richey Edwards, describing it as a "brave, compelling record that stands shoulder to shoulder with the Manics' best", and the twenty-third best album of 2009. Response from news publications was mostly positive, with Caroline Sullivan of The Guardian describing it as "a passionate rock album that honours the past yet is very much of the present", and Simon Price of The Independent declared Journal for Plague Lovers "the album of 2009 – hands down, no contest". David Cheal of The Daily Telegraph was critical, however, accusing them of being "a plodding indie-rock trio whose ambition has consistently outstripped their ability" and giving the record only two stars out of five. Elsewhere, Journal for Plague Lovers earned recognition as a return to form begun on previous album Send Away the Tigers ; for example, from Pitchfork ' s Joe Tangari, who summarized the album thus: "Even if it were the desperate or cynical move some people have claimed it is, there's no denying that purging Edwards' old lyric folder has helped the band create its best album in a decade. Quite simply, they haven't sounded so focused or so purposeful in a long, long time, and they are at their best with a sense of purpose underpinning their music." Likewise, Stephen Thomas Erlewine of AllMusic remarked that "they were making inroads in this direction on 2007's Send Away the Tigers – for tight, clanking, cantankerous guitars" and commended the album for its sense of hope: " Journal for Plague Lovers winds up being The Holy Bible in reverse: every moment of despair is a reason to keep on living instead of an excuse to pack it all in." Journal for Plague Lovers was placed at number 10 on Metacritic 's list of the fifty best-reviewed albums of 2009, and was placed on numerous critics' ranking lists for the year, particularly from British music magazines:Journal for Plague Lovers was placed at number 10 on Metacritic 's list of the fifty best-reviewed albums of 2009, and was placed on numerous critics' ranking lists for the year, particularly from British music magazines:All lyrics are written by Richey Edwards ; all music is composed by Manic Street Preachers ( James Dean Bradfield , Sean Moore , Nicky Wire )Manic Street Preachers Additional personnel Andy Walters – string arrangement, strings Katherine Thomas – harp Joanna Parkhurst – strings Bernard Kane – strings Nathan Stone – strings Technical personnel * Sales figures based on certification alone.Tracks from Journal for Plague Lovers have been remixed by a number of artists, and the Journal for Plague Lovers Remixes EP was released on 15 June 2009. Martin Noble of the band British Sea Power remixed the song "Me and Stephen Hawking"; Andrew Weatherall remixed " Peeled Apples ", which he has described as "sounding like Charlie Watts playing with PiL "; The Horrors remixed "Doors Closing Slowly"; NYPC remixed the song "Marlon J.D" and the EP also features remixes by Patrick Wolf , Underworld , Four Tet , Errors , Adem , Optimo and Fuck Buttons .

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Plague

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Manchurian plague

The Manchurian plague was a pneumonic plague that occurred mainly in Manchuria in 1910–1911. It killed 60,000 people, stimulating a multinational medical response and the wearing of the first personal protective equipment (PPE).The plague is thought to have originated from a tarbagan marmot infected with bacterial pneumonia. Tarbagan marmots were hunted for their fur in Manchuria. It was an airborne spread disease and was incredibly deadly, with a near 100 percent mortality rate. Its spread was magnified by marmot hunters gathering in the bitter winter months, and the eventual travel of migrant workers during the Chinese New Year . Russia and Japan both had economic interests in the region and needed to cooperate with Chinese authorities. The Cambridge -trained doctor Wu Lien-teh led Chinese efforts to end the plague, and promoted quarantine and the wearing of cloth face masks . He also convened the International Plague Conference in Mukden in April 1911, the first major event of its kind that brought together an international team of scientists concerned with disease control. The Chinese government also sought the support of foreign doctors, a number of whom died as a consequence of the disease. In Harbin, this included the Frenchman Gérald Mesny, from the Imperial Medical College in Tientsin, who disputed Wu's recommendation of masks; a few days later, he died after catching the plague when visiting patients without wearing a mask. Another was the 26-year-old Arthur F. Jackson, a United Free Church of Scotland missionary doctor , who fell ill within eight days of inspecting and quarantining hundreds of poor laborers; he died two days later in Mukden. In the end, the death toll reached some 60,000 lives. The hardest hit cities included Changchun , Harbin , and Mukden. Although the disease was largely confined to Manchuria, cases were found elsewhere in cities such as Beijing and Tianjin . The Manchurian plague is believed to have highlighted the importance of a multinational medical response, setting precedents for organizations such as the World Health Organization . Wu Lien-teh's widespread promotion of cloth plague mask -wearing by doctors, nurses, patients, contacts, and (to the degree that it was possible) the population at large was the first time such an epidemic containment measure had been attempted. The event was also influential in establishing the use of personal protective equipment to stop the spread of disease, and is credited for the origins of the modern hazmat suit . Parallels have also been made between the management and control of the Manchurian plague and other outbreaks of infectious disease such as the Ebola epidemic in West Africa (2013–2016) and COVID-19 pandemic (2019–present) .

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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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Yellow fever

Yellow fever is a viral disease of typically short duration . In most cases, symptoms include fever , chills , loss of appetite , nausea , muscle pains—particularly in the back—and headaches . Symptoms typically improve within five days. In about 15% of people, within a day of improving the fever comes back, abdominal pain occurs, and liver damage begins causing yellow skin . If this occurs, the risk of bleeding and kidney problems is increased. The disease is caused by the yellow fever virus and is spread by the bite of an infected mosquito . It infects humans, other primates , and several types of mosquitoes. In cities, it is spread primarily by Aedes aegypti , a type of mosquito found throughout the tropics and subtropics . The virus is an RNA virus of the genus Flavivirus . The disease may be difficult to tell apart from other illnesses, especially in the early stages. To confirm a suspected case, blood-sample testing with a polymerase chain reaction is required. A safe and effective vaccine against yellow fever exists, and some countries require vaccinations for travelers. Other efforts to prevent infection include reducing the population of the transmitting mosquitoes. In areas where yellow fever is common, early diagnosis of cases and immunization of large parts of the population are important to prevent outbreaks . Once a person is infected, management is symptomatic; no specific measures are effective against the virus. Death occurs in up to half of those who get severe disease. In 2013, yellow fever was estimated to have caused 130,000 severe infections and 78,000 deaths in Africa. Approximately 90 percent of an estimated 200,000 cases of yellow fever per year occur in Africa. Nearly a billion people live in an area of the world where the disease is common. It is common in tropical areas of the continents of South America and Africa, but not in Asia. Since the 1980s, the number of cases of yellow fever has been increasing. This is believed to be due to fewer people being immune, more people living in cities, people moving frequently, and changing climate increasing the habitat for mosquitoes. The disease originated in Africa and spread to the Americas starting in the 17th century with the European trafficking of enslaved Africans from sub-Saharan Africa. Since the 17th century, several major outbreaks of the disease have occurred in the Americas, Africa, and Europe. In the 18th and 19th centuries, yellow fever was considered one of the most dangerous infectious diseases ; numerous epidemics swept through major cities of the US and in other parts of the world. In 1927, yellow fever virus became the first human virus to be isolated. Yellow fever begins after an incubation period of three to six days. Most cases cause only mild infection with fever, headache, chills, back pain, fatigue, loss of appetite, muscle pain, nausea, and vomiting. In these cases, the infection lasts only three to six days. But in 15% of cases, people enter a second, toxic phase of the disease characterized by recurring fever, this time accompanied by jaundice due to liver damage , as well as abdominal pain . Bleeding in the mouth, nose, eyes, and the gastrointestinal tract cause vomit containing blood , hence one of the names in Spanish for yellow fever, vómito negro ("black vomit"). There may also be kidney failure, hiccups, and delirium. Among those who develop jaundice, the fatality rate is 20 to 50%, while the overall fatality rate is about 3 to 7.5%. Severe cases may have a mortality rate greater than 50%. Surviving the infection provides lifelong immunity , and normally results in no permanent organ damage. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. {| class="infobox biota" style="text-align: left; width: 200px; font-size: 100%" |- ! Yellow fever virus |- | |- | Flavivirus structure and genome |- |- |- |- ! Virus classification |- |(unranked): | Virus |- | Realm : | Riboviria |- |Kingdom: | Orthornavirae |- |Phylum: | Kitrinoviricota |- |Class: | Flasuviricetes |- |Order: | Amarillovirales |- |Family: | Flaviviridae |- |Genus: | Flavivirus |- | Species: | |- |- |- |- |- |- |- |- |- |- |- |- |- |- |- |} Yellow fever is caused by Yellow fever virus (YFV), an enveloped RNA virus 40–50 nm in width, the type species and namesake of the family Flaviviridae . It was the first illness shown to be transmissible by filtered human serum and transmitted by mosquitoes, by American doctor Walter Reed around 1900. The positive- sense , single-stranded RNA is around 10,862 nucleotides long and has a single open reading frame encoding a polyprotein . Host proteases cut this polyprotein into three structural (C, prM, E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding genes in the genome . Minimal YFV 3 ′ UTR region is required for stalling of the host 5 ′ -3 ′ exonuclease XRN1. The UTR contains PKS3 pseudoknot structure, which serves as a molecular signal to stall the exonuclease and is the only viral requirement for subgenomic flavivirus RNA (sfRNA) production. The sfRNAs are a result of incomplete degradation of the viral genome by the exonuclease and are important for viral pathogenicity. Yellow fever belongs to the group of hemorrhagic fevers . The viruses infect, amongst others, monocytes , macrophages , Schwann cells , and dendritic cells . They attach to the cell surfaces via specific receptors and are taken up by an endosomal vesicle . Inside the endosome , the decreased pH induces the fusion of the endosomal membrane with the virus envelope . The capsid enters the cytosol , decays, and releases the genome. Receptor binding, as well as membrane fusion, are catalyzed by the protein E, which changes its conformation at low pH, causing a rearrangement of the 90 homo dimers to 60 homo trimers . After entering the host cell, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the so-called vesicle packets. At first, an immature form of the virus particle is produced inside the ER, whose M-protein is not yet cleaved to its mature form, so is denoted as precursor M (prM) and forms a complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin , which cleaves prM to M. This releases E from the complex, which can now take its place in the mature, infectious virion . Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. After transmission from a mosquito, the viruses replicate in the lymph nodes and infect dendritic cells in particular. From there, they reach the liver and infect hepatocytes (probably indirectly via Kupffer cells ), which leads to eosinophilic degradation of these cells and to the release of cytokines . Apoptotic masses known as Councilman bodies appear in the cytoplasm of hepatocytes. Fatality may occur when cytokine storm , shock , and multiple organ failure follow. Yellow fever is most frequently a clinical diagnosis , based on symptomatology and travel history. Mild cases of the disease can only be confirmed virologically. Since mild cases of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea, and vomiting 6–10 days after leaving the affected area) is treated seriously. If yellow fever is suspected, the virus cannot be confirmed until 6–10 days following the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction , where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma ; this can take 1–4 weeks. Serologically, an enzyme-linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG titer (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a four-fold increase in IgG titer is considered sufficient indication for yellow fever. As these tests can cross-react with other flaviviruses, such as dengue virus , these indirect methods cannot conclusively prove yellow fever infection. Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens . Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable post mortem to confirm the cause of death. In a differential diagnosis , infections with yellow fever must be distinguished from other feverish illnesses such as malaria . Other viral hemorrhagic fevers , such as Ebola virus , Lassa virus , Marburg virus , and Junin virus , must be excluded as the cause. Personal prevention of yellow fever includes vaccination and avoidance of mosquito bites in areas where yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes and measures to control mosquitoes. Programmes for distribution of mosquito nets for use in homes produce reductions in cases of both malaria and yellow fever. Use of EPA-registered insect repellent is recommended when outdoors. Exposure for even a short time is enough for a potential mosquito bite. Long-sleeved clothing, long pants, and socks are useful for prevention. The application of larvicides to water-storage containers can help eliminate potential mosquito breeding sites. EPA-registered insecticide spray decreases the transmission of yellow fever. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. As with other Flavivirus infections, no cure is known for yellow fever. Hospitalization is advisable and intensive care may be necessary because of rapid deterioration in some cases. Certain acute treatment methods lack efficacy: passive immunization after the emergence of symptoms is probably without effect; ribavirin and other antiviral drugs , as well as treatment with interferons , are ineffective in yellow fever patients. Symptomatic treatment includes rehydration and pain relief with drugs such as paracetamol (acetaminophen). However, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are often avoided because of an increased risk of gastrointestinal bleeding due to their anticoagulant effects. Yellow fever is common in tropical and subtropical areas of South America and Africa. Worldwide, about 600 million people live in endemic areas. The WHO estimates 200,000 cases of yellow fever worldwide each year. About 15% of people infected with yellow fever progress to a severe form of the illness, and up to half of those will die, as there is no cure for yellow fever. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. In the hamster model of yellow fever, early administration of the antiviral ribavirin is an effective treatment of many pathological features of the disease. Ribavirin treatment during the first five days after virus infection improved survival rates, reduced tissue damage in the liver and spleen , prevented hepatocellular steatosis , and normalised levels of alanine aminotransferase, a liver damage marker. The mechanism of action of ribavirin in reducing liver pathology in yellow fever virus infection may be similar to its activity in treatment of hepatitis C , a related virus. Because ribavirin had failed to improve survival in a virulent rhesus model of yellow fever infection, it had been previously discounted as a possible therapy. Infection was reduced in mosquitoes with the wMel strain of Wolbachia . Yellow fever has been researched by several countries as a potential biological weapon .

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Plague

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Plague Park

Plague Park is Handsome Furs ' first full-length album. Handsome Furs is Dan Boeckner ( Wolf Parade , Atlas Strategic ) and his wife, Alexei Perry. The record is named after the park Ruttopuisto , situated in Helsinki , Finland . Commonly referred to as "Plague Park", the park grounds sit atop a mass grave that contains the victims of the 1710 plague. The recordings combine plaintive, angst-filled singing with loud, electronic accompaniment and heavy percussion. All tracks are written by Dan Boeckner and Alexei PerryPlague Park has received generally positive reviews. On the review aggregate site Metacritic , the album has a score of 72 out of 100, indicating "generally favorable reviews". The following people contributed to Plague Park: Handsome Furs - Audio Engineer, Audio Production H.F. - Engineer Chad Jones - Audio Engineer, Audio Production, Help Harris Newman - Mastering Arlen Thompson - Audio Engineer, Audio Production, Engineer, Mixing, ProducerHandsome Furs - Audio Engineer, Audio Production H.F. - Engineer Chad Jones - Audio Engineer, Audio Production, Help Harris Newman - Mastering Arlen Thompson - Audio Engineer, Audio Production, Engineer, Mixing, ProducerTrack nine is listed on Sub Pop's website as "The Radio's Hot Sun", but in the physical liner of the album, is listed as "In The Radio's Hot Sun".

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Plague

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The Plagues of Breslau

Patryk Vega Maciej Sojka Grzegorz Esz Jerzy Dzięgielewski 28 November 2018 ( 2018-11-28 ) The Plagues of Breslau ( Polish : Plagi Breslau ) is a 2018 Polish crime thriller directed by Patryk Vega. It premiered on 24 November 2018. The title corresponds to the former name of Wrocław , which from 1741 until 1945 was "Breslau". The film and plot were loosely based on a series of crime novels by Marek Krajewski , who often incorporates Breslau's pre- war crime scene into his works.Set in the city of Wrocław , detective Helena Rus finds a corpse sewn in a cowhide . The murders continue for the next five days and each victim is killed at precisely 18:00 (6 p.m.). The Polish police along with Helena Rus attempt to find and capture the serial killer before he strikes again.

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Plague

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Plague (1979 film)

July 11, 1979 ( 1979-07-11 ) Plague is a 1979 Canadian-American science fiction film about a genetic engineering accident, a fertilizing bacterium that escapes from a laboratory in Canada. The film is also known internationally as Induced Syndrome (UK), M-3: The Gemini Strain or Mutation (USA). When a group of scientist work to develop a bacterium to increase food yields is delayed by bureaucratic processes, Dr. Celia Graham (Brenda Donahue) ignores protocols and develops a bacteria called M3. The new bacteria is accidentally released and causes sickness in children and death in others around the world. The disease is highly contagious, and the epidemic increases geometrically. Dr. Graham is killed by the virus, while an infected but unaffected woman spreads the disease in the manner of Typhoid Mary . Scientists Dr. Bill Fuller (Daniel Pilon) and Dr. Jessica Morgan (Kate Reid) work tirelessly to develop an antidote to stop the contagion . The film was released theatrically in the United States by Group 1 International Distribution Organization Ltd. in January 1979. The film was released on DVD in the United Kingdom from Prism Leisure Corporation as part of a 4-film collection (with Bram Stoker's Legend of the Mummy 2 , Howling IV: The Original Nightmare and Night of the Living Dead ) on October 7, 2002. It was also release individually from Prism Leisure, and by Digital Entertainment Ltd in 2008. As of 2018, the film has still not been officially released on DVD in the United States.Creature Feature gave the movie two out of five stars. TV Guide found that the focus on the scientists in charge of finding the cure to be a plus, that overall the movie was laughable. Moira also gave the movie two stars, finding it dull and offering nothing original in the plague movie genre. It also found the production values to be shabby and its portrayal of a biolab 's operating procedures to be lacking.Nominated for best picture at the 1979 Catalonian International Film Festival and winner of the best screenplay at the same festival.

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Plague

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How to Survive a Plague

January 22, 2012 ( 2012-01-22 ) (Sundance Film Festival) September 21, 2012 ( 2012-09-21 ) (United States (limited)) How to Survive a Plague is a 2012 American documentary film about the early years of the AIDS epidemic , and the efforts of activist groups ACT UP and TAG . It was directed by David France , a journalist who covered AIDS from its beginnings. France's first film, it was dedicated to his partner Doug Gould who died of AIDS-related pneumonia in 1992. The documentary was produced using more than 700 hours of archived footage which included news coverage, interviews as well as film of demonstrations, meetings and conferences taken by ACT UP members themselves. France says they knew what they were doing was historic, and that many of them would die. The film opened in selected theatres across the United States on September 21, 2012, also includes footage of a demonstration during mass at St. Patrick's Cathedral in 1989. People featured in the film include:Beginning at the start of the HIV/AIDS epidemic in New York City, the documentary follows a group of AIDS activists and founders of the AIDS group ACT UP , and follows their struggle for response from the United States government and medical establishment in developing effective HIV/AIDS medications. Activists took it upon themselves to convince the FDA to approve drugs which could slow or even halt the HIV virus, and demanded that drug trials (which would usually take 7–10 years) be shortened so potentially life-saving treatments could be made available. The film also documents the underground market for HIV drugs: many people relied on drugs imported from other countries, which were believed to potentially slow down the HIV virus despite not being FDA-approved. At the time, the only drug available to slow the progression of HIV was AZT , which in many cases was toxic to HIV-infected people. The cost of AZT was about $10,000 per year in the late 1980s. ACT UP's efforts led to the creation of the International AIDS Conference . Eventually, DDI , an alternative to AZT that did not cause blindness, was released by the FDA despite not going through a full-length safety trial. HIV activists also protested the immigration policies banning HIV-positive people from immigrating to the United States as being discriminatory and homophobic . When existing drugs proved ineffective as treatment for HIV, TAG lobbied for more research into the HIV virus. In 1996, protease inhibitors were released. These consist of a combination of drugs which lower the HIV viral load in patients more than any drug had before. It was considered a breakthrough in HIV and AIDS research and continues to be used as a treatment for HIV and AIDS. The documentary included interviews with HIV activists, physicians and members of underground organizations as well as clips of the protests, meetings and news coverage taking place during the 1980s and 1990s. France's book of the same title, expanding on the material, events, and people covered in the film, was published in 2016 to critical acclaim. It was described as "the definitive book on AIDS activism", was long-listed for the Andrew Carnegie Medal for Excellence and was named to numerous best-of and top-ten lists, including the New York Times 100 Notable Books for 2016. Currently, the film has a rating of 98% on Rotten Tomatoes , and an average score of 8.40/10, based on 80 reviews. The website's critical consensus states, "Angry, powerful, and stirring, How to Survive a Plague is a brilliantly constructed documentary about the activists who pushed for action to combat the AIDS epidemic". It also has a score of 86 out of 100 on Metacritic , based on 23 critics, indicating "universal acclaim". AIDS historian Sarah Schulman has criticized the film for its focus on wealthy, white activists over the "different kinds of people from every class and background" involved in ACT UP. How to Survive a Plague received awards for best documentary of 2012 from the Gotham Independent Film Awards , GALECA: The Society of LGBTQ Entertainment Critics , and from the Boston Society of Film Critics . The Independent Spirit Awards nominated it for Best Documentary . It was nominated for the Academy Award for Best Documentary Feature at the 85th Academy Awards . The film also won a GLAAD Media Award for Outstanding Documentary and a Peabody Award . It was nominated for a Directors Guild Award and the Grand Jury Prize at the Sundance Film Festival. Critic A. O. Scott of The New York Times named How to Survive a Plague one of the best five documentaries of 2012. Fellow New York Times critic Stephen Holden called the documentary the eighth best film of 2012. It also won Documentary of the Year at Attitude magazine's Attitude Awards 2013.Currently, the film has a rating of 98% on Rotten Tomatoes , and an average score of 8.40/10, based on 80 reviews. The website's critical consensus states, "Angry, powerful, and stirring, How to Survive a Plague is a brilliantly constructed documentary about the activists who pushed for action to combat the AIDS epidemic". It also has a score of 86 out of 100 on Metacritic , based on 23 critics, indicating "universal acclaim". AIDS historian Sarah Schulman has criticized the film for its focus on wealthy, white activists over the "different kinds of people from every class and background" involved in ACT UP. How to Survive a Plague received awards for best documentary of 2012 from the Gotham Independent Film Awards , GALECA: The Society of LGBTQ Entertainment Critics , and from the Boston Society of Film Critics . The Independent Spirit Awards nominated it for Best Documentary . It was nominated for the Academy Award for Best Documentary Feature at the 85th Academy Awards . The film also won a GLAAD Media Award for Outstanding Documentary and a Peabody Award . It was nominated for a Directors Guild Award and the Grand Jury Prize at the Sundance Film Festival. Critic A. O. Scott of The New York Times named How to Survive a Plague one of the best five documentaries of 2012. Fellow New York Times critic Stephen Holden called the documentary the eighth best film of 2012. It also won Documentary of the Year at Attitude magazine's Attitude Awards 2013.

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Plague

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Red Plague

" Red Plague " ( Polish : "Czerwona Zaraza" ) is a Polish poem, written in 1944 by Józef Szczepański , a World War II –era poet, who died during the Warsaw Uprising . "Red Plague" inspired Polish Oscar -winning film director Andrzej Wajda to create the movie Kanał . The poem, which described the dashed hopes of Warsaw insurgents that the Red Army would save them, was banned in the People's Republic of Poland due to its anti-Soviet context; during the Joseph Stalin era the very possession of it was punishable by imprisonment. Szczepanski wrote it on August 29, 1944, just a few days before his death (he died on September 10). The author expressed his anger at the Red Army, telling the tale of desperation, of being brought to a point that the only way to save anything from this total ruin that engulfed Poland (with the Battle of Warsaw being the backdrop and an end game for Polish resistance fighters who made that last stand) was to surrender Poland to their worst, eternal and most despised of the enemies, one that could have helped but chose not to, one that was responsible for the majority of historical calamities that have befallen Poland, the source of all evil and darkness, a place that takes, never gives, a giant succubus that drained the Polish peoples' soul, sapped their spirit and feasted upon Poland's rotting carcass for centuries). Red Army units, which were positioned on the eastern bank of the Vistula , did not help the insurgents: We are waiting for you, red plague... you will be salvation welcomed with revulsion... we are waiting for you, our eternal enemy... bloody murderer of so many of our brethren.... Your red, victorious army has been lying at the bright feet of burning Warsaw and is feeding its soul with bloody pain of a handful of madmen who are dying in the ruins. "Red Plague" was recorded by De Press on their album Myśmy Rebelianci in 2009. Excerpts of the poem were used by a Polish rock band, Lao Che , in its Warsaw Uprising album (in the song " Czerniakow " ).

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Plague

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The Plague Within

The Plague Within is the fourteenth studio album by British gothic metal band Paradise Lost . It was released on 1 June 2015 in Europe and 2 June 2015 in North America via Century Media Records . This album shows the band returning to their death-doom roots, mixed with elements of the gothic metal sound they are most known for.All lyrics are written by Nick Holmes ; all music is composed by Greg MackintoshNick Holmes – vocals Greg Mackintosh – lead guitar Aaron Aedy – rhythm guitar Steve Edmondson – bass Adrian Erlandsson – drums Nick Holmes – vocals Greg Mackintosh – lead guitar Aaron Aedy – rhythm guitar Steve Edmondson – bass Adrian Erlandsson – drums

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Plague

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Brotha Lynch Hung

Rapper record producer songwriter Kevin Danell Mann (born January 10, 1969), better known by his stage name Brotha Lynch Hung , is an American rapper, songwriter and record producer from Sacramento, California who has been described as "the creator of horrorcore rap." He is also a former 24th Street Garden Blocc Crip gang member, which is a Crip -affiliated street gang based in Meadowview, Sacramento .Mann grew up in Sacramento. He became a fan of East Coast rappers such as Rakim and Slick Rick . He started rapping at the age of 13. He became a member of the 24 Street Garden Blocc Crips by age 16 during the 1980s. He was once shot in the side after trying to break up a confrontation between a Crip and a Blood at a house party ; the bullet was never removed. Although often credited as being a major pioneer and even the main creator of the horrorcore rap genre, Mann himself has claimed that his style is less literally "horrorcore" and instead falls more directly under his own distinct category or sub-category of rap called rip gut, which specifically emphasizes (usually) graphic violence. The ripgut genre itself reportedly stemmed from his love of meat , but this lyrical style is also sometimes considered to be either associated with or connected to the common thoughts and feelings occasionally experienced during manic and/or violent states of mind brought on by the use of certain illicit drugs such as phencyclidine (PCP). In 1993, Brotha Lynch Hung signed to Black Market Records and released his debut EP, 24 Deep . followed by the album Season of da Siccness in 1995. 24 Deep reached No. 91 on Billboard' s R&B/Hip-Hop Albums chart, and Season of da Siccness reached No. 26. [ citation needed ] Brotha Lynch Hung appeared on several No Limit Records 1997 releases such as West Coast Bad Boyz II , I'm Bout It , and Mr. Serv-On's Life Insurance . Brotha Lynch Hung wrote and produced all of his appearances. 2000 marked the release of Brotha Lynch Hung's first and only starring role in a film, Now Eat , a horror comedy based on his music, while an album of the same name was released to coincide with the film. After Lynch released his second LP, Loaded , he began a long-standing feud with label head Cedric Singleton over the rights to his back catalog. During the sessions of EBK4 , a home invasion took place during which the thieves had taken songs still in progress [ citation needed ] . Due to the disputes, Cedric Singleton released EBK4 without Lynch's permission, using other artists off the label to complete unfinished songs where extra verses were needed. This practice continued with his next solo album The Virus in 2001, and three compilations, Appearances: Book 1 , Remains: Book II , and Book III , in 2002. Brotha Lynch Hung left Black Market in 2003 and released his first album independent from the label, Lynch by Inch: Suicide Note . Lynch had three releases on different record labels during this period. He released Lynch by Inch: Suicide Note in June 2003 under Madesicc Music. He then released The Ripgut Collection compilation on Madesicc in 2007 and Snuff Tapes "mix tape" in 2008 available on Siccness.net. Both releases enter the Top R&B/Hip-Hop Albums peaking at 55 and 78 respectively. In May 2009, Mann signed a contract with Strange Music . He released three albums on the label, Dinner and a Movie (2010), Coathanga Strangla (2011), and Mannibalector (2013). The label offered to extend his contract after the third album was released, but he decided to stay on his own label Madesicc Musicc. After leaving Strange Music, Brotha Lynch Hung released several independent EPs and a collaboration album with Ren Da Heatmonsta titled Premeditated (2017). Brotha Lynch Hung is scheduled to release Kevlar: Season of da Siccness 2 under RBC Records, which has been teased as early as 2019. In 2023, Brotha Lynch Hung released a compilation album titled Choice Kuttz: Da Best of Brotha Lynch Hung , marking his return to the hip-hop scene.Although often credited as being a major pioneer and even the main creator of the horrorcore rap genre, Mann himself has claimed that his style is less literally "horrorcore" and instead falls more directly under his own distinct category or sub-category of rap called rip gut, which specifically emphasizes (usually) graphic violence. The ripgut genre itself reportedly stemmed from his love of meat , but this lyrical style is also sometimes considered to be either associated with or connected to the common thoughts and feelings occasionally experienced during manic and/or violent states of mind brought on by the use of certain illicit drugs such as phencyclidine (PCP).In 1993, Brotha Lynch Hung signed to Black Market Records and released his debut EP, 24 Deep . followed by the album Season of da Siccness in 1995. 24 Deep reached No. 91 on Billboard' s R&B/Hip-Hop Albums chart, and Season of da Siccness reached No. 26. [ citation needed ] Brotha Lynch Hung appeared on several No Limit Records 1997 releases such as West Coast Bad Boyz II , I'm Bout It , and Mr. Serv-On's Life Insurance . Brotha Lynch Hung wrote and produced all of his appearances. 2000 marked the release of Brotha Lynch Hung's first and only starring role in a film, Now Eat , a horror comedy based on his music, while an album of the same name was released to coincide with the film. After Lynch released his second LP, Loaded , he began a long-standing feud with label head Cedric Singleton over the rights to his back catalog. During the sessions of EBK4 , a home invasion took place during which the thieves had taken songs still in progress [ citation needed ] . Due to the disputes, Cedric Singleton released EBK4 without Lynch's permission, using other artists off the label to complete unfinished songs where extra verses were needed. This practice continued with his next solo album The Virus in 2001, and three compilations, Appearances: Book 1 , Remains: Book II , and Book III , in 2002. Brotha Lynch Hung left Black Market in 2003 and released his first album independent from the label, Lynch by Inch: Suicide Note .Lynch had three releases on different record labels during this period. He released Lynch by Inch: Suicide Note in June 2003 under Madesicc Music. He then released The Ripgut Collection compilation on Madesicc in 2007 and Snuff Tapes "mix tape" in 2008 available on Siccness.net. Both releases enter the Top R&B/Hip-Hop Albums peaking at 55 and 78 respectively.In May 2009, Mann signed a contract with Strange Music . He released three albums on the label, Dinner and a Movie (2010), Coathanga Strangla (2011), and Mannibalector (2013). The label offered to extend his contract after the third album was released, but he decided to stay on his own label Madesicc Musicc. After leaving Strange Music, Brotha Lynch Hung released several independent EPs and a collaboration album with Ren Da Heatmonsta titled Premeditated (2017). Brotha Lynch Hung is scheduled to release Kevlar: Season of da Siccness 2 under RBC Records, which has been teased as early as 2019. In 2023, Brotha Lynch Hung released a compilation album titled Choice Kuttz: Da Best of Brotha Lynch Hung , marking his return to the hip-hop scene.In September 1996, Joseph Edward "Bubba" Gallegos, an 18-year-old man from Bayfield, Colorado , killed his friends after repeatedly listening to Brotha Lynch Hung's song "Locc 2 da Brain". He was in turn killed by police. His minister suggested that the music played a role in the killings. 24 Deep (1993) Bullet Maker (2016) Torment (2019) The Turnmanator (2020) Fundamentals Of Ripgut Cannibalizum The Vault (2020) Fatal (2021)24 Deep (1993) Bullet Maker (2016) Torment (2019) The Turnmanator (2020) Fundamentals Of Ripgut Cannibalizum The Vault (2020) Fatal (2021)Appearances: Book I (2002) Remains: Book II (2002) Book III (2002)

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Plague (song)

" Plague " is a song by Canadian electronic music band, Crystal Castles . It is the first single of the band's 2012 album, (III) . On June 9, 2012, it was made available for free download on the duo's SoundCloud page. The song debuted at the band's live performance at Parklife Festival in Manchester , England, in June 2012. The band posted a Soundcloud link to the song on their Facebook page July 25, 2012, without providing any further information about the song or the next album. The release date of the album was eventually announced with the release of the next single, "Wrath of God", on June 6, 2012. The song mostly received positive reviews. Jason Lipshutz of Billboard magazine wrote: "Consisting of three movements between calm, ethereal verses and an assault of synthesizers and programmed drums on the refrain, "Plague" obscures Glass' lyrics as her voice tries to overpower an avalanche of noise." Tom Breihan of Stereogum called the song "their [Crystal Castles'] latest bit of bloodthirsty gothed -out dance music," while stating that "it will doubtless sound amazing the next time you see them in some dank cavern of a venue." Marc Hogan of Spin magazine contrasted the song with the previous album, inferring that the band is interested in "strobe lights and strangulated screams, not synchronized lanterns or future- R&B lullabies." Jamie Fullerton of NME noted "the ominous thump and nasty bass, plus eerie silences that act like post-apocalyptic drops", also further commenting that the band still sounds "dangerous, demented and utterly thrilling" with their new song. In his elaborative track review, Dean Lucas of This Is Fake DIY called the song an "almost a modern day interpretation of the ' O Fortuna ' movement of Carl Orff 's ' Carmina Burana ' as the drama builds thanks to an ominous-sounding beginning to a frighteningly huge catharsis." He also described Alice Glass' vocals as "sounding like a threat of suicide thanks to her petulant psycho-brat charm," while writing that "quieter build-up to its gothic chorus drenched in black keys is both immediately oppressive and haunting." To conclude his assessment of the song, he stated that "the song feels different to their previous efforts, as by their own standards, it's much more of a slow burner." The music video was released on September 24, 2012. It was originally directed as a fan-made video by Ivan Grbin, before being released as an official music video. It features footage from Andrzej Żuławski 's 1981 horror film, Possession .

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Plague

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Rinderpest

Rinderpest virus Rinderpest (also cattle plague or steppe murrain ) was an infectious viral disease of cattle , domestic buffalo , and many other species of even-toed ungulates , including gaurs , buffaloes , large antelope , deer , giraffes , wildebeests , and warthogs . The disease was characterized by fever , oral erosions, diarrhea , lymphoid necrosis , and high mortality. Death rates during outbreaks were usually extremely high, approaching 100% in immunologically naïve populations. Rinderpest was mainly transmitted by direct contact and by drinking contaminated water, although it could also be transmitted by air. Rinderpest is believed to have originated in Asia , later spreading through the transport of cattle. The term Rinderpest ( German: [ ˈʁɪndɐˌpɛst ] ⓘ ) is a German word meaning "cattle-plague". The rinderpest virus (RPV) is closely related to the measles and canine distemper viruses. The measles virus possibly emerged from rinderpest as a zoonotic disease around 600 BC, a period that coincides with the rise of large human settlements. After a global eradication campaign starting in the mid-20th century, the last confirmed case of rinderpest was diagnosed in 2001. In 2010, the United Nations Food and Agriculture Organization (FAO) announced that field activities in the decades-long, worldwide campaign to eradicate the disease were ending, paving the way for a formal declaration in June 2011 of the global eradication of rinderpest, making it only the second disease in history to be fully wiped out, following smallpox . Rinderpest virus (RPV), a member of the genus Morbillivirus , is closely related to the measles and canine distemper viruses. Like other members of the Paramyxoviridae family, it produces enveloped virions, and is a negative-sense single-stranded RNA virus . The virus is particularly fragile and is quickly inactivated by heat, desiccation and sunlight. Measles virus evolved from the then-widespread rinderpest virus most probably between the 11th and 12th centuries. The earliest likely origin is during the seventh century; some linguistic evidence exists for this earlier origin. In 2020 research on the measles virus has suggested a modified understanding of the evolution of rinderpest. Work on preserved older samples of measles (1912 and following) have been tested in various ways to determine the likely trajectory of the measles virus' divergence from rinderpest. It is thought based on this study that the earliest date at which the divergence could have occurred is the sixth century BC. Death rates during outbreaks were usually extremely high, approaching 100% in immunologically naïve populations. The disease was mainly spread by direct contact and by drinking contaminated water, although it could also be transmitted by air. Initial symptoms include fever, loss of appetite, and nasal and eye discharges. Subsequently, irregular erosions appear in the mouth, the lining of the nose, and the genital tract. Acute diarrhea, preceded by constipation, is also a common feature. Most animals die six to twelve days after the onset of these clinical signs. The delayed appearance of these signs of illness account for the steady spread of the disease once a historical outbreak began. An animal infected by rinderpest undergoes an incubation period of 3–15 days. Signs of the disease only manifest at the end of that time. Cattle and wild ungulates will normally die 8–12 days after signs of the disease emerge, by which time the animals may have travelled far from the place of infection and been mixed with many other animals. The disease is believed to have originated in Asia , later spreading through the transport of cattle. Other cattle epizootics are noted in ancient times: a cattle plague is thought to be one of the 10 plagues of Egypt described in the Hebrew Bible. By around 3,000 BC , a cattle plague had reached Egypt , and rinderpest later spread throughout the remainder of Africa , following European colonization. In the 4th century, Roman writer Severus Sanctus Endelechius described rinderpest in his book, On the Deaths of Cattle . Cattle plagues recurred throughout history, often accompanying wars and military campaigns. They hit Europe especially hard in the 18th century, with three long panzootics , which although varying in intensity and duration from region to region, took place in the periods of 1709–1720, 1742–1760, and 1768–1786. In the 18th century a deadly outbreak between 1769 and 1785 resulted in universal governmental action, but with somewhat divergent responses. The Dutch and the German principalities demanded quarantines and strict burial practices; England and large parts of Italy (the Papal States) saw slaughter of infected animals; in the Austrian Netherlands (Flanders) the response was inspection and precautionary slaughter coupled with compensation to the owners. There was no code of practice and no standard response. But for a hundred years thereafter in German-speaking countries there was intense focus on the problem of Rinderpest. In the early 18th century, the disease was seen as similar to smallpox , due to its analogous symptoms. The personal physician of the pope, Giovanni Maria Lancisi , recommended the destruction of all infected and exposed animals. This policy was not very popular and was used only sparingly in the first part of the century. Later, it was used successfully in several countries, although it was sometimes seen as too costly or drastic, and depended on a strong central authority to be effective (which was notably lacking in the Dutch Republic ). Because of these downsides, numerous attempts were made to inoculate animals against the disease. These attempts met with varying success, but the procedure was not widely used and was no longer practiced at all in 19th-century Western or Central Europe. Rinderpest was an immense problem, but inoculation was not a valid solution. In many cases, it caused too many losses. Even more importantly, it perpetuated the circulation of the virus in the cattle population. The pioneers of inoculation did contribute significantly to knowledge about infectious diseases. Their experiments confirmed the concepts of those who saw infectious diseases as caused by specific agents, and were the first to recognize maternally derived immunity . The first written report of rinderpest inoculation was published in a letter signed "T.S." in the November 1754 issue of The Gentleman's Magazine , a widely read journal which also supported the progress of smallpox inoculation. This letter reported that a Mr Dobsen had inoculated his cattle and had thus preserved 9 out of 10 of them, although this was retracted in the next issue, as it was apparently a Sir William St. Quintin who had done the inoculating (this was done by placing bits of material previously dipped in morbid discharge into an incision made in the dewlap of the animal). These letters encouraged further application of inoculation in the fight against diseases. The first inoculation against measles was made three years after their publication. From early 1755 onwards, experiments were taking place in the Netherlands, as well, results of which were also published in The Gentleman's Magazine . As in England, the disease was seen as analogous with smallpox. While these experiments were reasonably successful, they did not have a significant impact: the total number of inoculations in England appears to have been very limited, and after 1780, the English interest in inoculation disappeared almost entirely. Almost all further experimentation was done in the Netherlands, northern Germany and Denmark. [ citation needed ] Due to a very severe outbreak at the end of the 1760s, some of the best-known names in Dutch medicine became involved in the struggle against the disease. Several independent trials were begun, most notably by Pieter Camper in Groningen and Friesland . The results of his experiment in Friesland were encouraging, but they proved to be the exception; testing by others in the provinces of Utrecht and Friesland obtained disastrous results. As a result, the Frisian authorities concluded in 1769 that the cause of rinderpest was God's displeasure with the sinful behavior of the Frisian people , and proclaimed 15 November a day of fasting and prayer. Interest in inoculation declined sharply across the country. In this climate of discouragement and scepticism, Geert Reinders , a farmer in the province of Groningen and a self-taught man, decided to continue the experiments. He collaborated with Wijnold Munniks , who had supervised earlier trials. They tried different inoculation procedures and a variety of treatments to lighten the symptoms, all of them without significant effect. Although they were not able to perfect the inoculation procedure, they did make some useful observations. Reinders resumed his experiments in 1774, concentrating on the inoculation of calves from cows that had recovered from rinderpest. He was probably the first to make practical use of maternally derived immunity . The detailed results of his trials were published in 1776 and reprinted in 1777. His inoculation procedure did not differ much from what had been used previously, except for the use of three separate inoculations at an early age. This produced far better results, and the publication of his work renewed interest in inoculation. For the period of 1777 to 1781, 89% of inoculated animals survived, compared to a 29% survival rate after natural infection. In the Netherlands, too, interest in rinderpest inoculation declined in the 1780s because the disease itself decreased in intensity. [ citation needed ] Apart from the Dutch Republic, the only other regions where inoculation was used to any significant level were northern Germany and Denmark . Experiments started in Mecklenburg during the epizootic of the late 1770s. "Insurance companies" were created which provided inoculation in special "institutes". Although these were private initiatives, they were created with full encouragement from the authorities. Though neighboring states followed this practice with interest, the practice never caught on outside Mecklenburg; many were still opposed to inoculation. While some experimentation occurred in other countries (most extensively in Denmark), in the majority of European countries, the struggle against the disease was based on stamping it out. Sometimes, this could be done with minimal sacrifices; at other times, it required slaughter at a massive scale. There were major outbreaks of cattle plague documented from the mid-century onwards. Responses to these outbreaks differed across the world. A major outbreak affected the whole of the British Isles for three years after 1865. In August 1865 an Order of the British Privy Council required the slaughter of rinderpest-affected cattle. By early May 1867, the overall slaughter total was around 75,000 cattle, which at that time had a value of approximately £10 per head. Initially, £55,000 was granted (after a period of delay) to compensate farmers where they complied with the slaughter directive but had no other source of compensation. In certain areas, such as Aberdeenshire and Norfolk , farmers had banded together to provide mutual assurance by creating a resource pool against the risk of rinderpest. Because the initial slaughter regime was not backed by compensation, it was the presence of a voluntary mutual assurance scheme that drove down the infection rates by guaranteeing payment for compliance with the government instruction. The Privy Council ordered a detailed investigation of the disaster, which reported in 1868. In 1871, there was held an international Rinderpest convention in Vienna . It was purposed to establish mechanisms for reporting outbreaks to warn neighbouring countries, and so as to establish policies for inspections, quarantines and disinfections as well as monitoring the cattle trade. Around the turn of the century, a plague struck in Southern Africa. Spinage establishes a critical commentary on the theory that in 1888, rinderpest was introduced into Abyssinia (modern Ethiopia) by the invading Italian army, which supposedly brought with them infected cattle from India. The procurement chain is not traced beyond an Egyptian businessman from Cairo, but it is possible that the British Army got their draft oxen from India. However, the documentary chain only supported limited negative conclusions. "There is therefore no evidence in contemporary accounts that the rinderpest panzootic was imported from India with infected oxen to provision the Italian landing at Massawa ." It may now be impossible to disentangle the probabilities of where rinderpest initially came from- invading Italians, invading Egyptians or local break-outs in Eritrea . Once in progress, the infection eventually spread to the shores of Lake Victoria and into German Tanzania . Sunseri concentrates on the detailed progress of the epizootic in German Tanzania, endeavouring to show that the disease was known to be present but was not officially recognised as being rinderpest. He emphasises in particular the failure by the German government to rely on or accept a post mortem in 1892 professionally medically conducted on an affected animal that had been duly diagnosed as having rinderpest. The diagnosis was procured at the personal behest of the governor and remitted to Berlin . It appears that awareness of a cattle plague in general did not amount to the German government accepting that the plague was rinderpest, for which measures of a strict kind were prescribed in Germany itself. The governor, Julius von Soden , personally lost his own herd, and this may have led him to secure the post-mortem so as to challenge the official diagnostic silence. The impact on African-owned herds was drastic. The disease was locally described as "sadoka" and it also affected local wildlife. Sunseri's thesis basically explains the German government's failure to recognise the true nature of the disease as permitting ineffective policies. The local German government was short of cash, without a vet until the late 1890s and surrounded by innumerable serious cattle diseases apart from rinderpest. The 1885 protectorate status of Tanzania (ruled by the German East Africa Company ) had been interrupted by coastal rebellion: when formal German rule began and the military went inland in 1891 to "pacify" areas, they encountered massive cattle deaths ostensibly due to viral spread from wildlife (one assumes at waterholes). Some observers themselves described the outbreak as rinderpest, whereas argument and debate continued because of essentially lack of consistent information and detailed investigation. When the German governor requested confirmation as to a course of action, he would have been fully aware of the administrative consequences, had matters been dealt with in Germany (quarantines, slaughter policies, disinfection controls of cattle transport and control of products suspected of contact with contaminated animals). In the event, the post-mortem was reviewed in Berlin and determined to be incomplete: a diagnosis could only be made on the ground by a vet. Funding vets was not a priority as most of the cattle by then (1892) had died. Meanwhile, a German staff doctor with an interest in animal diseases opined (two long Reports for the German Colonial Service ) that the problem must be an Africa-specific matter not the familiar rinderpest. His confusion may derive from the absence of impact of rinderpest on German wildlife. This is now explained by the fenced and manicured German agricultural landscape of the day being insufficiently "wild" and livestock normally being kept apart. By 1893, government regulatory response was as though the disease had been rinderpest in Germany (and included preventive slaughter). Cattle exports were banned in 1893 (to improve local stocks not on grounds of confining spread, as some cattle were exempt). Nevertheless importation, legal or illegal or rebranded via Zanzibar , reached the British colonies in the south. Marquardt concentrates on the detailed progress of the disease in South Africa during the 1896 outbreak. Between 1896 and 1897, 95% of the cattle in South Africa were killed by the disease. The primary spreading agency seems to be the common use of waterholes by wild ungulates and herded cattle. The herded cattle were normally in transit and the long incubation period and delayed symptoms meant that spreading had taken place before illness was realised. His initial case study is Southern Bechuanaland settled as it then was by two distinct cattle-focused groups: the Tswana people and the Boers . It was flat, hot and dry and was considered good cattle-raising country. Water was regularly available by drilling 20-30 feet below the surface, though many farms had water only by drilling 50-100 feet down. From 1882 onwards, designated Tswana reserves were created adjoining white farms in many instances. African pastoralism was constrained by this. From 1895, increasing numbers of white settlers (now administered from the Cape) evicted the Tswana and tension between these groups was inevitable. The 1896 drought resulted in fewer watering places being available, and a greater density of usage including both groups of cattle-owners and the wild animals. By May 1896, the vast Clober farm had become a focus of infection with immediate slaughter policies in place. Three river drinking places, mainly used by the Tswana group, recorded over 12,000 head of cattle regularly each; the government was reluctant to embark on wholesale destruction. The government tried, and failed, to stop herds crossing rivers and perpetuating stock-mingling. The spread of the disease was relentless in the Bechuanaland Protectorate . The connection between rinderpest and starvation was recognised by the British government as cause for urgent intervention by delivery of food relief. In 1896, 30,000 tons of mealies (corn) were delivered for the relief of the Bechuanaland Protectorate. Meanwhile, the Crocodile River in the Transvaal was reported as choked with cattle and other animal corpses, but remained in use. During the dry season, the government made no attempt to control use of the watering holes, fearing the consequences if they did. The Boers essentially did no better, mainly because they continued to migrate their cattle between parcels of land rather than remaining stationery within a particular parcel. Complaint by both Boer and Tswana groups was focused on the government rather than mutual hostility. Fencing, and quarantining coupled with killing of infected cattle, was a policy barely controllable in the expanses of the colony, though it had some success in England. However, fencing resulted in herd-mingling and consequent infection. The Tswana herds were quarantined together; the Boer herds were also quarantined but on their own land. The system was very unpopular. The policy was scorned and pilloried in the press: plenty of reports came out to the effect that the disease was spread by the quarantine guards and by the vets, all of whom were less than careful about disinfecting themselves. It is plausible that the major spreader of disease should be negligent government officials or contractors moving directly from areas known to be diseased to other areas in protective quarantine. In Southern Bechuanaland alone, over 400 men were hired as quarantine guards. Owners from both groups resisted the guards and the Boers vigorously resisted the killing of their cattle. It is likely both groups raised the fences, and several Boer groups deliberately spread the disease in order to claim the compensation. By 1896, it was generally recognised the government campaign had completely failed, overwhelmed by a storm of contributory causes to the spread of the disease. The outbreak in the 1890s killed an estimated 80 to 90% of all cattle in eastern and southern Africa. Sir Arnold Theiler was instrumental in developing a vaccine that curbed the epizootic. : 300 The consequences for the Africans were especially severe. Though cattle numbers revived subsequently, the consequent human toll was mass starvation in the absence of herding, hunting and farming. It is estimated that the human losses were as high as one-third of the population of Ethiopia and two-thirds of the Maasai people of Tanzania. This famine caused significant depopulation in sub-Saharan Africa, allowing thornbush to colonise. This formed ideal habitat for tsetse fly , which carries sleeping sickness , and is unsuitable for livestock; "hence the European view of an empty unspoiled Africa teeming with game". Japan also sustained the presence of rinderpest in the 19th century as illustrated in an anonymous print. The disease was present for centuries in China, Japan and Korea. Japanese black and Korean yellow breed cattle were known to be especially susceptible to it. In 1868, there was a serious outbreak of rinderpest in India, which was investigated by Colonel James Hallen of the Indian Cattle Plague Commission leading to the publication of his survey in 1871. The Imperial Bacteriological Laboratory from 1893 was at Mukteshwar in India. It hosted much research work and many samples. Its founding director was British pathologist Alfred Lingard . In India, some farmers were reported as not hostile to tigers because of the consideration that their attacks on diseased or weaker animals reduced the risk of rinderpest. In his classic study of the Nuer of southern Sudan, E. E. Evans-Pritchard suggested rinderpest might have affected the Nuer's social organization before and during the 1930s. Since the Nuer were pastoralists , much of their livelihood was based on cattle husbandry, and bride-prices were paid in cattle; prices may have changed as a result of cattle depletion. Rinderpest might also have increased dependence on horticulture among the Nuer. Rinderpest was eradicated from Japan in 1922, as recorded by the Nippon Institute for Biological Science. Distinguished Japanese scientist and Director of the Nippon Institute for Biological Science, Junji Nakamura (1903-1975), was a major researcher into rinderpest, and the contribution of his work to the worldwide eradication of rinderpest was acknowledged by the Food and Agriculture Organisation of the United Nations. The FAO posthumously presented a certificate of appreciation in 2011. A more recent rinderpest outbreak in Africa in 1982–1984 resulted in an estimated US$2 billion in stock losses. In 1917–18, William Hutchins Boynton (1881–1959), the chief veterinary pathologist with the Philippine Bureau of Agriculture , developed an early vaccine for rinderpest, based on treated animal organ extracts. In 1959, rinderpest vaccine was prepared at government laboratories in Abuko in The Gambia from the spleen of infected cattle. Walter Plowright worked on a vaccine for the RBOK strain of the rinderpest virus for multiple years, from 1956 to 1962. Plowright was awarded the World Food Prize in 1999 for developing a vaccine against a strain of rinderpest. In 1999, the FAO predicted that with vaccination, rinderpest would be eradicated by 2010. The disease is believed to have originated in Asia , later spreading through the transport of cattle. Other cattle epizootics are noted in ancient times: a cattle plague is thought to be one of the 10 plagues of Egypt described in the Hebrew Bible. By around 3,000 BC , a cattle plague had reached Egypt , and rinderpest later spread throughout the remainder of Africa , following European colonization. In the 4th century, Roman writer Severus Sanctus Endelechius described rinderpest in his book, On the Deaths of Cattle . Cattle plagues recurred throughout history, often accompanying wars and military campaigns. They hit Europe especially hard in the 18th century, with three long panzootics , which although varying in intensity and duration from region to region, took place in the periods of 1709–1720, 1742–1760, and 1768–1786. In the 18th century a deadly outbreak between 1769 and 1785 resulted in universal governmental action, but with somewhat divergent responses. The Dutch and the German principalities demanded quarantines and strict burial practices; England and large parts of Italy (the Papal States) saw slaughter of infected animals; in the Austrian Netherlands (Flanders) the response was inspection and precautionary slaughter coupled with compensation to the owners. There was no code of practice and no standard response. But for a hundred years thereafter in German-speaking countries there was intense focus on the problem of Rinderpest. In the early 18th century, the disease was seen as similar to smallpox , due to its analogous symptoms. The personal physician of the pope, Giovanni Maria Lancisi , recommended the destruction of all infected and exposed animals. This policy was not very popular and was used only sparingly in the first part of the century. Later, it was used successfully in several countries, although it was sometimes seen as too costly or drastic, and depended on a strong central authority to be effective (which was notably lacking in the Dutch Republic ). Because of these downsides, numerous attempts were made to inoculate animals against the disease. These attempts met with varying success, but the procedure was not widely used and was no longer practiced at all in 19th-century Western or Central Europe. Rinderpest was an immense problem, but inoculation was not a valid solution. In many cases, it caused too many losses. Even more importantly, it perpetuated the circulation of the virus in the cattle population. The pioneers of inoculation did contribute significantly to knowledge about infectious diseases. Their experiments confirmed the concepts of those who saw infectious diseases as caused by specific agents, and were the first to recognize maternally derived immunity . The first written report of rinderpest inoculation was published in a letter signed "T.S." in the November 1754 issue of The Gentleman's Magazine , a widely read journal which also supported the progress of smallpox inoculation. This letter reported that a Mr Dobsen had inoculated his cattle and had thus preserved 9 out of 10 of them, although this was retracted in the next issue, as it was apparently a Sir William St. Quintin who had done the inoculating (this was done by placing bits of material previously dipped in morbid discharge into an incision made in the dewlap of the animal). These letters encouraged further application of inoculation in the fight against diseases. The first inoculation against measles was made three years after their publication. From early 1755 onwards, experiments were taking place in the Netherlands, as well, results of which were also published in The Gentleman's Magazine . As in England, the disease was seen as analogous with smallpox. While these experiments were reasonably successful, they did not have a significant impact: the total number of inoculations in England appears to have been very limited, and after 1780, the English interest in inoculation disappeared almost entirely. Almost all further experimentation was done in the Netherlands, northern Germany and Denmark. [ citation needed ] Due to a very severe outbreak at the end of the 1760s, some of the best-known names in Dutch medicine became involved in the struggle against the disease. Several independent trials were begun, most notably by Pieter Camper in Groningen and Friesland . The results of his experiment in Friesland were encouraging, but they proved to be the exception; testing by others in the provinces of Utrecht and Friesland obtained disastrous results. As a result, the Frisian authorities concluded in 1769 that the cause of rinderpest was God's displeasure with the sinful behavior of the Frisian people , and proclaimed 15 November a day of fasting and prayer. Interest in inoculation declined sharply across the country. In this climate of discouragement and scepticism, Geert Reinders , a farmer in the province of Groningen and a self-taught man, decided to continue the experiments. He collaborated with Wijnold Munniks , who had supervised earlier trials. They tried different inoculation procedures and a variety of treatments to lighten the symptoms, all of them without significant effect. Although they were not able to perfect the inoculation procedure, they did make some useful observations. Reinders resumed his experiments in 1774, concentrating on the inoculation of calves from cows that had recovered from rinderpest. He was probably the first to make practical use of maternally derived immunity . The detailed results of his trials were published in 1776 and reprinted in 1777. His inoculation procedure did not differ much from what had been used previously, except for the use of three separate inoculations at an early age. This produced far better results, and the publication of his work renewed interest in inoculation. For the period of 1777 to 1781, 89% of inoculated animals survived, compared to a 29% survival rate after natural infection. In the Netherlands, too, interest in rinderpest inoculation declined in the 1780s because the disease itself decreased in intensity. [ citation needed ] Apart from the Dutch Republic, the only other regions where inoculation was used to any significant level were northern Germany and Denmark . Experiments started in Mecklenburg during the epizootic of the late 1770s. "Insurance companies" were created which provided inoculation in special "institutes". Although these were private initiatives, they were created with full encouragement from the authorities. Though neighboring states followed this practice with interest, the practice never caught on outside Mecklenburg; many were still opposed to inoculation. While some experimentation occurred in other countries (most extensively in Denmark), in the majority of European countries, the struggle against the disease was based on stamping it out. Sometimes, this could be done with minimal sacrifices; at other times, it required slaughter at a massive scale. In the early 18th century, the disease was seen as similar to smallpox , due to its analogous symptoms. The personal physician of the pope, Giovanni Maria Lancisi , recommended the destruction of all infected and exposed animals. This policy was not very popular and was used only sparingly in the first part of the century. Later, it was used successfully in several countries, although it was sometimes seen as too costly or drastic, and depended on a strong central authority to be effective (which was notably lacking in the Dutch Republic ). Because of these downsides, numerous attempts were made to inoculate animals against the disease. These attempts met with varying success, but the procedure was not widely used and was no longer practiced at all in 19th-century Western or Central Europe. Rinderpest was an immense problem, but inoculation was not a valid solution. In many cases, it caused too many losses. Even more importantly, it perpetuated the circulation of the virus in the cattle population. The pioneers of inoculation did contribute significantly to knowledge about infectious diseases. Their experiments confirmed the concepts of those who saw infectious diseases as caused by specific agents, and were the first to recognize maternally derived immunity . The first written report of rinderpest inoculation was published in a letter signed "T.S." in the November 1754 issue of The Gentleman's Magazine , a widely read journal which also supported the progress of smallpox inoculation. This letter reported that a Mr Dobsen had inoculated his cattle and had thus preserved 9 out of 10 of them, although this was retracted in the next issue, as it was apparently a Sir William St. Quintin who had done the inoculating (this was done by placing bits of material previously dipped in morbid discharge into an incision made in the dewlap of the animal). These letters encouraged further application of inoculation in the fight against diseases. The first inoculation against measles was made three years after their publication. From early 1755 onwards, experiments were taking place in the Netherlands, as well, results of which were also published in The Gentleman's Magazine . As in England, the disease was seen as analogous with smallpox. While these experiments were reasonably successful, they did not have a significant impact: the total number of inoculations in England appears to have been very limited, and after 1780, the English interest in inoculation disappeared almost entirely. Almost all further experimentation was done in the Netherlands, northern Germany and Denmark. [ citation needed ]Due to a very severe outbreak at the end of the 1760s, some of the best-known names in Dutch medicine became involved in the struggle against the disease. Several independent trials were begun, most notably by Pieter Camper in Groningen and Friesland . The results of his experiment in Friesland were encouraging, but they proved to be the exception; testing by others in the provinces of Utrecht and Friesland obtained disastrous results. As a result, the Frisian authorities concluded in 1769 that the cause of rinderpest was God's displeasure with the sinful behavior of the Frisian people , and proclaimed 15 November a day of fasting and prayer. Interest in inoculation declined sharply across the country. In this climate of discouragement and scepticism, Geert Reinders , a farmer in the province of Groningen and a self-taught man, decided to continue the experiments. He collaborated with Wijnold Munniks , who had supervised earlier trials. They tried different inoculation procedures and a variety of treatments to lighten the symptoms, all of them without significant effect. Although they were not able to perfect the inoculation procedure, they did make some useful observations. Reinders resumed his experiments in 1774, concentrating on the inoculation of calves from cows that had recovered from rinderpest. He was probably the first to make practical use of maternally derived immunity . The detailed results of his trials were published in 1776 and reprinted in 1777. His inoculation procedure did not differ much from what had been used previously, except for the use of three separate inoculations at an early age. This produced far better results, and the publication of his work renewed interest in inoculation. For the period of 1777 to 1781, 89% of inoculated animals survived, compared to a 29% survival rate after natural infection. In the Netherlands, too, interest in rinderpest inoculation declined in the 1780s because the disease itself decreased in intensity. [ citation needed ]Apart from the Dutch Republic, the only other regions where inoculation was used to any significant level were northern Germany and Denmark . Experiments started in Mecklenburg during the epizootic of the late 1770s. "Insurance companies" were created which provided inoculation in special "institutes". Although these were private initiatives, they were created with full encouragement from the authorities. Though neighboring states followed this practice with interest, the practice never caught on outside Mecklenburg; many were still opposed to inoculation. While some experimentation occurred in other countries (most extensively in Denmark), in the majority of European countries, the struggle against the disease was based on stamping it out. Sometimes, this could be done with minimal sacrifices; at other times, it required slaughter at a massive scale. There were major outbreaks of cattle plague documented from the mid-century onwards. Responses to these outbreaks differed across the world. A major outbreak affected the whole of the British Isles for three years after 1865. In August 1865 an Order of the British Privy Council required the slaughter of rinderpest-affected cattle. By early May 1867, the overall slaughter total was around 75,000 cattle, which at that time had a value of approximately £10 per head. Initially, £55,000 was granted (after a period of delay) to compensate farmers where they complied with the slaughter directive but had no other source of compensation. In certain areas, such as Aberdeenshire and Norfolk , farmers had banded together to provide mutual assurance by creating a resource pool against the risk of rinderpest. Because the initial slaughter regime was not backed by compensation, it was the presence of a voluntary mutual assurance scheme that drove down the infection rates by guaranteeing payment for compliance with the government instruction. The Privy Council ordered a detailed investigation of the disaster, which reported in 1868. In 1871, there was held an international Rinderpest convention in Vienna . It was purposed to establish mechanisms for reporting outbreaks to warn neighbouring countries, and so as to establish policies for inspections, quarantines and disinfections as well as monitoring the cattle trade. Around the turn of the century, a plague struck in Southern Africa. Spinage establishes a critical commentary on the theory that in 1888, rinderpest was introduced into Abyssinia (modern Ethiopia) by the invading Italian army, which supposedly brought with them infected cattle from India. The procurement chain is not traced beyond an Egyptian businessman from Cairo, but it is possible that the British Army got their draft oxen from India. However, the documentary chain only supported limited negative conclusions. "There is therefore no evidence in contemporary accounts that the rinderpest panzootic was imported from India with infected oxen to provision the Italian landing at Massawa ." It may now be impossible to disentangle the probabilities of where rinderpest initially came from- invading Italians, invading Egyptians or local break-outs in Eritrea . Once in progress, the infection eventually spread to the shores of Lake Victoria and into German Tanzania . Sunseri concentrates on the detailed progress of the epizootic in German Tanzania, endeavouring to show that the disease was known to be present but was not officially recognised as being rinderpest. He emphasises in particular the failure by the German government to rely on or accept a post mortem in 1892 professionally medically conducted on an affected animal that had been duly diagnosed as having rinderpest. The diagnosis was procured at the personal behest of the governor and remitted to Berlin . It appears that awareness of a cattle plague in general did not amount to the German government accepting that the plague was rinderpest, for which measures of a strict kind were prescribed in Germany itself. The governor, Julius von Soden , personally lost his own herd, and this may have led him to secure the post-mortem so as to challenge the official diagnostic silence. The impact on African-owned herds was drastic. The disease was locally described as "sadoka" and it also affected local wildlife. Sunseri's thesis basically explains the German government's failure to recognise the true nature of the disease as permitting ineffective policies. The local German government was short of cash, without a vet until the late 1890s and surrounded by innumerable serious cattle diseases apart from rinderpest. The 1885 protectorate status of Tanzania (ruled by the German East Africa Company ) had been interrupted by coastal rebellion: when formal German rule began and the military went inland in 1891 to "pacify" areas, they encountered massive cattle deaths ostensibly due to viral spread from wildlife (one assumes at waterholes). Some observers themselves described the outbreak as rinderpest, whereas argument and debate continued because of essentially lack of consistent information and detailed investigation. When the German governor requested confirmation as to a course of action, he would have been fully aware of the administrative consequences, had matters been dealt with in Germany (quarantines, slaughter policies, disinfection controls of cattle transport and control of products suspected of contact with contaminated animals). In the event, the post-mortem was reviewed in Berlin and determined to be incomplete: a diagnosis could only be made on the ground by a vet. Funding vets was not a priority as most of the cattle by then (1892) had died. Meanwhile, a German staff doctor with an interest in animal diseases opined (two long Reports for the German Colonial Service ) that the problem must be an Africa-specific matter not the familiar rinderpest. His confusion may derive from the absence of impact of rinderpest on German wildlife. This is now explained by the fenced and manicured German agricultural landscape of the day being insufficiently "wild" and livestock normally being kept apart. By 1893, government regulatory response was as though the disease had been rinderpest in Germany (and included preventive slaughter). Cattle exports were banned in 1893 (to improve local stocks not on grounds of confining spread, as some cattle were exempt). Nevertheless importation, legal or illegal or rebranded via Zanzibar , reached the British colonies in the south. Marquardt concentrates on the detailed progress of the disease in South Africa during the 1896 outbreak. Between 1896 and 1897, 95% of the cattle in South Africa were killed by the disease. The primary spreading agency seems to be the common use of waterholes by wild ungulates and herded cattle. The herded cattle were normally in transit and the long incubation period and delayed symptoms meant that spreading had taken place before illness was realised. His initial case study is Southern Bechuanaland settled as it then was by two distinct cattle-focused groups: the Tswana people and the Boers . It was flat, hot and dry and was considered good cattle-raising country. Water was regularly available by drilling 20-30 feet below the surface, though many farms had water only by drilling 50-100 feet down. From 1882 onwards, designated Tswana reserves were created adjoining white farms in many instances. African pastoralism was constrained by this. From 1895, increasing numbers of white settlers (now administered from the Cape) evicted the Tswana and tension between these groups was inevitable. The 1896 drought resulted in fewer watering places being available, and a greater density of usage including both groups of cattle-owners and the wild animals. By May 1896, the vast Clober farm had become a focus of infection with immediate slaughter policies in place. Three river drinking places, mainly used by the Tswana group, recorded over 12,000 head of cattle regularly each; the government was reluctant to embark on wholesale destruction. The government tried, and failed, to stop herds crossing rivers and perpetuating stock-mingling. The spread of the disease was relentless in the Bechuanaland Protectorate . The connection between rinderpest and starvation was recognised by the British government as cause for urgent intervention by delivery of food relief. In 1896, 30,000 tons of mealies (corn) were delivered for the relief of the Bechuanaland Protectorate. Meanwhile, the Crocodile River in the Transvaal was reported as choked with cattle and other animal corpses, but remained in use. During the dry season, the government made no attempt to control use of the watering holes, fearing the consequences if they did. The Boers essentially did no better, mainly because they continued to migrate their cattle between parcels of land rather than remaining stationery within a particular parcel. Complaint by both Boer and Tswana groups was focused on the government rather than mutual hostility. Fencing, and quarantining coupled with killing of infected cattle, was a policy barely controllable in the expanses of the colony, though it had some success in England. However, fencing resulted in herd-mingling and consequent infection. The Tswana herds were quarantined together; the Boer herds were also quarantined but on their own land. The system was very unpopular. The policy was scorned and pilloried in the press: plenty of reports came out to the effect that the disease was spread by the quarantine guards and by the vets, all of whom were less than careful about disinfecting themselves. It is plausible that the major spreader of disease should be negligent government officials or contractors moving directly from areas known to be diseased to other areas in protective quarantine. In Southern Bechuanaland alone, over 400 men were hired as quarantine guards. Owners from both groups resisted the guards and the Boers vigorously resisted the killing of their cattle. It is likely both groups raised the fences, and several Boer groups deliberately spread the disease in order to claim the compensation. By 1896, it was generally recognised the government campaign had completely failed, overwhelmed by a storm of contributory causes to the spread of the disease. The outbreak in the 1890s killed an estimated 80 to 90% of all cattle in eastern and southern Africa. Sir Arnold Theiler was instrumental in developing a vaccine that curbed the epizootic. : 300 The consequences for the Africans were especially severe. Though cattle numbers revived subsequently, the consequent human toll was mass starvation in the absence of herding, hunting and farming. It is estimated that the human losses were as high as one-third of the population of Ethiopia and two-thirds of the Maasai people of Tanzania. This famine caused significant depopulation in sub-Saharan Africa, allowing thornbush to colonise. This formed ideal habitat for tsetse fly , which carries sleeping sickness , and is unsuitable for livestock; "hence the European view of an empty unspoiled Africa teeming with game". Japan also sustained the presence of rinderpest in the 19th century as illustrated in an anonymous print. The disease was present for centuries in China, Japan and Korea. Japanese black and Korean yellow breed cattle were known to be especially susceptible to it. In 1868, there was a serious outbreak of rinderpest in India, which was investigated by Colonel James Hallen of the Indian Cattle Plague Commission leading to the publication of his survey in 1871. The Imperial Bacteriological Laboratory from 1893 was at Mukteshwar in India. It hosted much research work and many samples. Its founding director was British pathologist Alfred Lingard . In India, some farmers were reported as not hostile to tigers because of the consideration that their attacks on diseased or weaker animals reduced the risk of rinderpest. A major outbreak affected the whole of the British Isles for three years after 1865. In August 1865 an Order of the British Privy Council required the slaughter of rinderpest-affected cattle. By early May 1867, the overall slaughter total was around 75,000 cattle, which at that time had a value of approximately £10 per head. Initially, £55,000 was granted (after a period of delay) to compensate farmers where they complied with the slaughter directive but had no other source of compensation. In certain areas, such as Aberdeenshire and Norfolk , farmers had banded together to provide mutual assurance by creating a resource pool against the risk of rinderpest. Because the initial slaughter regime was not backed by compensation, it was the presence of a voluntary mutual assurance scheme that drove down the infection rates by guaranteeing payment for compliance with the government instruction. The Privy Council ordered a detailed investigation of the disaster, which reported in 1868. In 1871, there was held an international Rinderpest convention in Vienna . It was purposed to establish mechanisms for reporting outbreaks to warn neighbouring countries, and so as to establish policies for inspections, quarantines and disinfections as well as monitoring the cattle trade. Around the turn of the century, a plague struck in Southern Africa. Spinage establishes a critical commentary on the theory that in 1888, rinderpest was introduced into Abyssinia (modern Ethiopia) by the invading Italian army, which supposedly brought with them infected cattle from India. The procurement chain is not traced beyond an Egyptian businessman from Cairo, but it is possible that the British Army got their draft oxen from India. However, the documentary chain only supported limited negative conclusions. "There is therefore no evidence in contemporary accounts that the rinderpest panzootic was imported from India with infected oxen to provision the Italian landing at Massawa ." It may now be impossible to disentangle the probabilities of where rinderpest initially came from- invading Italians, invading Egyptians or local break-outs in Eritrea . Once in progress, the infection eventually spread to the shores of Lake Victoria and into German Tanzania . Sunseri concentrates on the detailed progress of the epizootic in German Tanzania, endeavouring to show that the disease was known to be present but was not officially recognised as being rinderpest. He emphasises in particular the failure by the German government to rely on or accept a post mortem in 1892 professionally medically conducted on an affected animal that had been duly diagnosed as having rinderpest. The diagnosis was procured at the personal behest of the governor and remitted to Berlin . It appears that awareness of a cattle plague in general did not amount to the German government accepting that the plague was rinderpest, for which measures of a strict kind were prescribed in Germany itself. The governor, Julius von Soden , personally lost his own herd, and this may have led him to secure the post-mortem so as to challenge the official diagnostic silence. The impact on African-owned herds was drastic. The disease was locally described as "sadoka" and it also affected local wildlife. Sunseri's thesis basically explains the German government's failure to recognise the true nature of the disease as permitting ineffective policies. The local German government was short of cash, without a vet until the late 1890s and surrounded by innumerable serious cattle diseases apart from rinderpest. The 1885 protectorate status of Tanzania (ruled by the German East Africa Company ) had been interrupted by coastal rebellion: when formal German rule began and the military went inland in 1891 to "pacify" areas, they encountered massive cattle deaths ostensibly due to viral spread from wildlife (one assumes at waterholes). Some observers themselves described the outbreak as rinderpest, whereas argument and debate continued because of essentially lack of consistent information and detailed investigation. When the German governor requested confirmation as to a course of action, he would have been fully aware of the administrative consequences, had matters been dealt with in Germany (quarantines, slaughter policies, disinfection controls of cattle transport and control of products suspected of contact with contaminated animals). In the event, the post-mortem was reviewed in Berlin and determined to be incomplete: a diagnosis could only be made on the ground by a vet. Funding vets was not a priority as most of the cattle by then (1892) had died. Meanwhile, a German staff doctor with an interest in animal diseases opined (two long Reports for the German Colonial Service ) that the problem must be an Africa-specific matter not the familiar rinderpest. His confusion may derive from the absence of impact of rinderpest on German wildlife. This is now explained by the fenced and manicured German agricultural landscape of the day being insufficiently "wild" and livestock normally being kept apart. By 1893, government regulatory response was as though the disease had been rinderpest in Germany (and included preventive slaughter). Cattle exports were banned in 1893 (to improve local stocks not on grounds of confining spread, as some cattle were exempt). Nevertheless importation, legal or illegal or rebranded via Zanzibar , reached the British colonies in the south. Marquardt concentrates on the detailed progress of the disease in South Africa during the 1896 outbreak. Between 1896 and 1897, 95% of the cattle in South Africa were killed by the disease. The primary spreading agency seems to be the common use of waterholes by wild ungulates and herded cattle. The herded cattle were normally in transit and the long incubation period and delayed symptoms meant that spreading had taken place before illness was realised. His initial case study is Southern Bechuanaland settled as it then was by two distinct cattle-focused groups: the Tswana people and the Boers . It was flat, hot and dry and was considered good cattle-raising country. Water was regularly available by drilling 20-30 feet below the surface, though many farms had water only by drilling 50-100 feet down. From 1882 onwards, designated Tswana reserves were created adjoining white farms in many instances. African pastoralism was constrained by this. From 1895, increasing numbers of white settlers (now administered from the Cape) evicted the Tswana and tension between these groups was inevitable. The 1896 drought resulted in fewer watering places being available, and a greater density of usage including both groups of cattle-owners and the wild animals. By May 1896, the vast Clober farm had become a focus of infection with immediate slaughter policies in place. Three river drinking places, mainly used by the Tswana group, recorded over 12,000 head of cattle regularly each; the government was reluctant to embark on wholesale destruction. The government tried, and failed, to stop herds crossing rivers and perpetuating stock-mingling. The spread of the disease was relentless in the Bechuanaland Protectorate . The connection between rinderpest and starvation was recognised by the British government as cause for urgent intervention by delivery of food relief. In 1896, 30,000 tons of mealies (corn) were delivered for the relief of the Bechuanaland Protectorate. Meanwhile, the Crocodile River in the Transvaal was reported as choked with cattle and other animal corpses, but remained in use. During the dry season, the government made no attempt to control use of the watering holes, fearing the consequences if they did. The Boers essentially did no better, mainly because they continued to migrate their cattle between parcels of land rather than remaining stationery within a particular parcel. Complaint by both Boer and Tswana groups was focused on the government rather than mutual hostility. Fencing, and quarantining coupled with killing of infected cattle, was a policy barely controllable in the expanses of the colony, though it had some success in England. However, fencing resulted in herd-mingling and consequent infection. The Tswana herds were quarantined together; the Boer herds were also quarantined but on their own land. The system was very unpopular. The policy was scorned and pilloried in the press: plenty of reports came out to the effect that the disease was spread by the quarantine guards and by the vets, all of whom were less than careful about disinfecting themselves. It is plausible that the major spreader of disease should be negligent government officials or contractors moving directly from areas known to be diseased to other areas in protective quarantine. In Southern Bechuanaland alone, over 400 men were hired as quarantine guards. Owners from both groups resisted the guards and the Boers vigorously resisted the killing of their cattle. It is likely both groups raised the fences, and several Boer groups deliberately spread the disease in order to claim the compensation. By 1896, it was generally recognised the government campaign had completely failed, overwhelmed by a storm of contributory causes to the spread of the disease. The outbreak in the 1890s killed an estimated 80 to 90% of all cattle in eastern and southern Africa. Sir Arnold Theiler was instrumental in developing a vaccine that curbed the epizootic. : 300 The consequences for the Africans were especially severe. Though cattle numbers revived subsequently, the consequent human toll was mass starvation in the absence of herding, hunting and farming. It is estimated that the human losses were as high as one-third of the population of Ethiopia and two-thirds of the Maasai people of Tanzania. This famine caused significant depopulation in sub-Saharan Africa, allowing thornbush to colonise. This formed ideal habitat for tsetse fly , which carries sleeping sickness , and is unsuitable for livestock; "hence the European view of an empty unspoiled Africa teeming with game". Japan also sustained the presence of rinderpest in the 19th century as illustrated in an anonymous print. The disease was present for centuries in China, Japan and Korea. Japanese black and Korean yellow breed cattle were known to be especially susceptible to it. In 1868, there was a serious outbreak of rinderpest in India, which was investigated by Colonel James Hallen of the Indian Cattle Plague Commission leading to the publication of his survey in 1871. The Imperial Bacteriological Laboratory from 1893 was at Mukteshwar in India. It hosted much research work and many samples. Its founding director was British pathologist Alfred Lingard . In India, some farmers were reported as not hostile to tigers because of the consideration that their attacks on diseased or weaker animals reduced the risk of rinderpest. In his classic study of the Nuer of southern Sudan, E. E. Evans-Pritchard suggested rinderpest might have affected the Nuer's social organization before and during the 1930s. Since the Nuer were pastoralists , much of their livelihood was based on cattle husbandry, and bride-prices were paid in cattle; prices may have changed as a result of cattle depletion. Rinderpest might also have increased dependence on horticulture among the Nuer. Rinderpest was eradicated from Japan in 1922, as recorded by the Nippon Institute for Biological Science. Distinguished Japanese scientist and Director of the Nippon Institute for Biological Science, Junji Nakamura (1903-1975), was a major researcher into rinderpest, and the contribution of his work to the worldwide eradication of rinderpest was acknowledged by the Food and Agriculture Organisation of the United Nations. The FAO posthumously presented a certificate of appreciation in 2011. A more recent rinderpest outbreak in Africa in 1982–1984 resulted in an estimated US$2 billion in stock losses. In 1917–18, William Hutchins Boynton (1881–1959), the chief veterinary pathologist with the Philippine Bureau of Agriculture , developed an early vaccine for rinderpest, based on treated animal organ extracts. In 1959, rinderpest vaccine was prepared at government laboratories in Abuko in The Gambia from the spleen of infected cattle. Walter Plowright worked on a vaccine for the RBOK strain of the rinderpest virus for multiple years, from 1956 to 1962. Plowright was awarded the World Food Prize in 1999 for developing a vaccine against a strain of rinderpest. In 1999, the FAO predicted that with vaccination, rinderpest would be eradicated by 2010. Widespread eradication efforts began in the early 20th century although, until the 1950s, they mostly took place on an individual country basis, using vaccination campaigns. In 1924, the World Organisation for Animal Health (OIE) was formed in response to rinderpest. In 1950, the Inter-African Bureau of Epizootic Diseases was formed, with the stated goal of eliminating rinderpest from Africa. With the loss of its wildebeest population, the Serengeti experienced radical fire regime shift to intense annual wildfires. During the 1960s, a program called JP 15 attempted to vaccinate all cattle in participating countries and, by 1979, only one of the countries involved, Sudan , reported cases of rinderpest. In the decades since, the wildebeest have returned to the Serengeti and tree cover has returned with them. In 1969, an outbreak of the disease originated in Afghanistan , travelling westwards and promoting a mass vaccination plan, which by 1972, had eliminated rinderpest in all areas of Asia except for Lebanon and India; both countries were the site of further occurrences of the disease in the 1980s. During the 1980s, however, an outbreak of rinderpest from Sudan spread throughout Africa, killing millions of cattle, as well as wildlife. In response, the Pan-African Rinderpest Campaign was initiated in 1987, using vaccination and surveillance to combat the disease. By the 1990s, nearly all of Africa, with the exception of parts of Sudan and Somalia , was declared free of rinderpest. Worldwide, the Global Rinderpest Eradication Programme was initiated in 1994, supported by the Food and Agriculture Organization , the OIE, and the International Atomic Energy Agency . This program was successful in reducing rinderpest outbreaks to few and far between by the late 1990s. The program is estimated to have saved affected farmers approximately 58 million net euros. The end was in sight by 2000 when only the Horn of Africa and Pakistan appeared to have a continued presence. Mariner et al. , 2000 introduced participatory disease surveillance to rinderpest efforts. : 61 The last confirmed case of rinderpest was reported in Kenya in 2001. Since then, while no cases have been confirmed, the disease is believed to have been present in parts of Somalia past that date. The final vaccinations were administered in 2006, and the last surveillance operations took place in 2009, failing to find any evidence of the disease. The Mariner method continued to be used in those two locations (the Horn and Pakistan) to track down possible lingering refugia in the coming years. In 2008, scientists involved in rinderpest eradication efforts believed a good chance existed that rinderpest would join smallpox as officially "wiped off the face of the planet". The FAO, which had been co-ordinating the global eradication program for the disease, announced in November 2009 that it expected the disease to be eradicated within 18 months. In October 2010, the FAO announced it was confident the disease has been eradicated. The agency said that "[a]s of mid 2010, FAO is confident that the rinderpest virus has been eliminated from Europe, Asia, Middle East, Arabian Peninsula, and Africa," which were the locations where the virus had been last reported. Eradication was confirmed by the World Organization for Animal Health on 25 May 2011. On 28 June 2011, FAO and its members countries officially recognized global freedom from the deadly cattle virus. On this day, the FAO Conference, the highest body of the UN agency, adopted a resolution declaring the eradication of rinderpest. The resolution also called on the world community to follow up by ensuring that samples of rinderpest viruses and vaccines be kept under safe laboratory conditions and that rigorous standards for disease surveillance and reporting be applied. "While we are celebrating one of the greatest successes for FAO and its partners, I wish to remind you that this extraordinary achievement would not have been possible without the joint efforts and strong commitments of governments, the main organizations in Africa, Asia and Europe, and without the continuous support of donors and international institutions", FAO Director-General Jacques Diouf commented. The rinderpest eradication effort is estimated to have cost $5 billion. Stocks of the rinderpest virus are still maintained by highly specialized laboratories. In 2015, FAO launched a campaign calling for the destruction or sequestering of the remaining stocks of rinderpest virus in laboratories in 24 countries, citing risks of inadvertent or malicious release. On 14 June 2019, the largest stock of the rinderpest virus was destroyed at the Pirbright Institute . Rinderpest was one of more than a dozen agents the United States government researched as potential biological weapons before terminating its biological weapons program . Rinderpest is of concern as a biological weapon for the following reasons: The disease has high rates of morbidity and mortality. The disease is highly communicable and spreads rapidly once introduced into nonimmune herds. Cattle herds are no longer immunized against RPV, so are susceptible to infection. Rinderpest was also considered as a biological weapon in a United Kingdom government programme during World War II.

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After the Plague

After the Plague is a 2001 collection of short stories by T. C. Boyle . The book was released on September 10, 2001 through Viking Adult and contains sixteen stories, some of which were previously published in The New Yorker , O. Henry Prize Stories , and The Best American Short Stories .The collected stories range in subject matter, from the apocalyptic titular story "After the Plague" to "Peep Hall", which centers on a man discovering a website that streams live footage of a local house full of women. Other stories feature themes such as bullying and first love. "Termination Dust" "She Wasn't Soft" "Killing Babies" "Captured by the Indians" "Achates McNeil" "Mexico" "The Love of My Life" "Rust" "Peep Hall" "Going Down" "Friendly Skies" "The Black and White Sisters" "Death of the Cool" "My Widow" "The Underground Gardens" "After the Plague""Termination Dust" "She Wasn't Soft" "Killing Babies" "Captured by the Indians" "Achates McNeil" "Mexico" "The Love of My Life" "Rust" "Peep Hall" "Going Down" "Friendly Skies" "The Black and White Sisters" "Death of the Cool" "My Widow" "The Underground Gardens" "After the Plague"Critical reception for the collection was mostly positive. Sven Birkerts , reviewing for The New York Times , gave a mostly positive review to After the Plague , stating that he enjoyed the collection but that at times the characters overwhelm the stories and "subvert the deeper claims of the work". The Guardian praised the collection, noting that "Boyle writes so beautifully that it always feels natural, never forced." The Lexington Herald-Leader gave a more mixed review, opining that although the stories are "artfully woven" they are also "plagued by illogic".

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Mouse plagues in Australia

Mouse plagues have occurred several times throughout parts of Australia since wild house mice ( Mus musculus ) were introduced by European colonists along with the First Fleet in 1788. Australia and China are the two countries in the world where plagues of mice are known to occur. Mouse plagues occur in southern and eastern Australia, usually in the grain-growing regions, around every four years. Aggregating around food sources during plagues, mice can reach a density of up to 3,000 per hectare (1,200/acre) . Mice probably arrived in Australia as stowaways on board the First Fleet of British colonists in 1788. An early localised plague of mice occurred around Walgett in New South Wales in 1871. In 1872 another plague was recorded near Saddleworth in South Australia with farmers ploughing the soil to destroy mice nests. In 1880 a plague of mice was noted along an area of the Goulburn River . South Australia experienced another plague in 1890 in the Mid North region in areas around Oladdie , Mundoora and Georgetown . In 1904, further plagues occurred in parts of New South Wales including Condobolin and other parts of the Lachlan River and around Moree, New South Wales extending all the way to coastal areas. The plague of 1917 was one of the largest mouse plagues in Australia that occurred on and around the Darling Downs area of Queensland, areas around Beulah , Campbells Creek and Willenabrina in Victoria and parts of South Australia including Balaklava . Eventually mice reached the Goldfields-Esperance and Wheatbelt regions of Western Australia. Plagues of mice have been occurring ever since with increasing frequency. More incidences of plagues occurred in 1918 in parts of Victoria and New South Wales. In 1922 areas around Dubbo, New South Wales and Tamworth in New South Wales were hit again followed by more plagues through the Riverina in 1925. Mice struck again in 1928 in parts of Queensland around Warwick . Further plagues occurred around Wimmera in Victoria, Loxton in South Australia and Winton in Queensland in 1931 and more were recorded in parts of New South Wales in 1932 including Culgoa and Parkes . The next plague hit areas around Warracknabeal and Hopetoun in Victoria but was less intense than the 1932 plagues. In 1952, parts of Victoria and South Australia were struck by mouse plagues. Areas in New South Wales and Queensland were hit by mouse plagues in 1955. In 1956 parts of the Eyre Peninsula in South Australia experienced the worst mouse plague the area had known. Parts of outback New South Wales around Bourke were hit by plagues of mice in 1967. In 1972, parts of Queensland were hit by mouse plagues as were parts of Victoria and New South Wales in 1975. A plague in Victoria in 1979 cost farmers A$ 15 million in lost crops and damaged machinery. The plagues continued into 1980. Another plague occurred in 1994 affecting parts of New South Wales, the Australian Capital Territory, South Australia and northern Victoria. Australia's worst ever mouse plague occurred in 1993 and caused an estimated A$ 96 million worth of damage to crops and attacked livestock in piggeries and poultry farms. They also destroyed rubber and electrical insulation, damaged farm vehicles, and ruined cars and buildings. Mouse numbers built to plague numbers in early 2011 in southern Queensland, through New South Wales, western Victoria and South Australia spreading to the Nullarbor Plain region of Western Australia in late 2011. A mouse plague affecting parts of Queensland and New South Wales began in mid-2020 and continued into 2021. Co-occurring with the COVID-19 pandemic, mice were initially not susceptible but researchers showed that a type of mutation called aromatic substitution in position 501 or position 498 (but not both) in the SARS-CoV-2 virus spike protein would adapt the novel Coronavirus to mice. In January 2021, the mice continued to cause problems, and raised concerns for crops in areas of New South Wales and Queensland. In March 2021, mice were stripping food and other items from the shelves of a supermarket in Gulargambone ( 382 km (237 mi) north west of Sydney). Health concerns for people were raised when mice killed by baits were found in drinking water tanks. Trundle and Tottenham have also been affected. In May 2021, the Central West town of Canowindra and residents were featured in a CNN report on the phenomena. In the meantime, mice were chewing through walls and ceilings, and were estimated to have caused $100 million in damage to crops and grain stores. Homeowners setting traps were reporting catching 500 to 600 mice per night. The plague caused the complete evacuation (420 inmates and 200 staff) of the Wellington Correctional Centre in June 2021 as dead mice and damage to infrastructure led to concerns for health and safety of inmates and staff. Mice probably arrived in Australia as stowaways on board the First Fleet of British colonists in 1788. An early localised plague of mice occurred around Walgett in New South Wales in 1871. In 1872 another plague was recorded near Saddleworth in South Australia with farmers ploughing the soil to destroy mice nests. In 1880 a plague of mice was noted along an area of the Goulburn River . South Australia experienced another plague in 1890 in the Mid North region in areas around Oladdie , Mundoora and Georgetown . In 1904, further plagues occurred in parts of New South Wales including Condobolin and other parts of the Lachlan River and around Moree, New South Wales extending all the way to coastal areas. The plague of 1917 was one of the largest mouse plagues in Australia that occurred on and around the Darling Downs area of Queensland, areas around Beulah , Campbells Creek and Willenabrina in Victoria and parts of South Australia including Balaklava . Eventually mice reached the Goldfields-Esperance and Wheatbelt regions of Western Australia. Plagues of mice have been occurring ever since with increasing frequency. More incidences of plagues occurred in 1918 in parts of Victoria and New South Wales. In 1922 areas around Dubbo, New South Wales and Tamworth in New South Wales were hit again followed by more plagues through the Riverina in 1925. Mice struck again in 1928 in parts of Queensland around Warwick . Further plagues occurred around Wimmera in Victoria, Loxton in South Australia and Winton in Queensland in 1931 and more were recorded in parts of New South Wales in 1932 including Culgoa and Parkes . The next plague hit areas around Warracknabeal and Hopetoun in Victoria but was less intense than the 1932 plagues. In 1952, parts of Victoria and South Australia were struck by mouse plagues. Areas in New South Wales and Queensland were hit by mouse plagues in 1955. In 1956 parts of the Eyre Peninsula in South Australia experienced the worst mouse plague the area had known. Parts of outback New South Wales around Bourke were hit by plagues of mice in 1967. In 1972, parts of Queensland were hit by mouse plagues as were parts of Victoria and New South Wales in 1975. A plague in Victoria in 1979 cost farmers A$ 15 million in lost crops and damaged machinery. The plagues continued into 1980. Another plague occurred in 1994 affecting parts of New South Wales, the Australian Capital Territory, South Australia and northern Victoria. Australia's worst ever mouse plague occurred in 1993 and caused an estimated A$ 96 million worth of damage to crops and attacked livestock in piggeries and poultry farms. They also destroyed rubber and electrical insulation, damaged farm vehicles, and ruined cars and buildings. Mouse numbers built to plague numbers in early 2011 in southern Queensland, through New South Wales, western Victoria and South Australia spreading to the Nullarbor Plain region of Western Australia in late 2011. A mouse plague affecting parts of Queensland and New South Wales began in mid-2020 and continued into 2021. Co-occurring with the COVID-19 pandemic, mice were initially not susceptible but researchers showed that a type of mutation called aromatic substitution in position 501 or position 498 (but not both) in the SARS-CoV-2 virus spike protein would adapt the novel Coronavirus to mice. In January 2021, the mice continued to cause problems, and raised concerns for crops in areas of New South Wales and Queensland. In March 2021, mice were stripping food and other items from the shelves of a supermarket in Gulargambone ( 382 km (237 mi) north west of Sydney). Health concerns for people were raised when mice killed by baits were found in drinking water tanks. Trundle and Tottenham have also been affected. In May 2021, the Central West town of Canowindra and residents were featured in a CNN report on the phenomena. In the meantime, mice were chewing through walls and ceilings, and were estimated to have caused $100 million in damage to crops and grain stores. Homeowners setting traps were reporting catching 500 to 600 mice per night. The plague caused the complete evacuation (420 inmates and 200 staff) of the Wellington Correctional Centre in June 2021 as dead mice and damage to infrastructure led to concerns for health and safety of inmates and staff.

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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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Corrupted Blood incident

The Corrupted Blood incident (also known as the World of Warcraft pandemic ) took place between September 13 and October 8, 2005, in World of Warcraft , a massively multiplayer online role-playing game (MMORPG) developed by Blizzard Entertainment . When participating in a boss battle at the end of a raid , player characters would become infected with a debuff that was transmitted between characters in close proximity. While developers intended to keep the effects of the debuff in the boss's game region, a programming oversight soon led to an in-game pandemic throughout the fictional world of Azeroth . World of Warcraft introduced the game region of Zul'Gurub on September 13. The boss of the region, Hakkar the Soulflayer, cast Corrupted Blood on raid participants; the debuff's effects expired when players defeated Hakkar. Corrupted Blood soon spread beyond Zul'Gurub as players reacted to the infection with panic, either fast traveling to heavily-populated game regions or deactivating their animal companions. When those companions were reactivated, they still carried the debuff, becoming disease vectors , while non-player characters became asymptomatic carriers . Player reactions to the Corrupted Blood pandemic varied: some provided aid by healing players or warning them of outbreak zones, while griefers intentionally contracted the debuff to spread it across the game world. After several failed hotfixes , Blizzard ended the pandemic by performing a hard reset , and a later patch prevented companions from contracting Corrupted Blood entirely. Although it was the result of a software bug , the Corrupted Blood incident gained attention from World of Warcraft players and disease researchers. Blizzard developed intentional in-game pandemics in two expansion sets : Wrath of the Lich King in 2008 and Shadowlands in 2020. Epidemiologists, meanwhile, took interest in how MMORPGs, unlike mathematical models, could capture individual human responses to disease outbreaks rather than generating assumptions about behavior.Blizzard Entertainment released World of Warcraft , a massively multiplayer online role-playing game (MMORPG), on November 23, 2004, in North America and Australia, and a European release followed in February 2005. As a role-playing game, players create their player characters by choosing among various fantasy races, character classes , and allegiance to one of the game's in-universe factions. After creating their character, the player begins a quest in the fantasy world of Azeroth, where they may fight monsters either alone or together with other players in parties . For larger dungeon crawls , players may create a raid group of up to 40 characters. Player characters gain experience levels through the completion of quests and the defeat of non-player characters (NPCs) such as monsters or dragons. Gaining experience levels, higher-level armor, and improved weaponry then allows player characters to participate in more difficult dungeon crawls. World of Warcraft was immediately popular upon its release, with over 240,000 subscribers within 24 hours of its North American launch. By March 2005, its subscriber base had reached 1.5 million individuals. By the time of the Corrupted Blood incident, World of Warcraft had over four million subscribers, corresponding to a $700 million annual revenue stream. It was significantly more popular than other MMORPGs of the time: EverQuest II had approximately 500,000 subscribers in September 2005, while The Matrix Online struggled to acquire 50,000 subscribers within three months of its release. To retain their subscribers after players finished all the content that was available upon World of Warcraft ' s release, Blizzard maintained a team of developers to regularly add new content such as raids. Zul'Gurub was added to the game's open world on Sept 17 2005 with patch 1.7, it was the game's 4th major raid and the first intended for 20 players. The boss of this region was Hakkar the Soulflayer, who would cast a debuff on players called "Corrupted Blood". After Hakkar cast Corrupted Blood on one player in a raid group, the debuff would be transmitted to other player characters in close proximity. The effects of Corrupted Blood were intended to last for 10 seconds, or until the players defeated Hakkar, whichever came first. One of Hakkar's healing mechanisms was to temporarily stun a raid party and drain their blood. Blizzard developers intended for players to defeat Hakkar by first weakening him with attacks and then exposing themselves to Corrupted Blood. Developers had intended to limit the effects of the debuff to the Zul'Gurub region, but several factors led to its spread throughout the in-game universe. First, World of Warcraft enabled fast travel , which allowed player characters to quickly move to large population centers from more remote regions like Zul'Gurub, sometimes while still under the effects of Corrupted Blood. A programming oversight further contributed to the spread of the in-game pandemic. Players with animal companions could protect their pets during boss battles by placing them into a type of suspended animation mid-fight. Pet companions could contract Corrupted Blood, and after noticing that their pet had become infected, many players would place the animal into its suspended state to protect them from death. These pets were subsequently re-activated after the completion of the boss battle, but developers had forgotten to include an "off-switch" that would recognize the conclusion of the raid and remove the debuff from companions. Players who defeated Hakkar would subsequently fast travel to markets in urban centers in order to repair their damaged armor and weaponry. They then re-activated their infected pets, who became disease vectors , allowing Corrupted Blood to spread beyond players involved in the raid. Other NPCs could become infected with the disease, but they were incapable of dying, and instead became asymptomatic carriers for player characters. Once it spread beyond the Zul'Gurub region, Corrupted Blood quickly became pandemic in Azeroth. No index case was ever identified. Outbreaks soon occurred in Orgrimmar, the capital city of the Orcs , and in the dwarf city of Ironforge. There was no in-game cure for Corrupted Blood, which inflicted between 263 and 317 hit points of damage every two seconds. This level of damage would kill a character of average experience level between 60 and 90 seconds. While World of Warcraft player characters are resurrected after death, the items that the characters had acquired would become damaged upon each revival, making character death inconvenient for players. The sudden arrival and spread of the Corrupted Blood pandemic created widespread panic among World of Warcraft ' s user base. One player told The Washington Post that the " world chat would explode any time a city fell. We kept a close eye not only on our guild chat but on world chat as well to see where not to go. We didn't want to catch it." Casual World of Warcraft players who had read about the incident on the news would log into their accounts to better understand the pandemic, promptly infecting their characters. The in-game environment soon filled with the skeletons and corpses of player characters who had succumbed to the infection, and internet forums described seeing "hundreds" of these bodies throughout Azeroth's population centers. One player described Azeroth as "filled to the brim with corpses", the "streets literally white with the bones of the dead". Another posted that "[s]ome servers have gotten so bad that you can't go into the major cities without getting the plague. And anyone less than like Level 50 nearly immediately dies." Some players incorrectly speculated that the Corrupted Blood incident had been intentional, with developers intending for the Hakkar boss battle to lead directly into a pandemic-based game event. Once players realized the scope of the pandemic, individual reactions to the infection varied. Some players whose characters possessed healing abilities headed to major cities as impromptu first responders , but these characters often contracted and died from the disease as well. Healing measures were largely ineffective, as only one character class, Paladins, were capable of removing debuffs of Corrupted Blood's nature, and players risked reinfection almost immediately upon healing. More often, rather than removing the Corrupted Blood infection, healing characters merely kept characters alive and contagious, thereby prolonging the spread of the infection. Less powerful player characters, meanwhile, would stand at the edges of infected towns, warning other player characters not to enter. Players transmitted information from afar by using the game's farthest-reaching chat function, "yell". At least one player became an unofficial town crier , making announcements about new pandemic developments in the open world's public spaces. Other players enacted self-quarantine methods, remaining in less-populated wilderness areas of Azeroth rather than entering towns or cities where they risked infection. Although the pandemic did not extend to the real world, epidemiologist Nina Fefferman noted that "players seemed to really feel they were at risk and took the threat of infection seriously, even though it was only a game." Griefers , players who engage in bad faith multiplayer game tactics, took advantage of the Corrupted Blood incident to target and inconvenience other players. These players would purposely contract Corrupted Blood and travel to densely populated areas to further its spread. One griefer whose guild engaged in this practice told Wired that he did so because he was amused by the reactions of other players, saying, "It's just funny to watch people run away screaming". Fefferman compared these players to Typhoid Mary , an asymptomatic carrier of typhoid fever who resisted warnings and quarantines to infect others with the disease. Discussion on internet chat forums about Corrupted Blood often included misinformation among general confusion. At approximately 1:15 p.m. ( EDT ) on the afternoon of September 16, a Blizzard staff member reported that the team was "aware of the issue and working on it". While the company quickly became aware that Corrupted Blood had spread beyond its intended reach, identifying and fixing the issue that led to the pandemic proved difficult. One of the first steps that Blizzard took to attempt containment of the virus was to institute quarantine zones, placing barriers around heavily infected areas. The effect that this quarantine had was limited, as some players managed to bypass Blizzard's containment measures. Developers, meanwhile, faced difficulties in isolating and removing the virus from the pet companions that were driving its spread. Their two options for healing pet companions were to manually check every animal in the game universe for Corrupted Blood infection or developing "really hacky code" that would automatically check for infection every time a companion was summoned. Blizzard attempted to put a stop to the pandemic with hotfixes , including restarting each game server on a rolling basis, but Corrupted Blood outbreaks soon re-emerged in restarted areas. These outbreaks also came on a rolling basis: the plague would dissipate after running through a particular game region, only to re-emerge once players, believing that the danger had passed, repopulated the area. After one week without finding a suitable remedy, Blizzard performed hard resets on the World of Warcraft servers, resetting Azeroth to its state from just before the introduction of Corrupted Blood. On October 8, Blizzard released a patch for World of Warcraft that made pet companions immune to contracting Corrupted Blood. Zul'Gurub was added to the game's open world on Sept 17 2005 with patch 1.7, it was the game's 4th major raid and the first intended for 20 players. The boss of this region was Hakkar the Soulflayer, who would cast a debuff on players called "Corrupted Blood". After Hakkar cast Corrupted Blood on one player in a raid group, the debuff would be transmitted to other player characters in close proximity. The effects of Corrupted Blood were intended to last for 10 seconds, or until the players defeated Hakkar, whichever came first. One of Hakkar's healing mechanisms was to temporarily stun a raid party and drain their blood. Blizzard developers intended for players to defeat Hakkar by first weakening him with attacks and then exposing themselves to Corrupted Blood. Developers had intended to limit the effects of the debuff to the Zul'Gurub region, but several factors led to its spread throughout the in-game universe. First, World of Warcraft enabled fast travel , which allowed player characters to quickly move to large population centers from more remote regions like Zul'Gurub, sometimes while still under the effects of Corrupted Blood. A programming oversight further contributed to the spread of the in-game pandemic. Players with animal companions could protect their pets during boss battles by placing them into a type of suspended animation mid-fight. Pet companions could contract Corrupted Blood, and after noticing that their pet had become infected, many players would place the animal into its suspended state to protect them from death. These pets were subsequently re-activated after the completion of the boss battle, but developers had forgotten to include an "off-switch" that would recognize the conclusion of the raid and remove the debuff from companions. Players who defeated Hakkar would subsequently fast travel to markets in urban centers in order to repair their damaged armor and weaponry. They then re-activated their infected pets, who became disease vectors , allowing Corrupted Blood to spread beyond players involved in the raid. Other NPCs could become infected with the disease, but they were incapable of dying, and instead became asymptomatic carriers for player characters. Once it spread beyond the Zul'Gurub region, Corrupted Blood quickly became pandemic in Azeroth. No index case was ever identified. Outbreaks soon occurred in Orgrimmar, the capital city of the Orcs , and in the dwarf city of Ironforge. There was no in-game cure for Corrupted Blood, which inflicted between 263 and 317 hit points of damage every two seconds. This level of damage would kill a character of average experience level between 60 and 90 seconds. While World of Warcraft player characters are resurrected after death, the items that the characters had acquired would become damaged upon each revival, making character death inconvenient for players. The sudden arrival and spread of the Corrupted Blood pandemic created widespread panic among World of Warcraft ' s user base. One player told The Washington Post that the " world chat would explode any time a city fell. We kept a close eye not only on our guild chat but on world chat as well to see where not to go. We didn't want to catch it." Casual World of Warcraft players who had read about the incident on the news would log into their accounts to better understand the pandemic, promptly infecting their characters. The in-game environment soon filled with the skeletons and corpses of player characters who had succumbed to the infection, and internet forums described seeing "hundreds" of these bodies throughout Azeroth's population centers. One player described Azeroth as "filled to the brim with corpses", the "streets literally white with the bones of the dead". Another posted that "[s]ome servers have gotten so bad that you can't go into the major cities without getting the plague. And anyone less than like Level 50 nearly immediately dies." Some players incorrectly speculated that the Corrupted Blood incident had been intentional, with developers intending for the Hakkar boss battle to lead directly into a pandemic-based game event. Once players realized the scope of the pandemic, individual reactions to the infection varied. Some players whose characters possessed healing abilities headed to major cities as impromptu first responders , but these characters often contracted and died from the disease as well. Healing measures were largely ineffective, as only one character class, Paladins, were capable of removing debuffs of Corrupted Blood's nature, and players risked reinfection almost immediately upon healing. More often, rather than removing the Corrupted Blood infection, healing characters merely kept characters alive and contagious, thereby prolonging the spread of the infection. Less powerful player characters, meanwhile, would stand at the edges of infected towns, warning other player characters not to enter. Players transmitted information from afar by using the game's farthest-reaching chat function, "yell". At least one player became an unofficial town crier , making announcements about new pandemic developments in the open world's public spaces. Other players enacted self-quarantine methods, remaining in less-populated wilderness areas of Azeroth rather than entering towns or cities where they risked infection. Although the pandemic did not extend to the real world, epidemiologist Nina Fefferman noted that "players seemed to really feel they were at risk and took the threat of infection seriously, even though it was only a game." Griefers , players who engage in bad faith multiplayer game tactics, took advantage of the Corrupted Blood incident to target and inconvenience other players. These players would purposely contract Corrupted Blood and travel to densely populated areas to further its spread. One griefer whose guild engaged in this practice told Wired that he did so because he was amused by the reactions of other players, saying, "It's just funny to watch people run away screaming". Fefferman compared these players to Typhoid Mary , an asymptomatic carrier of typhoid fever who resisted warnings and quarantines to infect others with the disease. Discussion on internet chat forums about Corrupted Blood often included misinformation among general confusion. At approximately 1:15 p.m. ( EDT ) on the afternoon of September 16, a Blizzard staff member reported that the team was "aware of the issue and working on it". While the company quickly became aware that Corrupted Blood had spread beyond its intended reach, identifying and fixing the issue that led to the pandemic proved difficult. One of the first steps that Blizzard took to attempt containment of the virus was to institute quarantine zones, placing barriers around heavily infected areas. The effect that this quarantine had was limited, as some players managed to bypass Blizzard's containment measures. Developers, meanwhile, faced difficulties in isolating and removing the virus from the pet companions that were driving its spread. Their two options for healing pet companions were to manually check every animal in the game universe for Corrupted Blood infection or developing "really hacky code" that would automatically check for infection every time a companion was summoned. Blizzard attempted to put a stop to the pandemic with hotfixes , including restarting each game server on a rolling basis, but Corrupted Blood outbreaks soon re-emerged in restarted areas. These outbreaks also came on a rolling basis: the plague would dissipate after running through a particular game region, only to re-emerge once players, believing that the danger had passed, repopulated the area. After one week without finding a suitable remedy, Blizzard performed hard resets on the World of Warcraft servers, resetting Azeroth to its state from just before the introduction of Corrupted Blood. On October 8, Blizzard released a patch for World of Warcraft that made pet companions immune to contracting Corrupted Blood. While Blizzard had not intended to create a pandemic event with the Corrupted Blood incident, the company noted the popularity that the pandemic had received. In 2008, Blizzard released an intentional plague in World of Warcraft to echo the success of the Corrupted Blood pandemic. On October 22, shortly before the release of a World of Warcraft expansion set titled Wrath of the Lich King , several mysterious crates appeared in one Azeroth town. Player characters who inspected these crates became infected with an unknown disease, and if they did not find a cure within 10 minutes, they would be transformed into zombies . Unlike Corrupted Blood, it was possible to cure the zombie infection through healing spells or NPC aid. As the number of infected characters grew, however, the time frame for healing became shorter and the virus became resistant to cleansing. Blizzard put a stop to the Lich King plague on October 28 after receiving complaints from players that the zombie infection was detracting from other parts of the game. Another zombie pandemic known as the Scourge invasion was featured in 2020's World of Warcraft: Shadowlands expansion. To limit griefing attacks, the 2020 Scourge invasion was designed to make opting into the event more of a conscious choice by players who wanted to fight against the zombie hordes. The Scourge invasion received criticism, however, for its handling of new players. Shadowlands created a new starting area for players, Exile's Reach, in which new characters were separated from the rest of the game until they reached level 10. While this alternative starting area was isolated from the zombie pandemic, players whose characters began in other starting areas remained susceptible to infection and death. In 2012, Star Wars: The Old Republic , a MMORPG by BioWare , released an online disease resembling the Corrupted Blood plague. Characters infected with the Rakghoul Plague would develop a signature cough that became progressively louder before they transformed into a zombie-like creature. Because the plague was transmitted more easily in heavily populated centers, player characters conducted business in more remote business areas to avoid infection. Unlike the Corrupted Blood incident, BioWare intentionally released the Rakghoul Plague, and player characters who succumbed to the disease received special items. Lead designer Daniel Erickson told reporters that the Rakghoul Plague was inspired by the Corrupted Blood incident, but that developers wanted to steer players away from griefing and towards positive interactions with the pandemic. Blizzard closed the Zul'Gurub raid in 2010 as part of a larger update which transformed the region into a five-person dungeon with new bosses. The region was added to World of Warcraft Classic in 2020, but because Classic was derived from code created after the Corrupted Blood patch, pets were immune to Corrupted Blood, preventing another pandemic. The impact that the Corrupted Blood pandemic had on World of Warcraft players gained the attention of epidemiologists. The Centers for Disease Control and Prevention (CDC) contacted Blizzard after the incident, asking if they could use data from what they perceived as a planned disease simulation to inform their disease modeling research. Blizzard informed the facility that the Corrupted Blood outbreak was the unintentional result of a software bug and they thus had no usable data. Despite its accidental nature, the Corrupted Blood incident bore several resemblances to real-world pandemics, leading researchers to explore the event as a disease model. In an article for the journal Epidemiology , Ran Balicer of the Ben-Gurion University of the Negev compared the role that pet companions played in the spread of Corrupted Blood to avian influenza , which spread through asymptomatic ducks. The use of fast travel to quickly spread the disease between distant locations was also compared to the role that air travel played in the 2002–2004 SARS outbreak . Of particular interest to researchers in the use of MMORPGs for epidemiology is that character responses to a virtual pandemic are the result of individual player reactions, adding "a level of authenticity that doesn't exist in other simulations". Disease researchers typically study disease spread and control through the use of three general models, all of which make significant assumptions about human behavior. As behavior is difficult to predict, the effectiveness of these models is limited. The use of MMORPG environments like World of Warcraft introduces human behavior into disease models: while player characters are virtual, players are attached to the health and success of their characters and others, creating an immersive social environment. Video game models necessarily include player behaviors that would not be included in a general model. For instance, characters may deliberately enter infected areas in the hope that a healing character would protect them, just as individuals may expose themselves to infection under the belief that a vaccine may be in the region. Some researchers have responded skeptically to the notion that games like World of Warcraft may accurately model real-world infectious disease patterns. Although Gary Smith, a professor at the University of Pennsylvania , admitted that mathematical disease models fail to take into account the spectrum of human behavior, he questioned the ability of a video game to remedy this error, saying that "the study is just as 'observational' as disease outbreak studies in the real world". Dmitri Williams, an associate professor at the University of Southern California and a World of Warcraft player, questioned whether a player's behavior in a game "where you are encouraged to behave in a way that you would never behave offline" would be applicable to the real world. Neil Ferguson , director of the MRC Centre for Global Infectious Disease Analysis , noted that because characters could regenerate, there was not as much risk in becoming infected with a virtual disease, limiting the applicability of player behavior to the real world. While the Corrupted Blood incident created a focus on video games as tools of disease research, there were some specific aspects of the debuff that limited its applicability to other pandemics. For instance, the basic reproduction number of Corrupted Blood was significantly higher than any observed real-world pathogen, which in turn affected the rate of spread and player reactions. Additionally, players who had been infected with Corrupted Blood did not gain immunity to the debuff, which kept the infection circulating in perpetuity. Outside of disease research, some have speculated that the griefing attacks that took place during the Corrupted Blood pandemic may provide a model for bioterrorism research. Charles Blair of the Center for Terrorism and Intelligence Studies told Wired that, just as the human behavior in World of Warcraft supplemented general disease models, the behavior of griefers could augment the computer-modeled tactical decision-making enacted by terrorist researchers. The sudden impact of the COVID-19 pandemic in 2020 led several researchers to turn to the Corrupted Blood incident as a potential model for understanding the virus's sociological impact. The Elysium Project, an independent fan-led organization maintaining early versions of World of Warcraft , ran an experiment titled "Pandemic In Azeroth" which mimicked both the Corrupted Blood incident and the COVID-19 pandemic. The pandemic infected 88 percent of active players, but by implementing sanitation and isolation measures, this number soon dropped to 42.2 percent. Other researchers noted the similarities between the game and the real-world pandemics. Both had an immediate impact on dense urban areas, which limited the effectiveness of containment procedures in stopping the spread of disease, while air travel, like fast travel, allowed infections to spread across large parts of the world with ease. Lofgren compared the in-game "first responders", many of whom contracted Corrupted Blood when they attempted to heal others, to healthcare workers that were overrun with COVID-19 patients and became infected themselves. While a direct analogue was not made to griefers, meanwhile, Lofgren also acknowledged individuals who contracted the COVID-19 virus but chose not to quarantine , thus infecting others through negligence. While Blizzard had not intended to create a pandemic event with the Corrupted Blood incident, the company noted the popularity that the pandemic had received. In 2008, Blizzard released an intentional plague in World of Warcraft to echo the success of the Corrupted Blood pandemic. On October 22, shortly before the release of a World of Warcraft expansion set titled Wrath of the Lich King , several mysterious crates appeared in one Azeroth town. Player characters who inspected these crates became infected with an unknown disease, and if they did not find a cure within 10 minutes, they would be transformed into zombies . Unlike Corrupted Blood, it was possible to cure the zombie infection through healing spells or NPC aid. As the number of infected characters grew, however, the time frame for healing became shorter and the virus became resistant to cleansing. Blizzard put a stop to the Lich King plague on October 28 after receiving complaints from players that the zombie infection was detracting from other parts of the game. Another zombie pandemic known as the Scourge invasion was featured in 2020's World of Warcraft: Shadowlands expansion. To limit griefing attacks, the 2020 Scourge invasion was designed to make opting into the event more of a conscious choice by players who wanted to fight against the zombie hordes. The Scourge invasion received criticism, however, for its handling of new players. Shadowlands created a new starting area for players, Exile's Reach, in which new characters were separated from the rest of the game until they reached level 10. While this alternative starting area was isolated from the zombie pandemic, players whose characters began in other starting areas remained susceptible to infection and death. In 2012, Star Wars: The Old Republic , a MMORPG by BioWare , released an online disease resembling the Corrupted Blood plague. Characters infected with the Rakghoul Plague would develop a signature cough that became progressively louder before they transformed into a zombie-like creature. Because the plague was transmitted more easily in heavily populated centers, player characters conducted business in more remote business areas to avoid infection. Unlike the Corrupted Blood incident, BioWare intentionally released the Rakghoul Plague, and player characters who succumbed to the disease received special items. Lead designer Daniel Erickson told reporters that the Rakghoul Plague was inspired by the Corrupted Blood incident, but that developers wanted to steer players away from griefing and towards positive interactions with the pandemic. Blizzard closed the Zul'Gurub raid in 2010 as part of a larger update which transformed the region into a five-person dungeon with new bosses. The region was added to World of Warcraft Classic in 2020, but because Classic was derived from code created after the Corrupted Blood patch, pets were immune to Corrupted Blood, preventing another pandemic. The impact that the Corrupted Blood pandemic had on World of Warcraft players gained the attention of epidemiologists. The Centers for Disease Control and Prevention (CDC) contacted Blizzard after the incident, asking if they could use data from what they perceived as a planned disease simulation to inform their disease modeling research. Blizzard informed the facility that the Corrupted Blood outbreak was the unintentional result of a software bug and they thus had no usable data. Despite its accidental nature, the Corrupted Blood incident bore several resemblances to real-world pandemics, leading researchers to explore the event as a disease model. In an article for the journal Epidemiology , Ran Balicer of the Ben-Gurion University of the Negev compared the role that pet companions played in the spread of Corrupted Blood to avian influenza , which spread through asymptomatic ducks. The use of fast travel to quickly spread the disease between distant locations was also compared to the role that air travel played in the 2002–2004 SARS outbreak . Of particular interest to researchers in the use of MMORPGs for epidemiology is that character responses to a virtual pandemic are the result of individual player reactions, adding "a level of authenticity that doesn't exist in other simulations". Disease researchers typically study disease spread and control through the use of three general models, all of which make significant assumptions about human behavior. As behavior is difficult to predict, the effectiveness of these models is limited. The use of MMORPG environments like World of Warcraft introduces human behavior into disease models: while player characters are virtual, players are attached to the health and success of their characters and others, creating an immersive social environment. Video game models necessarily include player behaviors that would not be included in a general model. For instance, characters may deliberately enter infected areas in the hope that a healing character would protect them, just as individuals may expose themselves to infection under the belief that a vaccine may be in the region. Some researchers have responded skeptically to the notion that games like World of Warcraft may accurately model real-world infectious disease patterns. Although Gary Smith, a professor at the University of Pennsylvania , admitted that mathematical disease models fail to take into account the spectrum of human behavior, he questioned the ability of a video game to remedy this error, saying that "the study is just as 'observational' as disease outbreak studies in the real world". Dmitri Williams, an associate professor at the University of Southern California and a World of Warcraft player, questioned whether a player's behavior in a game "where you are encouraged to behave in a way that you would never behave offline" would be applicable to the real world. Neil Ferguson , director of the MRC Centre for Global Infectious Disease Analysis , noted that because characters could regenerate, there was not as much risk in becoming infected with a virtual disease, limiting the applicability of player behavior to the real world. While the Corrupted Blood incident created a focus on video games as tools of disease research, there were some specific aspects of the debuff that limited its applicability to other pandemics. For instance, the basic reproduction number of Corrupted Blood was significantly higher than any observed real-world pathogen, which in turn affected the rate of spread and player reactions. Additionally, players who had been infected with Corrupted Blood did not gain immunity to the debuff, which kept the infection circulating in perpetuity. Outside of disease research, some have speculated that the griefing attacks that took place during the Corrupted Blood pandemic may provide a model for bioterrorism research. Charles Blair of the Center for Terrorism and Intelligence Studies told Wired that, just as the human behavior in World of Warcraft supplemented general disease models, the behavior of griefers could augment the computer-modeled tactical decision-making enacted by terrorist researchers. The sudden impact of the COVID-19 pandemic in 2020 led several researchers to turn to the Corrupted Blood incident as a potential model for understanding the virus's sociological impact. The Elysium Project, an independent fan-led organization maintaining early versions of World of Warcraft , ran an experiment titled "Pandemic In Azeroth" which mimicked both the Corrupted Blood incident and the COVID-19 pandemic. The pandemic infected 88 percent of active players, but by implementing sanitation and isolation measures, this number soon dropped to 42.2 percent. Other researchers noted the similarities between the game and the real-world pandemics. Both had an immediate impact on dense urban areas, which limited the effectiveness of containment procedures in stopping the spread of disease, while air travel, like fast travel, allowed infections to spread across large parts of the world with ease. Lofgren compared the in-game "first responders", many of whom contracted Corrupted Blood when they attempted to heal others, to healthcare workers that were overrun with COVID-19 patients and became infected themselves. While a direct analogue was not made to griefers, meanwhile, Lofgren also acknowledged individuals who contracted the COVID-19 virus but chose not to quarantine , thus infecting others through negligence.

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Plague

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The Absence (band)

The Absence is an American melodic death metal band from Tampa , Florida . Their style has been described as aggressive thrash metal with Scandinavian metal influences. They were previously signed to Metal Blade Records and are now signed to M-Theory Audio. The band released a self-titled EP in 2004 and followed up with their debut album, From Your Grave , in 2005. The band's second album, Riders of the Plague , was released in 2007. The album was praised in a review for finding an "interesting balance" between the genres death metal and thrash metal . In 2007, bassist Michael Leon joined the band. Drummer Jeramie Kling left the band that same year and was temporarily replaced by Chris Pistillo from the Tampa death metal scene. The band recruited Justin Reynolds as their new drummer in early 2008. The Absence stated in late 2008 that they would be entering the studio to record a new album in March 2009. Due to time constraints and touring duties, the band said they would enter the studio on September 10 since the original date "wasn't the right time." The band delayed the recording of the album again and later entered Mana Recording Studios on November 2, 2009, to record Enemy Unbound . Their third studio album, Enemy Unbound was released on September 14, 2010, and reached No. 55 on the Billboard Heatseekers chart. Jeramie Kling rejoined the band during summer 2010. On September 27, 2010, The Absence released their music video of "Enemy Unbound" from their eponymous album Enemy Unbound . As of January 1, 2013, guitarist Peter Joseph parted ways with The Absence. On January 22, 2013, it was announced that Per Nilsson of Scar Symmetry had joined the band. On July 25, 2015, guitarist Patrick Scott Pintavalle announced on Facebook that he had left the band. On March 30, 2021, the band announced their fifth full-length album, would be titled Coffinized . It was released June 25, 2021. On January 4, 2024, the band announced their self-titled sixth studio album would be released on March 29. Jamie Stewart – vocals (2002–present) Jeramie Kling – drums (2003–2007, 2010–present) Taylor Nordberg – guitars (2013–present) Patrick Pintavalle – guitars (2002–2015) Nicholas Calaci – bass (2002–2007) Christopher Tolan – guitars (2002–2003) Justin Grant – drums (2002–2003) Peter Joseph – guitars (2003–2013) Mike Leon – bass (2007–2021) Justin Reynolds – drums (2008–2010) Per Nilsson – guitars (2013–2016) Joey Concepcion – guitars (2016–2021)Jamie Stewart – vocals (2002–present) Jeramie Kling – drums (2003–2007, 2010–present) Taylor Nordberg – guitars (2013–present)Patrick Pintavalle – guitars (2002–2015) Nicholas Calaci – bass (2002–2007) Christopher Tolan – guitars (2002–2003) Justin Grant – drums (2002–2003) Peter Joseph – guitars (2003–2013) Mike Leon – bass (2007–2021) Justin Reynolds – drums (2008–2010) Per Nilsson – guitars (2013–2016) Joey Concepcion – guitars (2016–2021)From Your Grave (2005) Riders of the Plague (2007) Enemy Unbound (2010) A Gift for the Obsessed (2018) Coffinized (2021) The Absence (2024) The Absence (2004) "From Your Grave" (2005) "Dead and Gone" (2008) "Enemy Unbound" (2010) "Oceans" (2013) "Septic Testament" (2016)From Your Grave (2005) Riders of the Plague (2007) Enemy Unbound (2010) A Gift for the Obsessed (2018) Coffinized (2021) The Absence (2024)The Absence (2004)"From Your Grave" (2005) "Dead and Gone" (2008) "Enemy Unbound" (2010) "Oceans" (2013) "Septic Testament" (2016)

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Plague

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

Pest house

A pest house , plague house , pesthouse or fever shed was a type of building used for persons afflicted with communicable diseases such as tuberculosis , cholera , smallpox or typhus . Often used for forcible quarantine , many towns and cities had one or more pesthouses accompanied by a cemetery or a waste pond nearby for disposal of the dead.Fever sheds were built in several communities across Eastern Canada in 1847, to quarantine sick and dying Irish immigrants, who contracted typhus during the voyage to the New World during the Great Famine . [ citation needed ] In Montreal , between 3,500 and 6,000 Irish immigrants died in fever sheds in a quarantine area known as Windmill Point . Three sheds were initially constructed, 150 feet (46 m) long by 40 to 50 feet (15 m) wide. As thousands more sick immigrants landed, more sheds had to be erected. The number of sheds would grow to 22, with troops cordoning off the area so the sick could not escape. In Toronto , during the summer of 1847, 863 Irish immigrants died of typhus at fever sheds built by the Toronto Board of Health at the northwest corner of King and John Street . There were at least 12 sheds, 22 metres long by 7.5 metres wide. Partridge Island, New Brunswick , just outside the main harbour of Saint John , was chosen as the location for a pest house and quarantine station as far back as 1785. In 1847, with a large influx of Irish migrants, the typhus epidemic quickly filled the fever shed with sick and dying. By the 1847 typhus season, 2115 people had died in New Brunswick, with 1196 dying at Partridge Island and in Saint John. In Montreal , between 3,500 and 6,000 Irish immigrants died in fever sheds in a quarantine area known as Windmill Point . Three sheds were initially constructed, 150 feet (46 m) long by 40 to 50 feet (15 m) wide. As thousands more sick immigrants landed, more sheds had to be erected. The number of sheds would grow to 22, with troops cordoning off the area so the sick could not escape. In Toronto , during the summer of 1847, 863 Irish immigrants died of typhus at fever sheds built by the Toronto Board of Health at the northwest corner of King and John Street . There were at least 12 sheds, 22 metres long by 7.5 metres wide. Partridge Island, New Brunswick , just outside the main harbour of Saint John , was chosen as the location for a pest house and quarantine station as far back as 1785. In 1847, with a large influx of Irish migrants, the typhus epidemic quickly filled the fever shed with sick and dying. By the 1847 typhus season, 2115 people had died in New Brunswick, with 1196 dying at Partridge Island and in Saint John. There are eight surviving pest houses, including: Deddington , Oxfordshire has a Pest House Field. Richmond, London has a Pesthouse common . Great Chart, Kent Cranbrook, Kent There is an extant pest house in Leiden , the Pesthuis ( nl ), built in 1661 to accommodate many patients, although it has never served this purpose. [ citation needed ]There are eight surviving pest houses, including: Deddington , Oxfordshire has a Pest House Field. Richmond, London has a Pesthouse common . Great Chart, Kent Cranbrook, KentThere is an extant pest house in Leiden , the Pesthuis ( nl ), built in 1661 to accommodate many patients, although it has never served this purpose. [ citation needed ]

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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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Plague

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Plague cross

The term plague cross can refer to either a mark placed on a building occupied by victims of plague ; or a permanent structure erected, to enable plague sufferers to trade while minimising the risk of contagion . A wide variety of plague cross existed in Britain and elsewhere in Europe, until the plague largely disappeared by the eighteenth century. Additionally, the term "plague cross" can specifically refer to the "Plague Cross of Saint Zacharias of Jerusalem ", a Western Christian sacramental invoking God 's protection against diseases and plagues that often takes the form of a cross necklace or a wall cross. At times of plague, it was common to mark the doors of victims of the disease with a large painted cross, either in red or black paint. In later times, large printed crosses were often affixed to doors. Daniel Defoe reported, at the time of the Great Plague in 1665, that the Lord Mayor of London , in his regulations, stated: "That every house visited [by the disease] be marked with a red cross of a foot long in the middle of the door, evident to be seen, and with these usual printed words, that is to say, "Lord, have mercy upon us," to be set close over the same cross, there to continue until lawful opening of the same house." About the same time, Samuel Pepys wrote on 7 June 1665: "I did in Drury-lane see two or three houses marked with a red cross upon the doors, and "Lord have mercy upon us" writ there - which was a sad sight to me, being the first of that kind that to my remembrance I ever saw."In some locations, stone structures were set up outside established market areas, as temporary market crosses denoting places where town and country dwellers could trade with one another while supposedly minimising the risk of contagion. For example, at Macclesfield in Cheshire in 1603 and 1646, Greenway cross was "used as a 'plague cross,' to which country people came to sell their provisions to the dwellers in the town." At York , stone crosses were erected during an outbreak of plague in 1604, on main roads about one mile outside the city, to denote temporary locations where trading could take place. There, each cross held a small pool of water into which money was placed and from which it could be removed in trading. In Derby in 1665 , a headless cross or "vinegar stone" was erected, in which the water was replaced by vinegar as a disinfectant. The "vinegar stone" at Wentworth in Yorkshire is supposed to have a similar origin. In Germany , stone crosses or Pestkreuze were also set up in some locations to commemorate those who died as a result of the plague. Memorial crosses to individual plague victims were also set up at churches, as at Trittenheim . [ citation needed ]Plague columns, also known as Marian or Holy Trinity columns , are found throughout Europe, and frequently as thanksgiving for the ending of a plague. Examples include:

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Plague

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Dancing mania

Dancing mania (also known as dancing plague , choreomania , St. John's Dance , tarantism and St. Vitus' Dance ) was a social phenomenon that occurred primarily in mainland Europe between the 14th and 17th centuries. It involved groups of people dancing erratically, sometimes thousands at a time. The mania affected adults and children who danced until they collapsed from exhaustion and injuries, and sometimes died. One of the first major outbreaks was in Aachen , in the Holy Roman Empire (within modern-day Germany ), in 1374, and it quickly spread throughout Europe; one particularly notable outbreak occurred in Strasbourg in 1518 in Alsace , also in the Holy Roman Empire (now in modern-day France). Affecting thousands of people across several centuries, dancing mania was not an isolated event, and was well documented in contemporary reports. It was nevertheless poorly understood, and remedies were based on guesswork. Often musicians accompanied dancers, due to a belief that music would treat the mania, but this tactic sometimes backfired by encouraging more to join in. There is no consensus among modern-day scholars as to the cause of dancing mania. The several theories proposed range from religious cults being behind the processions to people dancing to relieve themselves of stress and put the poverty of the period out of their minds. It is speculated to have been a mass psychogenic illness , in which physical symptoms with no known physical cause are observed to affect a group of people, as a form of social influence. "Dancing mania" is derived from the term "choreomania", from the Greek choros (dance) and mania (madness), : 133–134 and is also known as "dancing plague". : 125 The term was coined by Paracelsus , : 126 and the condition was initially considered a curse sent by a saint, usually St. John the Baptist : 32 or St. Vitus , and was therefore known as "St. Vitus' Dance" or "St. John's Dance". Victims of dancing mania often ended their processions at places dedicated to that saint, : 136 who was prayed to in an effort to end the dancing; : 126 incidents often broke out around the time of the feast of St. Vitus. : 201 St. Vitus' Dance was diagnosed, in the 17th century, as Sydenham chorea . Dancing mania has also been known as epidemic chorea : 125 and epidemic dancing. A disease of the nervous system, chorea is characterized by symptoms resembling those of dancing mania, : 134 which has also rather unconvincingly been considered a form of epilepsy . : 32 Other scientists have described dancing mania as a "collective mental disorder", "collective hysterical disorder" and "mass madness". : 136The earliest-known outbreak of dancing mania occurred in the 7th century. One of the earliest-known incidents occurred sometime in the 1020s in Bernburg , where 18 peasants began singing and dancing around a church, disturbing a Christmas Eve service. : 202 Further outbreaks occurred during the 13th century, including one in 1237 in which a large group of children travelled from Erfurt to Arnstadt (about 20 km (12 mi) ), jumping and dancing all the way, : 201 in marked similarity to the legend of the Pied Piper of Hamelin , a legend that originated at around the same time. Another incident, in 1278, involved about 200 people dancing on a bridge over the River Meuse resulting in its collapse. Many of the survivors were restored to full health at a nearby chapel dedicated to St. Vitus. : 134 The first major outbreak of the mania occurred between 1373 and 1374, with incidents reported in England, Germany and the Netherlands . : 33 On 24 June 1374, one of the biggest outbreaks began in Aachen , : 126 before spreading to other places such as Cologne , Flanders , Franconia , Hainaut , Metz , Strasbourg , Tongeren , Utrecht , : 33 and regions and countries such as Italy and Luxembourg . Further episodes occurred in 1375 and 1376, with incidents in France, Germany, and the Netherlands, : 138 and in 1381, there was an outbreak in Augsburg . : 33 Further incidents occurred in 1418 in Strasbourg, where people fasted for days and the outbreak was possibly caused by exhaustion. : 137 In another outbreak, in 1428 in Schaffhausen , a monk danced to death and, in the same year, a group of women in Zürich were reportedly in a dancing frenzy. Another of the most extensive outbreaks occurred in July 1518, in Strasbourg (see Dancing plague of 1518 ), where a woman began dancing in the street, and between 50 and 400 people joined her. : 33 Further incidents occurred during the 16th century when the mania was at its peak: in 1536 in Basel , involving a group of children; and in 1551 in Anhalt , involving just one man. : 37 In the 17th century, incidents of recurrent dancing were recorded by professor of medicine Gregor Horst, who noted: Several women who annually visit the chapel of St. Vitus in Drefelhausen... dance madly all day and all night until they collapse in ecstasy. In this way they come to themselves again and feel little or nothing until the next May, when they are again... forced around St. Vitus' Day to betake themselves to that place... [o]ne of these women is said to have danced every year for the past twenty years, another for a full thirty-two. : 39 According to John Waller, although numerous incidents were recorded, the best documented cases are the outbreaks of 1374 and 1518, for which there is abundant contemporary evidence. The outbreaks of dancing mania varied, and several characteristics of it have been recorded. Generally occurring in times of hardship, : 136 up to tens of thousands of people would appear to dance for hours, : 133 days, weeks, and even months. : 132 Women have often been portrayed in modern literature as the usual participants in dancing mania, although contemporary sources suggest otherwise. : 139 Whether the dancing was spontaneous, or an organized event, is also debated. : 138 What is certain, however, is that dancers seemed to be in a state of unconsciousness : 201 and unable to control themselves. : 136 In his research into social phenomena, author Robert Bartholomew notes that contemporary sources record that participants often did not reside where the dancing took place. Such people would travel from place to place, and others would join them along the way. With them they brought customs and behaviour that were strange to the local people. : 137 Bartholomew describes how dancers wore "strange, colorful attire" and "held wooden sticks". : 132 Robert Marks, in his study of hypnotism, notes that some decorated their hair with garlands . : 201 However, not all outbreaks involved foreigners, and not all were particularly calm. Bartholomew notes that some "paraded around naked" : 132 and made "obscene gestures". : 133 Some even had sexual intercourse. : 136 Others acted like animals, : 133 and jumped, : 32 hopped and leaped about. : 33 They hardly stopped, and some danced until they broke their ribs and subsequently died. : 32 Throughout, dancers screamed, laughed, or cried, : 132 and some sang. : 60 Bartholomew also notes that observers of dancing mania were sometimes treated violently if they refused to join in. : 139 Participants demonstrated odd reactions to the color red; in A History of Madness in Sixteenth-Century Germany , Midelfort notes they "could not perceive the color red at all", : 32 and Bartholomew reports "it was said that dancers could not stand... the color red, often becoming violent on seeing [it]". Bartholomew also notes that dancers "could not stand pointed shoes", and that dancers enjoyed their feet being hit. : 133 Throughout, those affected by dancing mania suffered from a variety of ailments, including chest pains, convulsions, hallucinations, hyperventilation, : 136 epileptic fits, : 126 and visions. : 71 In the end, most simply dropped down, overwhelmed with exhaustion. : 126 Midelfort, however, describes how some ended up in a state of ecstasy. : 39 Typically, the mania was contagious but it often struck small groups, such as families and individuals. : 37–38 In Italy , a similar phenomenon was tarantism , in which the victims were said to have been poisoned by a tarantula or scorpion . Its earliest-known outbreak was in the 13th century, and the only antidote known was to dance to particular music to separate the venom from the blood. : 133 It occurred only in the summer months. As with dancing mania, people would suddenly begin to dance, sometimes affected by a perceived bite or sting and were joined by others, who believed the venom from their own old bites was reactivated by the heat or the music. : 134 Dancers would perform a tarantella , accompanied by music which would eventually "cure" the victim, at least temporarily. : 135 Some participated in further activities, such as tying themselves up with vines and whipping each other, pretending to sword fight, drinking large amounts of wine, and jumping into the sea. Sufferers typically had symptoms resembling those of dancing mania, such as headaches, trembling, twitching and visions. : 134 As with dancing mania, participants apparently did not like the color black, : 133 and women were reported to be most affected. : 136 Unlike dancing mania, tarantism was confined to Italy and southern Europe . It was common until the 17th century, but ended suddenly, with only very small outbreaks in Italy until as late as 1959. : 134 A study of the phenomenon in 1959 by religious history professor Ernesto de Martino revealed that most cases of tarantism were probably unrelated to spider bites. Many participants admitted that they had not been bitten, but believed they were infected by someone who had been, or that they had simply touched a spider. The result was mass panic, with a "cure" that allowed people to behave in ways that were, normally, prohibited at the time. : 135 Despite their differences, tarantism and dancing mania are often considered synonymous. : 134In Italy , a similar phenomenon was tarantism , in which the victims were said to have been poisoned by a tarantula or scorpion . Its earliest-known outbreak was in the 13th century, and the only antidote known was to dance to particular music to separate the venom from the blood. : 133 It occurred only in the summer months. As with dancing mania, people would suddenly begin to dance, sometimes affected by a perceived bite or sting and were joined by others, who believed the venom from their own old bites was reactivated by the heat or the music. : 134 Dancers would perform a tarantella , accompanied by music which would eventually "cure" the victim, at least temporarily. : 135 Some participated in further activities, such as tying themselves up with vines and whipping each other, pretending to sword fight, drinking large amounts of wine, and jumping into the sea. Sufferers typically had symptoms resembling those of dancing mania, such as headaches, trembling, twitching and visions. : 134 As with dancing mania, participants apparently did not like the color black, : 133 and women were reported to be most affected. : 136 Unlike dancing mania, tarantism was confined to Italy and southern Europe . It was common until the 17th century, but ended suddenly, with only very small outbreaks in Italy until as late as 1959. : 134 A study of the phenomenon in 1959 by religious history professor Ernesto de Martino revealed that most cases of tarantism were probably unrelated to spider bites. Many participants admitted that they had not been bitten, but believed they were infected by someone who had been, or that they had simply touched a spider. The result was mass panic, with a "cure" that allowed people to behave in ways that were, normally, prohibited at the time. : 135 Despite their differences, tarantism and dancing mania are often considered synonymous. : 134As the real cause of dancing mania was unknown, many of the treatments for it were simply hopeful guesses, although in some instances they were effective. The 1374 outbreak occurred only decades after the Black Death , and was treated in a similar fashion: dancers were isolated, and some were exorcised . : 70 People believed that the dancing was a curse brought about by St. Vitus ; they responded by praying : 126 and making pilgrimages to places dedicated to St. Vitus. : 34 Prayers were also made to St. John the Baptist , who some believed also caused the dancing. : 32 Others claimed to be possessed by demons, : 136 or Satan , therefore exorcisms were often performed on dancers. : 60 Bartholomew notes that music was often played while participants danced, as that was believed to be an effective remedy, : 136 and during some outbreaks musicians were even employed to play. : 139 Midelfort describes how the music encouraged others to join in, however, and thus effectively made things worse, as did the dancing places that were sometimes set up. : 35Numerous hypotheses have been proposed for the causes of dancing mania, and it remains unclear whether it was a real illness or a social phenomenon. One of the most prominent theories is that victims suffered from ergot poisoning, which was known as St. Anthony's fire in the Middle Ages. During floods and damp periods, ergots were able to grow and affect rye and other crops. Some historians link ergot poisoning to phenomena like the dancing plagues during the late medieval and Renaissance periods, and even the Salem Witch hysteria , as suggested by Oliver Sacks . Ergotism can cause hallucinations and convulsions, but cannot account for the other strange behaviour most commonly identified with dancing mania. : 140 : 126 : 43 Other theories suggest that the symptoms were similar to encephalitis , epilepsy , and typhus , but as with ergotism, those conditions cannot account for all symptoms. : 126 Numerous sources discuss how dancing mania, and tarantism, may have simply been the result of stress and tension caused by natural disasters around the time, : 43 such as plagues and floods. : 72 The recurring waves of the Black Death, other natural disasters, would have combined with the dawn of Reformation to make for a great deal of uncertainty and challenge for the people of Europe during this time period. Hetherington and Munro describe dancing mania as a result of "shared stress"; : 73 people may have danced to relieve themselves of the stress and poverty of the day, : 72 and in so doing, attempted to become ecstatic and see visions. According to Deborah Hyde , the spontaneous spread of this phenomenon through social networks played a significant role: "It's hard to deny that the dancing mania was marked by social contagion exacerbated by stress. Outbreaks occurred along trade routes or reoccurred in the same areas – where people had knowledge of the format, in other words. Beliefs and behaviour can travel just like pathogens." Another popular theory is that the outbreaks were all staged, : 71 and the appearance of strange behaviour was due to its unfamiliarity. : 137 Religious cults may have been acting out well-organised dances, in accordance with ancient Greek and Roman rituals. : 136 : 137 Despite being banned at the time, these rituals could be performed under the guise of uncontrollable dancing mania. : 140 Justus Hecker , a 19th-century medical writer, described it as a kind of festival, where a practice known as "the kindling of the Nodfyr " was carried out. This involved jumping through fire and smoke, in an attempt to ward off disease. Bartholomew notes how participants in this ritual would often continue to jump and leap long after the flames had gone. : 139 It is certain that many participants of dancing mania were psychologically disturbed, : 136 but it is also likely that some took part out of fear, or simply wished to copy everyone else. : 43 Sources agree that dancing mania was one of the earliest-recorded forms of mass hysteria , : 135 : 73 and describe it as a "psychic epidemic", with numerous explanations that might account for the behaviour of the dancers. : 43 It has been suggested that the outbreaks may have been due to cultural contagion triggered, in times of particular hardship, by deeply rooted popular beliefs in the region regarding angry spirits capable of inflicting a "dancing curse" to punish their victims.

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Plague

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Plague Maiden

The Plague Maiden ( Polish : Morowa dziewica a.k.a. The Maid of Pestilence ), is the name given to an apparition from a Lithuanian-Polish folktale. She was said to appear before a plague befell a town. She is often described as waving a red handkerchief through victim's doors, either because it is dyed that way or because it is soaked with blood. Some folktales say that she wears white and has a fiery wreath across her temples. Another such description of her shows that she is an older woman, haggard and tall. Her ailing frame is draped by a decrepit white robe. Another such folktale appears in Slovenia, with a so called plague woman who is an outsider to a small township and dares not enter the township without some help. She is shunned by many of the townsfolk except one man whom she manages to convince to give her a ride into the town using his cart. In recompense for his actions she remembers his house. As the plague wreaked havoc on the town, he managed to survive the plague, saved by virtue of his kindness A popular ballad told the tale of a man who killed the plague maiden using a sword inscribed with the names of Jesus and the Virgin Mary and stole her handkerchief. At the end of the ballad, though the man and his family die, their town is never again touched by plague. The red handkerchief was supposedly kept at the town church, but the location is never named. The legend was mentioned by Adam Mickiewicz in his poem Konrad Wallenrod .

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Plague

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La peste (TV series)

La peste ( The Plague ) is a Spanish historical drama television series created by Alberto Rodríguez and Rafael Cobos for Movistar+ . It tells a crime story set in the 16th century Seville during an outbreak of the bubonic plague . The series premiered on 12 January 2018 on Movistar+'s VOD service and on #0 . Before it first aired, on 30 September 2017, it was announced that it had been renewed for a second season, which premiered on 15 November 2019. "During an outbreak of the bubonic plague in the magnificent Seville of 1597, Mateo, a former soldier, returns, honouring his word to find and extract a dead friend's son from the city. Previously, Mateo had been forced to flee the city to save his life, having been sentenced to death by the Inquisition for printing forbidden books. Before he can complete his task, Mateo is arrested by the Inquisitor's bailiffs, who promise to pardon his life in exchange for solving a series of crimes of diabolic overtones being committed in Seville." The second season was shot in Cuevas del Almanzora , Almería , from 15 October 2018 to 19 October.

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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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Plague

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Romeo and Juliet

Romeo and Juliet is a tragedy written by William Shakespeare early in his career about the romance between two Italian youths from feuding families. It was among Shakespeare's most popular plays during his lifetime and, along with Hamlet , is one of his most frequently performed. Today, the title characters are regarded as archetypal young lovers. Romeo and Juliet belongs to a tradition of tragic romances stretching back to antiquity . The plot is based on an Italian tale written by Matteo Bandello and translated into verse as The Tragical History of Romeus and Juliet by Arthur Brooke in 1562 and retold in prose in Palace of Pleasure by William Painter in 1567. Shakespeare borrowed heavily from both but expanded the plot by developing a number of supporting characters, in particular Mercutio and Paris . Believed to have been written between 1591 and 1595, the play was first published in a quarto version in 1597. The text of the first quarto version was of poor quality, however, and later editions corrected the text to conform more closely with Shakespeare's original. Shakespeare's use of poetic dramatic structure (including effects such as switching between comedy and tragedy to heighten tension, the expansion of minor characters, and numerous sub-plots to embellish the story) has been praised as an early sign of his dramatic skill. The play ascribes different poetic forms to different characters, sometimes changing the form as the character develops. Romeo, for example, grows more adept at the sonnet over the course of the play. Romeo and Juliet has been adapted numerous times for stage, film, musical, and opera venues. During the English Restoration , it was revived and heavily revised by William Davenant . David Garrick 's 18th-century version also modified several scenes, removing material then considered indecent, and Georg Benda 's Romeo und Julie omitted much of the action and used a happy ending. Performances in the 19th century, including Charlotte Cushman 's, restored the original text and focused on greater realism . John Gielgud 's 1935 version kept very close to Shakespeare's text and used Elizabethan costumes and staging to enhance the drama. In the 20th and into the 21st century, the play has been adapted in versions as diverse as George Cukor 's 1936 film Romeo and Juliet , Franco Zeffirelli 's 1968 film Romeo and Juliet , Baz Luhrmann 's 1996 film Romeo + Juliet , and most recently, Carlo Carlei 's 2013 film Romeo and Juliet .The play, set in Verona , Italy , begins with a street brawl between Montague and Capulet servants who, like the masters they serve, are sworn enemies. Prince Escalus of Verona intervenes and declares that further breach of the peace will be punishable by death. Later, Count Paris talks to Capulet about marrying his daughter Juliet , but Capulet asks Paris to wait another two years and invites him to attend a planned Capulet ball . Lady Capulet and Juliet's Nurse try to persuade Juliet to accept Paris's courtship. Meanwhile, Benvolio talks with his cousin Romeo , Montague's son, about Romeo's recent depression. Benvolio discovers that it stems from unrequited infatuation for a girl named Rosaline , one of Capulet's nieces. Persuaded by Benvolio and Mercutio , Romeo attends the ball at the Capulet house in hopes of meeting Rosaline. However, Romeo instead meets and falls in love with Juliet. Juliet's cousin, Tybalt , is enraged at Romeo for sneaking into the ball but is stopped from killing Romeo by Juliet's father, who does not wish to shed blood in his house. After the ball, in what is now famously known as the "balcony scene", Romeo sneaks into the Capulet orchard and overhears Juliet at her window vowing her love to him in spite of her family's hatred of the Montagues. Romeo makes himself known to her, and they agree to be married. With the help of Friar Laurence , who hopes to reconcile the two families through their children's union, they are secretly married the next day. Tybalt, meanwhile, still incensed that Romeo had sneaked into the Capulet ball, challenges him to a duel. Romeo, now considering Tybalt his kinsman, refuses to fight. Mercutio is offended by Tybalt's insolence, as well as Romeo's "vile submission", and accepts the duel on Romeo's behalf. Mercutio is fatally wounded when Romeo attempts to break up the fight, and declares a curse upon both households before he dies. ("A plague o' both your houses!") Grief-stricken and racked with guilt, Romeo confronts and slays Tybalt. Montague argues that Romeo has justly executed Tybalt for the murder of Mercutio. The Prince, now having lost a kinsman in the warring families' feud, exiles Romeo from Verona, under penalty of death if he ever returns. Romeo secretly spends the night in Juliet's chamber, where they consummate their marriage. Capulet, misinterpreting Juliet's grief, agrees to marry her to Count Paris and threatens to disown her when she refuses to become Paris's "joyful bride". When she then pleads for the marriage to be delayed, her mother rejects her. Juliet visits Friar Laurence for help, and he offers her a potion that will put her into a deathlike coma or catalepsy for "two and forty hours". The Friar promises to send a messenger to inform Romeo of the plan so that he can rejoin her when she awakens. On the night before the wedding, she takes the drug and, when discovered apparently dead, she is laid in the family crypt . The messenger, however, does not reach Romeo and, instead, Romeo learns of Juliet's apparent death from his servant, Balthasar. Heartbroken, Romeo buys poison from an apothecary and goes to the Capulet crypt. He encounters Paris who has come to mourn Juliet privately. Believing Romeo to be a vandal, Paris confronts him and, in the ensuing battle, Romeo kills Paris. Still believing Juliet to be dead, he drinks the poison. Juliet then awakens and, discovering that Romeo is dead, stabs herself with his dagger and joins him in death. The feuding families and the Prince meet at the tomb to find all three dead. Friar Laurence recounts the story of the two "star-cross'd lovers", fulfilling the curse that Mercutio swore. The families are reconciled by their children's deaths and agree to end their violent feud. The play ends with the Prince's elegy for the lovers: "For never was a story of more woe / Than this of Juliet and her Romeo." Romeo and Juliet borrows from a tradition of tragic love stories dating back to antiquity. One of these is Pyramus and Thisbe , from Ovid 's Metamorphoses , which contains parallels to Shakespeare's story: the lovers' parents despise each other, and Pyramus falsely believes his lover Thisbe is dead. The Ephesiaca of Xenophon of Ephesus , written in the 3rd century, also contains several similarities to the play, including the separation of the lovers, and a potion that induces a deathlike sleep. One of the earliest references to the names Montague and Capulet is from Dante 's Divine Comedy , who mentions the Montecchi ( Montagues ) and the Cappelletti ( Capulets ) in canto six of Purgatorio : Come and see, you who are negligent, Montagues and Capulets, Monaldi and Filippeschi One lot already grieving, the other in fear. However, the reference is part of a polemic against what Dante saw as moral decay of Florence , Lombardy , and the Italian states in general; through his characters, Dante aimed to chastise Albert I of Germany for neglecting what Dante felt were his responsibilities towards Italy ("you who are negligent") as " King of the Romans ", as well as successive popes for their encroachment from purely spiritual affairs, thus leading to a climate of incessant bickering and warfare between rival political parties in Lombardy. History records the name of the family Montague as being lent to such a political party in Verona , but that of the Capulets as from a Cremonese family, both of whom play out their conflict in Lombardy as a whole rather than within the confines of Verona. Allied to rival political factions, the parties are grieving ("One lot already grieving") because their endless warfare has led to the destruction of both parties, rather than a grief from the loss of their ill-fated offspring as the play sets forth, which appears to be a solely poetic creation within this context. The earliest known version of the Romeo and Juliet tale akin to Shakespeare's play is the story of Mariotto and Ganozza by Masuccio Salernitano , in the 33rd novel of his Il Novellino published in 1476. Salernitano sets the story in Siena and insists its events took place in his own lifetime. His version of the story includes the secret marriage, the colluding friar, the fray where a prominent citizen is killed, Mariotto's exile, Ganozza's forced marriage, the potion plot, and the crucial message that goes astray. In this version, Mariotto is caught and beheaded and Ganozza dies of grief. Luigi da Porto (1485–1529) adapted the story as Giulietta e Romeo and included it in his Historia novellamente ritrovata di due nobili amanti (A Newly-Discovered History of two Noble Lovers ), written in 1524 and published posthumously in 1531 in Venice. Da Porto drew on Pyramus and Thisbe , Boccaccio 's Decameron , and Salernitano's Mariotto e Ganozza , but it is likely that his story is also autobiographical: He was a soldier present at a ball on 26 February 1511, at a residence of the pro- Venice Savorgnan clan in Udine , following a peace ceremony attended by the opposing pro- Imperial Strumieri clan. There, Da Porto fell in love with Lucina, a Savorgnan daughter, but the family feud frustrated their courtship. The next morning, the Savorgnans led an attack on the city , and many members of the Strumieri were murdered. Years later, still half-paralyzed from a battle-wound, Luigi wrote Giulietta e Romeo in Montorso Vicentino (from which he could see the "castles" of Verona), dedicating the novella to the bellisima e leggiadra (the beautiful and graceful) Lucina Savorgnan. Da Porto presented his tale as historically factual and claimed it took place at least a century earlier than Salernitano had it, in the days Verona was ruled by Bartolomeo della Scala (anglicized as Prince Escalus ). Da Porto presented the narrative in close to its modern form, including the names of the lovers, the rival families of Montecchi and Capuleti (Cappelletti) and the location in Verona. He named the friar Laurence ( frate Lorenzo ) and introduced the characters Mercutio ( Marcuccio Guertio ), Tybalt ( Tebaldo Cappelletti ), Count Paris ( conte (Paride) di Lodrone ), the faithful servant, and Giulietta's nurse . Da Porto originated the remaining basic elements of the story: the feuding families, Romeo—left by his mistress—meeting Giulietta at a dance at her house, the love scenes (including the balcony scene), the periods of despair, Romeo killing Giulietta's cousin (Tebaldo), and the families' reconciliation after the lovers' suicides. In da Porto's version, Romeo takes poison and Giulietta keeps her breath until she dies. In 1554, Matteo Bandello published the second volume of his Novelle , which included his version of Giuletta e Romeo , probably written between 1531 and 1545. Bandello lengthened and weighed down the plot while leaving the storyline basically unchanged (though he did introduce Benvolio ). Bandello's story was translated into French by Pierre Boaistuau in 1559 in the first volume of his Histoires Tragiques . Boaistuau adds much moralising and sentiment, and the characters indulge in rhetorical outbursts. In his 1562 narrative poem The Tragical History of Romeus and Juliet , Arthur Brooke translated Boaistuau faithfully but adjusted it to reflect parts of Chaucer's Troilus and Criseyde . There was a trend among writers and playwrights to publish works based on Italian novelle —Italian tales were very popular among theatre-goers—and Shakespeare may well have been familiar with William Painter 's 1567 collection of Italian tales titled Palace of Pleasure . This collection included a version in prose of the Romeo and Juliet story named "The goodly History of the true and constant love of Romeo and Juliett" . Shakespeare took advantage of this popularity: The Merchant of Venice , Much Ado About Nothing , All's Well That Ends Well , Measure for Measure , and Romeo and Juliet are all from Italian novelle . Romeo and Juliet is a dramatization of Brooke's translation, and Shakespeare follows the poem closely but adds detail to several major and minor characters (the Nurse and Mercutio in particular). Christopher Marlowe 's Hero and Leander and Dido, Queen of Carthage , both similar stories written in Shakespeare's day, are thought to be less of a direct influence, although they may have helped create an atmosphere in which tragic love stories could thrive. It is unknown when exactly Shakespeare wrote Romeo and Juliet . Juliet's Nurse refers to an earthquake she says occurred 11 years ago. This may refer to the Dover Straits earthquake of 1580 , which would date that particular line to 1591. Other earthquakes—both in England and in Verona—have been proposed in support of the different dates. But the play's stylistic similarities with A Midsummer Night's Dream and other plays conventionally dated around 1594–95, place its composition sometime between 1591 and 1595. [lower-alpha 2] One conjecture is that Shakespeare may have begun a draft in 1591, which he completed in 1595. Shakespeare's Romeo and Juliet was published in two quarto editions prior to the publication of the First Folio of 1623. These are referred to as Q1 and Q2. The first printed edition, Q1, appeared in early 1597, printed by John Danter. Because its text contains numerous differences from the later editions, it is labelled a so-called ' bad quarto '; the 20th-century editor T. J. B. Spencer described it as "a detestable text, probably a reconstruction of the play from the imperfect memories of one or two of the actors", suggesting that it had been pirated for publication. An alternative explanation for Q1's shortcomings is that the play (like many others of the time) may have been heavily edited before performance by the playing company. However, "the theory, formulated by [Alfred] Pollard," that the 'bad quarto' was reconstructed from memory by some of the actors is now under attack. Alternative theories are that some or all of 'the bad quartos' are early versions by Shakespeare or abbreviations made either for Shakespeare's company or for other companies." In any event, its appearance in early 1597 makes 1596 the latest possible date for the play's composition. The superior Q2 called the play The Most Excellent and Lamentable Tragedie of Romeo and Juliet . It was printed in 1599 by Thomas Creede and published by Cuthbert Burby . Q2 is about 800 lines longer than Q1. Its title page describes it as "Newly corrected, augmented and amended". Scholars believe that Q2 was based on Shakespeare's pre-performance draft (called his foul papers ) since there are textual oddities such as variable tags for characters and "false starts" for speeches that were presumably struck through by the author but erroneously preserved by the typesetter. It is a much more complete and reliable text and was reprinted in 1609 (Q3), 1622 (Q4) and 1637 (Q5). In effect, all later Quartos and Folios of Romeo and Juliet are based on Q2, as are all modern editions since editors believe that any deviations from Q2 in the later editions (whether good or bad) are likely to have arisen from editors or compositors, not from Shakespeare. The First Folio text of 1623 was based primarily on Q3, with clarifications and corrections possibly coming from a theatrical prompt book or Q1. Other Folio editions of the play were printed in 1632 (F2), 1664 (F3), and 1685 (F4). Modern versions—that take into account several of the Folios and Quartos—first appeared with Nicholas Rowe 's 1709 edition, followed by Alexander Pope 's 1723 version. Pope began a tradition of editing the play to add information such as stage directions missing in Q2 by locating them in Q1. This tradition continued late into the Romantic period. Fully annotated editions first appeared in the Victorian period and continue to be produced today, printing the text of the play with footnotes describing the sources and culture behind the play. Scholars have found it extremely difficult to assign one specific, overarching theme to the play. Proposals for a main theme include a discovery by the characters that human beings are neither wholly good nor wholly evil, but instead are more or less alike, awaking out of a dream and into reality, the danger of hasty action, or the power of tragic fate. None of these have widespread support. However, even if an overall theme cannot be found it is clear that the play is full of several small thematic elements that intertwine in complex ways. Several of those most often debated by scholars are discussed below. " Romeo If I profane with my unworthiest hand This holy shrine, the gentle sin is this: My lips, two blushing pilgrims, ready stand To smooth that rough touch with a tender kiss. Juliet Good pilgrim, you do wrong your hand too much, Which mannerly devotion shows in this; For saints have hands that pilgrims' hands do touch, And palm to palm is holy palmers' kiss." — Romeo and Juliet , Act I, Scene V Romeo and Juliet is sometimes considered to have no unifying theme, save that of young love. Romeo and Juliet have become emblematic of young lovers and doomed love. Since it is such an obvious subject of the play, several scholars have explored the language and historical context behind the romance of the play. On their first meeting, Romeo and Juliet use a form of communication recommended by many etiquette authors in Shakespeare's day: metaphor. By using metaphors of saints and sins, Romeo was able to test Juliet's feelings for him in a non-threatening way. This method was recommended by Baldassare Castiglione (whose works had been translated into English by this time). He pointed out that if a man used a metaphor as an invitation, the woman could pretend she did not understand him, and he could retreat without losing honour. Juliet, however, participates in the metaphor and expands on it. The religious metaphors of "shrine", "pilgrim", and "saint" were fashionable in the poetry of the time and more likely to be understood as romantic rather than blasphemous, as the concept of sainthood was associated with the Catholicism of an earlier age. Later in the play, Shakespeare removes the more daring allusions to Christ's resurrection in the tomb he found in his source work: Brooke's Romeus and Juliet . In the later balcony scene, Shakespeare has Romeo overhear Juliet's soliloquy, but in Brooke's version of the story, her declaration is done alone. By bringing Romeo into the scene to eavesdrop, Shakespeare breaks from the normal sequence of courtship. Usually, a woman was required to be modest and shy to make sure that her suitor was sincere, but breaking this rule serves to speed along the plot. The lovers are able to skip courting and move on to plain talk about their relationship—agreeing to be married after knowing each other for only one night. In the final suicide scene, there is a contradiction in the message—in the Catholic religion, suicides were often thought to be condemned to Hell, whereas people who die to be with their loves under the " Religion of Love " are joined with their loves in Paradise. Romeo and Juliet's love seems to be expressing the "Religion of Love" view rather than the Catholic view. Another point is that, although their love is passionate, it is only consummated in marriage, which keeps them from losing the audience's sympathy. The play arguably equates love and sex with death. Throughout the story, both Romeo and Juliet, along with the other characters, fantasise about it as a dark being , often equating it with a lover. Capulet, for example, when he first discovers Juliet's (faked) death, describes it as having deflowered his daughter. Juliet later erotically compares Romeo and death. Right before her suicide, she grabs Romeo's dagger, saying "O happy dagger! This is thy sheath. There rust, and let me die." "O, I am fortune's fool!" —Romeo, Act III Scene I Scholars are divided on the role of fate in the play. No consensus exists on whether the characters are truly fated to die together or whether the events take place by a series of unlucky chances. Arguments in favour of fate often refer to the description of the lovers as " star-cross'd ". This phrase seems to hint that the stars have predetermined the lovers' future. John W. Draper points out the parallels between the Elizabethan belief in the four humours and the main characters of the play (for example, Tybalt as a choleric). Interpreting the text in the light of humours reduces the amount of plot attributed to chance by modern audiences. Still, other scholars see the play as a series of unlucky chances—many to such a degree that they do not see it as a tragedy at all, but an emotional melodrama . Ruth Nevo believes the high degree to which chance is stressed in the narrative makes Romeo and Juliet a "lesser tragedy" of happenstance, not of character. For example, Romeo's challenging Tybalt is not impulsive; it is, after Mercutio's death, the expected action to take. In this scene, Nevo reads Romeo as being aware of the dangers of flouting social norms , identity, and commitments. He makes the choice to kill, not because of a tragic flaw , but because of circumstance. "O brawling love, O loving hate, O any thing of nothing first create! O heavy lightness, serious vanity, Misshapen chaos of well-seeming forms, Feather of lead, bright smoke, cold fire, sick health, Still-waking sleep, that is not what it is!" —Romeo, Act I, Scene I Scholars have long noted Shakespeare's widespread use of light and dark imagery throughout the play. Caroline Spurgeon considers the theme of light as "symbolic of the natural beauty of young love" and later critics have expanded on this interpretation. For example, both Romeo and Juliet see the other as light in a surrounding darkness. Romeo describes Juliet as being like the sun, brighter than a torch, a jewel sparkling in the night, and a bright angel among dark clouds. Even when she lies apparently dead in the tomb, he says her "beauty makes / This vault a feasting presence full of light." Juliet describes Romeo as "day in night" and "Whiter than snow upon a raven's back." This contrast of light and dark can be expanded as symbols—contrasting love and hate, youth and age in a metaphoric way. Sometimes these intertwining metaphors create dramatic irony . For example, Romeo and Juliet's love is a light in the midst of the darkness of the hate around them, but all of their activity together is done in night and darkness while all of the feuding is done in broad daylight. This paradox of imagery adds atmosphere to the moral dilemma facing the two lovers: loyalty to family or loyalty to love. At the end of the story, when the morning is gloomy and the sun hiding its face for sorrow, light and dark have returned to their proper places, the outward darkness reflecting the true, inner darkness of the family feud out of sorrow for the lovers. All characters now recognise their folly in light of recent events, and things return to the natural order, thanks to the love and death of Romeo and Juliet. The "light" theme in the play is also heavily connected to the theme of time since light was a convenient way for Shakespeare to express the passage of time through descriptions of the sun, moon, and stars. "These times of woe afford no time to woo." —Paris, Act III, Scene IV Time plays an important role in the language and plot of the play. Both Romeo and Juliet struggle to maintain an imaginary world void of time in the face of the harsh realities that surround them. For instance, when Romeo swears his love to Juliet by the moon, she protests "O swear not by the moon, th'inconstant moon, / That monthly changes in her circled orb, / Lest that thy love prove likewise variable." From the very beginning, the lovers are designated as "star-cross'd" [lower-alpha 3] referring to an astrologic belief associated with time. Stars were thought to control the fates of humanity, and as time passed, stars would move along their course in the sky, also charting the course of human lives below. Romeo speaks of a foreboding he feels in the stars' movements early in the play, and when he learns of Juliet's death, he defies the stars' course for him. Another central theme is haste: Shakespeare's Romeo and Juliet spans a period of four to six days, in contrast to Brooke's poems spanning nine months. Scholars such as G. Thomas Tanselle believe that time was "especially important to Shakespeare" in this play, as he used references to "short-time" for the young lovers as opposed to references to "long-time" for the "older generation" to highlight "a headlong rush towards doom". Romeo and Juliet fight time to make their love last forever. In the end, the only way they seem to defeat time is through a death that makes them immortal through art. Time is also connected to the theme of light and dark. In Shakespeare's day, plays were most often performed at noon or in the afternoon in broad daylight. [lower-alpha 4] This forced the playwright to use words to create the illusion of day and night in his plays. Shakespeare uses references to the night and day, the stars, the moon, and the sun to create this illusion. He also has characters frequently refer to days of the week and specific hours to help the audience understand that time has passed in the story. All in all, no fewer than 103 references to time are found in the play, adding to the illusion of its passage. " Romeo If I profane with my unworthiest hand This holy shrine, the gentle sin is this: My lips, two blushing pilgrims, ready stand To smooth that rough touch with a tender kiss. Juliet Good pilgrim, you do wrong your hand too much, Which mannerly devotion shows in this; For saints have hands that pilgrims' hands do touch, And palm to palm is holy palmers' kiss." — Romeo and Juliet , Act I, Scene V Romeo and Juliet is sometimes considered to have no unifying theme, save that of young love. Romeo and Juliet have become emblematic of young lovers and doomed love. Since it is such an obvious subject of the play, several scholars have explored the language and historical context behind the romance of the play. On their first meeting, Romeo and Juliet use a form of communication recommended by many etiquette authors in Shakespeare's day: metaphor. By using metaphors of saints and sins, Romeo was able to test Juliet's feelings for him in a non-threatening way. This method was recommended by Baldassare Castiglione (whose works had been translated into English by this time). He pointed out that if a man used a metaphor as an invitation, the woman could pretend she did not understand him, and he could retreat without losing honour. Juliet, however, participates in the metaphor and expands on it. The religious metaphors of "shrine", "pilgrim", and "saint" were fashionable in the poetry of the time and more likely to be understood as romantic rather than blasphemous, as the concept of sainthood was associated with the Catholicism of an earlier age. Later in the play, Shakespeare removes the more daring allusions to Christ's resurrection in the tomb he found in his source work: Brooke's Romeus and Juliet . In the later balcony scene, Shakespeare has Romeo overhear Juliet's soliloquy, but in Brooke's version of the story, her declaration is done alone. By bringing Romeo into the scene to eavesdrop, Shakespeare breaks from the normal sequence of courtship. Usually, a woman was required to be modest and shy to make sure that her suitor was sincere, but breaking this rule serves to speed along the plot. The lovers are able to skip courting and move on to plain talk about their relationship—agreeing to be married after knowing each other for only one night. In the final suicide scene, there is a contradiction in the message—in the Catholic religion, suicides were often thought to be condemned to Hell, whereas people who die to be with their loves under the " Religion of Love " are joined with their loves in Paradise. Romeo and Juliet's love seems to be expressing the "Religion of Love" view rather than the Catholic view. Another point is that, although their love is passionate, it is only consummated in marriage, which keeps them from losing the audience's sympathy. The play arguably equates love and sex with death. Throughout the story, both Romeo and Juliet, along with the other characters, fantasise about it as a dark being , often equating it with a lover. Capulet, for example, when he first discovers Juliet's (faked) death, describes it as having deflowered his daughter. Juliet later erotically compares Romeo and death. Right before her suicide, she grabs Romeo's dagger, saying "O happy dagger! This is thy sheath. There rust, and let me die." "O, I am fortune's fool!" —Romeo, Act III Scene I Scholars are divided on the role of fate in the play. No consensus exists on whether the characters are truly fated to die together or whether the events take place by a series of unlucky chances. Arguments in favour of fate often refer to the description of the lovers as " star-cross'd ". This phrase seems to hint that the stars have predetermined the lovers' future. John W. Draper points out the parallels between the Elizabethan belief in the four humours and the main characters of the play (for example, Tybalt as a choleric). Interpreting the text in the light of humours reduces the amount of plot attributed to chance by modern audiences. Still, other scholars see the play as a series of unlucky chances—many to such a degree that they do not see it as a tragedy at all, but an emotional melodrama . Ruth Nevo believes the high degree to which chance is stressed in the narrative makes Romeo and Juliet a "lesser tragedy" of happenstance, not of character. For example, Romeo's challenging Tybalt is not impulsive; it is, after Mercutio's death, the expected action to take. In this scene, Nevo reads Romeo as being aware of the dangers of flouting social norms , identity, and commitments. He makes the choice to kill, not because of a tragic flaw , but because of circumstance. "O brawling love, O loving hate, O any thing of nothing first create! O heavy lightness, serious vanity, Misshapen chaos of well-seeming forms, Feather of lead, bright smoke, cold fire, sick health, Still-waking sleep, that is not what it is!" —Romeo, Act I, Scene I Scholars have long noted Shakespeare's widespread use of light and dark imagery throughout the play. Caroline Spurgeon considers the theme of light as "symbolic of the natural beauty of young love" and later critics have expanded on this interpretation. For example, both Romeo and Juliet see the other as light in a surrounding darkness. Romeo describes Juliet as being like the sun, brighter than a torch, a jewel sparkling in the night, and a bright angel among dark clouds. Even when she lies apparently dead in the tomb, he says her "beauty makes / This vault a feasting presence full of light." Juliet describes Romeo as "day in night" and "Whiter than snow upon a raven's back." This contrast of light and dark can be expanded as symbols—contrasting love and hate, youth and age in a metaphoric way. Sometimes these intertwining metaphors create dramatic irony . For example, Romeo and Juliet's love is a light in the midst of the darkness of the hate around them, but all of their activity together is done in night and darkness while all of the feuding is done in broad daylight. This paradox of imagery adds atmosphere to the moral dilemma facing the two lovers: loyalty to family or loyalty to love. At the end of the story, when the morning is gloomy and the sun hiding its face for sorrow, light and dark have returned to their proper places, the outward darkness reflecting the true, inner darkness of the family feud out of sorrow for the lovers. All characters now recognise their folly in light of recent events, and things return to the natural order, thanks to the love and death of Romeo and Juliet. The "light" theme in the play is also heavily connected to the theme of time since light was a convenient way for Shakespeare to express the passage of time through descriptions of the sun, moon, and stars. "These times of woe afford no time to woo." —Paris, Act III, Scene IV Time plays an important role in the language and plot of the play. Both Romeo and Juliet struggle to maintain an imaginary world void of time in the face of the harsh realities that surround them. For instance, when Romeo swears his love to Juliet by the moon, she protests "O swear not by the moon, th'inconstant moon, / That monthly changes in her circled orb, / Lest that thy love prove likewise variable." From the very beginning, the lovers are designated as "star-cross'd" [lower-alpha 3] referring to an astrologic belief associated with time. Stars were thought to control the fates of humanity, and as time passed, stars would move along their course in the sky, also charting the course of human lives below. Romeo speaks of a foreboding he feels in the stars' movements early in the play, and when he learns of Juliet's death, he defies the stars' course for him. Another central theme is haste: Shakespeare's Romeo and Juliet spans a period of four to six days, in contrast to Brooke's poems spanning nine months. Scholars such as G. Thomas Tanselle believe that time was "especially important to Shakespeare" in this play, as he used references to "short-time" for the young lovers as opposed to references to "long-time" for the "older generation" to highlight "a headlong rush towards doom". Romeo and Juliet fight time to make their love last forever. In the end, the only way they seem to defeat time is through a death that makes them immortal through art. Time is also connected to the theme of light and dark. In Shakespeare's day, plays were most often performed at noon or in the afternoon in broad daylight. [lower-alpha 4] This forced the playwright to use words to create the illusion of day and night in his plays. Shakespeare uses references to the night and day, the stars, the moon, and the sun to create this illusion. He also has characters frequently refer to days of the week and specific hours to help the audience understand that time has passed in the story. All in all, no fewer than 103 references to time are found in the play, adding to the illusion of its passage. The earliest known critic of the play was diarist Samuel Pepys , who wrote in 1662: "it is a play of itself the worst that I ever heard in my life." Poet John Dryden wrote 10 years later in praise of the play and its comic character Mercutio: "Shakespear show'd the best of his skill in his Mercutio , and he said himself, that he was forc'd to kill him in the third Act, to prevent being killed by him." Criticism of the play in the 18th century was less sparse but no less divided. Publisher Nicholas Rowe was the first critic to ponder the theme of the play, which he saw as the just punishment of the two feuding families. In mid-century, writer Charles Gildon and philosopher Lord Kames argued that the play was a failure in that it did not follow the classical rules of drama: the tragedy must occur because of some character flaw , not an accident of fate. Writer and critic Samuel Johnson , however, considered it one of Shakespeare's "most pleasing" plays. In the later part of the 18th and through the 19th century, criticism centred on debates over the moral message of the play. Actor and playwright David Garrick 's 1748 adaptation excluded Rosaline: Romeo abandoning her for Juliet was seen as fickle and reckless. Critics such as Charles Dibdin argued that Rosaline had been included in the play in order to show how reckless the hero was and that this was the reason for his tragic end. Others argued that Friar Laurence might be Shakespeare's spokesman in his warnings against undue haste. At the beginning of the 20th century, these moral arguments were disputed by critics such as Richard Green Moulton : he argued that accident, and not some character flaw, led to the lovers' deaths. In Romeo and Juliet , Shakespeare employs several dramatic techniques that have garnered praise from critics, most notably the abrupt shifts from comedy to tragedy (an example is the punning exchange between Benvolio and Mercutio just before Tybalt arrives). Before Mercutio's death in Act III, the play is largely a comedy. After his accidental demise, the play suddenly becomes serious and takes on a tragic tone. When Romeo is banished, rather than executed, and Friar Laurence offers Juliet a plan to reunite her with Romeo, the audience can still hope that all will end well. They are in a "breathless state of suspense" by the opening of the last scene in the tomb: If Romeo is delayed long enough for the Friar to arrive, he and Juliet may yet be saved. These shifts from hope to despair, reprieve, and new hope serve to emphasise the tragedy when the final hope fails and both the lovers die at the end. Shakespeare also uses sub-plots to offer a clearer view of the actions of the main characters. For example, when the play begins, Romeo is in love with Rosaline, who has refused all of his advances. Romeo's infatuation with her stands in obvious contrast to his later love for Juliet. This provides a comparison through which the audience can see the seriousness of Romeo and Juliet's love and marriage. Paris' love for Juliet also sets up a contrast between Juliet's feelings for him and her feelings for Romeo. The formal language she uses around Paris, as well as the way she talks about him to her Nurse, show that her feelings clearly lie with Romeo. Beyond this, the sub-plot of the Montague–Capulet feud overarches the whole play, providing an atmosphere of hate that is the main contributor to the play's tragic end. Shakespeare uses a variety of poetic forms throughout the play. He begins with a 14-line prologue in the form of a Shakespearean sonnet , spoken by a Chorus. Most of Romeo and Juliet is, however, written in blank verse , and much of it in strict iambic pentameter , with less rhythmic variation than in most of Shakespeare's later plays. In choosing forms, Shakespeare matches the poetry to the character who uses it. Friar Laurence, for example, uses sermon and sententiae forms and the Nurse uses a unique blank verse form that closely matches colloquial speech . Each of these forms is also moulded and matched to the emotion of the scene the character occupies. For example, when Romeo talks about Rosaline earlier in the play, he attempts to use the Petrarchan sonnet form. Petrarchan sonnets were often used by men to exaggerate the beauty of women who were impossible for them to attain, as in Romeo's situation with Rosaline. This sonnet form is used by Lady Capulet to describe Count Paris to Juliet as a handsome man. When Romeo and Juliet meet, the poetic form changes from the Petrarchan (which was becoming archaic in Shakespeare's day) to a then more contemporary sonnet form, using "pilgrims" and "saints" as metaphors. Finally, when the two meet on the balcony, Romeo attempts to use the sonnet form to pledge his love, but Juliet breaks it by saying "Dost thou love me?" By doing this, she searches for true expression, rather than a poetic exaggeration of their love. Juliet uses monosyllabic words with Romeo but uses formal language with Paris. Other forms in the play include an epithalamium by Juliet, a rhapsody in Mercutio's Queen Mab speech, and an elegy by Paris. Shakespeare saves his prose style most often for the common people in the play, though at times he uses it for other characters, such as Mercutio. Humour, also, is important: scholar Molly Mahood identifies at least 175 puns and wordplays in the text. Many of these jokes are sexual in nature, especially those involving Mercutio and the Nurse. Early psychoanalytic critics saw the problem of Romeo and Juliet in terms of Romeo's impulsiveness, deriving from "ill-controlled, partially disguised aggression", which leads both to Mercutio's death and to the double suicide. [lower-alpha 5] Romeo and Juliet is not considered to be exceedingly psychologically complex, and sympathetic psychoanalytic readings of the play make the tragic male experience equivalent with sicknesses. Norman Holland, writing in 1966, considers Romeo's dream as a realistic "wish fulfilling fantasy both in terms of Romeo's adult world and his hypothetical childhood at stages oral, phallic and oedipal" – while acknowledging that a dramatic character is not a human being with mental processes separate from those of the author. Critics such as Julia Kristeva focus on the hatred between the families, arguing that this hatred is the cause of Romeo and Juliet's passion for each other. That hatred manifests itself directly in the lovers' language: Juliet, for example, speaks of "my only love sprung from my only hate" and often expresses her passion through an anticipation of Romeo's death. This leads on to speculation as to the playwright's psychology, in particular to a consideration of Shakespeare's grief for the death of his son, Hamnet . Feminist literary critics argue that the blame for the family feud lies in Verona's patriarchal society . For Coppélia Kahn , for example, the strict, masculine code of violence imposed on Romeo is the main force driving the tragedy to its end. When Tybalt kills Mercutio, Romeo shifts into a violent mode, regretting that Juliet has made him so "effeminate". In this view, the younger males "become men" by engaging in violence on behalf of their fathers, or in the case of the servants, their masters. The feud is also linked to male virility, as the numerous jokes about maidenheads aptly demonstrate. Juliet also submits to a female code of docility by allowing others, such as the Friar, to solve her problems for her. Other critics, such as Dympna Callaghan, look at the play's feminism from a historicist angle, stressing that when the play was written the feudal order was being challenged by increasingly centralised government and the advent of capitalism. At the same time, emerging Puritan ideas about marriage were less concerned with the "evils of female sexuality" than those of earlier eras and more sympathetic towards love-matches: when Juliet dodges her father's attempt to force her to marry a man she has no feeling for, she is challenging the patriarchal order in a way that would not have been possible at an earlier time. A number of critics have found the character of Mercutio to have unacknowledged homoerotic desire for Romeo. Jonathan Goldberg examined the sexuality of Mercutio and Romeo utilising queer theory in Queering the Renaissance (1994), comparing their friendship with sexual love. Mercutio, in friendly conversation, mentions Romeo's phallus , suggesting traces of homoeroticism . An example is his joking wish "To raise a spirit in his mistress' circle ... letting it there stand / Till she had laid it and conjured it down." Romeo's homoeroticism can also be found in his attitude to Rosaline, a woman who is distant and unavailable and brings no hope of offspring. As Benvolio argues, she is best replaced by someone who will reciprocate. Shakespeare's procreation sonnets describe another young man who, like Romeo, is having trouble creating offspring and who may be seen as being a homosexual. Goldberg believes that Shakespeare may have used Rosaline as a way to express homosexual problems of procreation in an acceptable way. In this view, when Juliet says "...that which we call a rose, by any other name would smell as sweet", she may be raising the question of whether there is any difference between the beauty of a man and the beauty of a woman. The balcony scene was introduced by Da Porto in 1524. He had Romeo walk frequently by her house, "sometimes climbing to her chamber window", and wrote, "It happened one night, as love ordained, when the moon shone unusually bright, that whilst Romeo was climbing the balcony, the young lady ... opened the window, and looking out saw him". After this they have a conversation in which they declare eternal love to each other. A few decades later, Bandello greatly expanded this scene, diverging from the familiar one: Julia has her nurse deliver a letter asking Romeo to come to her window with a rope ladder, and he climbs the balcony with the help of his servant, Julia and the nurse (the servants discreetly withdraw after this). Nevertheless, in October 2014, Lois Leveen pointed out in The Atlantic that the original Shakespeare play did not contain a balcony; it just says that Juliet appears at a window. The word balcone is not known to have existed in the English language until two years after Shakespeare's death. The balcony was certainly used in Thomas Otway 's 1679 play, The History and Fall of Caius Marius , which had borrowed much of its story from Romeo and Juliet and placed the two lovers in a balcony reciting a speech similar to that between Romeo and Juliet. Leveen suggested that during the 18th century, David Garrick chose to use a balcony in his adaptation and revival of Romeo and Juliet and modern adaptations have continued this tradition. The earliest known critic of the play was diarist Samuel Pepys , who wrote in 1662: "it is a play of itself the worst that I ever heard in my life." Poet John Dryden wrote 10 years later in praise of the play and its comic character Mercutio: "Shakespear show'd the best of his skill in his Mercutio , and he said himself, that he was forc'd to kill him in the third Act, to prevent being killed by him." Criticism of the play in the 18th century was less sparse but no less divided. Publisher Nicholas Rowe was the first critic to ponder the theme of the play, which he saw as the just punishment of the two feuding families. In mid-century, writer Charles Gildon and philosopher Lord Kames argued that the play was a failure in that it did not follow the classical rules of drama: the tragedy must occur because of some character flaw , not an accident of fate. Writer and critic Samuel Johnson , however, considered it one of Shakespeare's "most pleasing" plays. In the later part of the 18th and through the 19th century, criticism centred on debates over the moral message of the play. Actor and playwright David Garrick 's 1748 adaptation excluded Rosaline: Romeo abandoning her for Juliet was seen as fickle and reckless. Critics such as Charles Dibdin argued that Rosaline had been included in the play in order to show how reckless the hero was and that this was the reason for his tragic end. Others argued that Friar Laurence might be Shakespeare's spokesman in his warnings against undue haste. At the beginning of the 20th century, these moral arguments were disputed by critics such as Richard Green Moulton : he argued that accident, and not some character flaw, led to the lovers' deaths. In Romeo and Juliet , Shakespeare employs several dramatic techniques that have garnered praise from critics, most notably the abrupt shifts from comedy to tragedy (an example is the punning exchange between Benvolio and Mercutio just before Tybalt arrives). Before Mercutio's death in Act III, the play is largely a comedy. After his accidental demise, the play suddenly becomes serious and takes on a tragic tone. When Romeo is banished, rather than executed, and Friar Laurence offers Juliet a plan to reunite her with Romeo, the audience can still hope that all will end well. They are in a "breathless state of suspense" by the opening of the last scene in the tomb: If Romeo is delayed long enough for the Friar to arrive, he and Juliet may yet be saved. These shifts from hope to despair, reprieve, and new hope serve to emphasise the tragedy when the final hope fails and both the lovers die at the end. Shakespeare also uses sub-plots to offer a clearer view of the actions of the main characters. For example, when the play begins, Romeo is in love with Rosaline, who has refused all of his advances. Romeo's infatuation with her stands in obvious contrast to his later love for Juliet. This provides a comparison through which the audience can see the seriousness of Romeo and Juliet's love and marriage. Paris' love for Juliet also sets up a contrast between Juliet's feelings for him and her feelings for Romeo. The formal language she uses around Paris, as well as the way she talks about him to her Nurse, show that her feelings clearly lie with Romeo. Beyond this, the sub-plot of the Montague–Capulet feud overarches the whole play, providing an atmosphere of hate that is the main contributor to the play's tragic end. Shakespeare uses a variety of poetic forms throughout the play. He begins with a 14-line prologue in the form of a Shakespearean sonnet , spoken by a Chorus. Most of Romeo and Juliet is, however, written in blank verse , and much of it in strict iambic pentameter , with less rhythmic variation than in most of Shakespeare's later plays. In choosing forms, Shakespeare matches the poetry to the character who uses it. Friar Laurence, for example, uses sermon and sententiae forms and the Nurse uses a unique blank verse form that closely matches colloquial speech . Each of these forms is also moulded and matched to the emotion of the scene the character occupies. For example, when Romeo talks about Rosaline earlier in the play, he attempts to use the Petrarchan sonnet form. Petrarchan sonnets were often used by men to exaggerate the beauty of women who were impossible for them to attain, as in Romeo's situation with Rosaline. This sonnet form is used by Lady Capulet to describe Count Paris to Juliet as a handsome man. When Romeo and Juliet meet, the poetic form changes from the Petrarchan (which was becoming archaic in Shakespeare's day) to a then more contemporary sonnet form, using "pilgrims" and "saints" as metaphors. Finally, when the two meet on the balcony, Romeo attempts to use the sonnet form to pledge his love, but Juliet breaks it by saying "Dost thou love me?" By doing this, she searches for true expression, rather than a poetic exaggeration of their love. Juliet uses monosyllabic words with Romeo but uses formal language with Paris. Other forms in the play include an epithalamium by Juliet, a rhapsody in Mercutio's Queen Mab speech, and an elegy by Paris. Shakespeare saves his prose style most often for the common people in the play, though at times he uses it for other characters, such as Mercutio. Humour, also, is important: scholar Molly Mahood identifies at least 175 puns and wordplays in the text. Many of these jokes are sexual in nature, especially those involving Mercutio and the Nurse. Early psychoanalytic critics saw the problem of Romeo and Juliet in terms of Romeo's impulsiveness, deriving from "ill-controlled, partially disguised aggression", which leads both to Mercutio's death and to the double suicide. [lower-alpha 5] Romeo and Juliet is not considered to be exceedingly psychologically complex, and sympathetic psychoanalytic readings of the play make the tragic male experience equivalent with sicknesses. Norman Holland, writing in 1966, considers Romeo's dream as a realistic "wish fulfilling fantasy both in terms of Romeo's adult world and his hypothetical childhood at stages oral, phallic and oedipal" – while acknowledging that a dramatic character is not a human being with mental processes separate from those of the author. Critics such as Julia Kristeva focus on the hatred between the families, arguing that this hatred is the cause of Romeo and Juliet's passion for each other. That hatred manifests itself directly in the lovers' language: Juliet, for example, speaks of "my only love sprung from my only hate" and often expresses her passion through an anticipation of Romeo's death. This leads on to speculation as to the playwright's psychology, in particular to a consideration of Shakespeare's grief for the death of his son, Hamnet . Feminist literary critics argue that the blame for the family feud lies in Verona's patriarchal society . For Coppélia Kahn , for example, the strict, masculine code of violence imposed on Romeo is the main force driving the tragedy to its end. When Tybalt kills Mercutio, Romeo shifts into a violent mode, regretting that Juliet has made him so "effeminate". In this view, the younger males "become men" by engaging in violence on behalf of their fathers, or in the case of the servants, their masters. The feud is also linked to male virility, as the numerous jokes about maidenheads aptly demonstrate. Juliet also submits to a female code of docility by allowing others, such as the Friar, to solve her problems for her. Other critics, such as Dympna Callaghan, look at the play's feminism from a historicist angle, stressing that when the play was written the feudal order was being challenged by increasingly centralised government and the advent of capitalism. At the same time, emerging Puritan ideas about marriage were less concerned with the "evils of female sexuality" than those of earlier eras and more sympathetic towards love-matches: when Juliet dodges her father's attempt to force her to marry a man she has no feeling for, she is challenging the patriarchal order in a way that would not have been possible at an earlier time. A number of critics have found the character of Mercutio to have unacknowledged homoerotic desire for Romeo. Jonathan Goldberg examined the sexuality of Mercutio and Romeo utilising queer theory in Queering the Renaissance (1994), comparing their friendship with sexual love. Mercutio, in friendly conversation, mentions Romeo's phallus , suggesting traces of homoeroticism . An example is his joking wish "To raise a spirit in his mistress' circle ... letting it there stand / Till she had laid it and conjured it down." Romeo's homoeroticism can also be found in his attitude to Rosaline, a woman who is distant and unavailable and brings no hope of offspring. As Benvolio argues, she is best replaced by someone who will reciprocate. Shakespeare's procreation sonnets describe another young man who, like Romeo, is having trouble creating offspring and who may be seen as being a homosexual. Goldberg believes that Shakespeare may have used Rosaline as a way to express homosexual problems of procreation in an acceptable way. In this view, when Juliet says "...that which we call a rose, by any other name would smell as sweet", she may be raising the question of whether there is any difference between the beauty of a man and the beauty of a woman. The balcony scene was introduced by Da Porto in 1524. He had Romeo walk frequently by her house, "sometimes climbing to her chamber window", and wrote, "It happened one night, as love ordained, when the moon shone unusually bright, that whilst Romeo was climbing the balcony, the young lady ... opened the window, and looking out saw him". After this they have a conversation in which they declare eternal love to each other. A few decades later, Bandello greatly expanded this scene, diverging from the familiar one: Julia has her nurse deliver a letter asking Romeo to come to her window with a rope ladder, and he climbs the balcony with the help of his servant, Julia and the nurse (the servants discreetly withdraw after this). Nevertheless, in October 2014, Lois Leveen pointed out in The Atlantic that the original Shakespeare play did not contain a balcony; it just says that Juliet appears at a window. The word balcone is not known to have existed in the English language until two years after Shakespeare's death. The balcony was certainly used in Thomas Otway 's 1679 play, The History and Fall of Caius Marius , which had borrowed much of its story from Romeo and Juliet and placed the two lovers in a balcony reciting a speech similar to that between Romeo and Juliet. Leveen suggested that during the 18th century, David Garrick chose to use a balcony in his adaptation and revival of Romeo and Juliet and modern adaptations have continued this tradition. Romeo and Juliet ranks with Hamlet as one of Shakespeare's most performed plays. Its many adaptations have made it one of his most enduring and famous stories. Even in Shakespeare's lifetime, it was extremely popular. Scholar Gary Taylor measures it as the sixth most popular of Shakespeare's plays, in the period after the death of Christopher Marlowe and Thomas Kyd but before the ascendancy of Ben Jonson during which Shakespeare was London's dominant playwright. [lower-alpha 6] The date of the first performance is unknown. The First Quarto, printed in 1597, reads "it hath been often (and with great applause) plaid publiquely", setting the first performance before that date. The Lord Chamberlain's Men were certainly the first to perform it. Besides their strong connections with Shakespeare, the Second Quarto actually names one of its actors, Will Kemp , instead of Peter, in a line in Act V. Richard Burbage was probably the first Romeo, being the company's chief tragedian; and Master Robert Goffe (a boy), the first Juliet. The premiere is likely to have been at The Theatre , with other early productions at the Curtain . Romeo and Juliet is one of the first Shakespeare plays to have been performed outside England: a shortened and simplified version was performed in Nördlingen in 1604. All theatres were closed down by the puritan government on 6 September 1642. Upon the restoration of the monarchy in 1660, two patent companies (the King's Company and the Duke's Company ) were established, and the existing theatrical repertoire was divided between them. Sir William Davenant of the Duke's Company staged a 1662 adaptation in which Henry Harris played Romeo, Thomas Betterton Mercutio, and Betterton's wife Mary Saunderson Juliet: she was probably the first woman to play the role professionally. Another version closely followed Davenant's adaptation and was also regularly performed by the Duke's Company. This was a tragicomedy by James Howard, in which the two lovers survive. Thomas Otway 's The History and Fall of Caius Marius , one of the more extreme of the Restoration adaptations of Shakespeare, debuted in 1680. The scene is shifted from Renaissance Verona to ancient Rome ; Romeo is Marius, Juliet is Lavinia, the feud is between patricians and plebeians; Juliet/Lavinia wakes from her potion before Romeo/Marius dies. Otway's version was a hit, and was acted for the next seventy years. His innovation in the closing scene was even more enduring, and was used in adaptations throughout the next 200 years: Theophilus Cibber 's adaptation of 1744, and David Garrick 's of 1748 both used variations on it. These versions also eliminated elements deemed inappropriate at the time. For example, Garrick's version transferred all language describing Rosaline to Juliet, to heighten the idea of faithfulness and downplay the love-at-first-sight theme. In 1750, a "Battle of the Romeos" began, with Spranger Barry and Susannah Maria Arne (Mrs. Theophilus Cibber) at Covent Garden versus David Garrick and George Anne Bellamy at Drury Lane . The earliest known production in North America was an amateur one: on 23 March 1730, a physician named Joachimus Bertrand placed an advertisement in the Gazette newspaper in New York, promoting a production in which he would play the apothecary. The first professional performances of the play in North America were those of the Hallam Company . Garrick's altered version of the play was very popular, and ran for nearly a century. Not until 1845 did Shakespeare's original return to the stage in the United States with the sisters Susan and Charlotte Cushman as Juliet and Romeo, respectively, and then in 1847 in Britain with Samuel Phelps at Sadler's Wells Theatre . Cushman adhered to Shakespeare's version, beginning a string of eighty-four performances. Her portrayal of Romeo was considered genius by many. The Times wrote: "For a long time Romeo has been a convention. Miss Cushman's Romeo is a creative, a living, breathing, animated, ardent human being." Queen Victoria wrote in her journal that "no-one would ever have imagined she was a woman". Cushman's success broke the Garrick tradition and paved the way for later performances to return to the original storyline. Professional performances of Shakespeare in the mid-19th century had two particular features: firstly, they were generally star vehicles , with supporting roles cut or marginalised to give greater prominence to the central characters. Secondly, they were "pictorial", placing the action on spectacular and elaborate sets (requiring lengthy pauses for scene changes) and with the frequent use of tableaux . Henry Irving 's 1882 production at the Lyceum Theatre (with himself as Romeo and Ellen Terry as Juliet) is considered an archetype of the pictorial style. In 1895, Sir Johnston Forbes-Robertson took over from Irving and laid the groundwork for a more natural portrayal of Shakespeare that remains popular today. Forbes-Robertson avoided the showiness of Irving and instead portrayed a down-to-earth Romeo, expressing the poetic dialogue as realistic prose and avoiding melodramatic flourish. American actors began to rival their British counterparts. Edwin Booth (brother to John Wilkes Booth ) and Mary McVicker (soon to be Edwin's wife) opened as Romeo and Juliet at the sumptuous Booth's Theatre (with its European-style stage machinery , and an air conditioning system unique in New York) on 3 February 1869. Some reports said it was one of the most elaborate productions of Romeo and Juliet ever seen in America; it was certainly the most popular, running for over six weeks and earning over $60,000 ( equivalent to $1,000,000 in 2023 ). [lower-alpha 7] [lower-alpha 8] The programme noted that: "The tragedy will be produced in strict accordance with historical propriety, in every respect, following closely the text of Shakespeare." [lower-alpha 9] The first professional performance of the play in Japan may have been George Crichton Miln's company's production, which toured to Yokohama in 1890. Throughout the 19th century, Romeo and Juliet had been Shakespeare's most popular play, measured by the number of professional performances. In the 20th century it would become the second most popular, behind Hamlet . In 1933, the play was revived by actress Katharine Cornell and her director husband Guthrie McClintic and was taken on a seven-month nationwide tour throughout the United States. It starred Orson Welles , Brian Aherne and Basil Rathbone . The production was a modest success, and so upon the return to New York, Cornell and McClintic revised it, and for the first time the play was presented with almost all the scenes intact, including the Prologue. The new production opened on Broadway in December 1934. Critics wrote that Cornell was "the greatest Juliet of her time", "endlessly haunting", and "the most lovely and enchanting Juliet our present-day theatre has seen". John Gielgud 's New Theatre production in 1935 featured Gielgud and Laurence Olivier as Romeo and Mercutio, exchanging roles six weeks into the run, with Peggy Ashcroft as Juliet. Gielgud used a scholarly combination of Q1 and Q2 texts and organised the set and costumes to match as closely as possible the Elizabethan period . His efforts were a huge success at the box office, and set the stage for increased historical realism in later productions. Olivier later compared his performance and Gielgud's: "John, all spiritual, all spirituality, all beauty, all abstract things; and myself as all earth, blood, humanity ... I've always felt that John missed the lower half and that made me go for the other ... But whatever it was, when I was playing Romeo I was carrying a torch, I was trying to sell realism in Shakespeare." Peter Brook 's 1947 version was the beginning of a different style of Romeo and Juliet performances. Brook was less concerned with realism, and more concerned with translating the play into a form that could communicate with the modern world. He argued, "A production is only correct at the moment of its correctness, and only good at the moment of its success." Brook excluded the final reconciliation of the families from his performance text. Throughout the century, audiences, influenced by the cinema, became less willing to accept actors distinctly older than the teenage characters they were playing. A significant example of more youthful casting was in Franco Zeffirelli 's Old Vic production in 1960, with John Stride and Judi Dench , which would serve as the basis for his 1968 film . Zeffirelli borrowed from Brook's ideas, altogether removing around a third of the play's text to make it more accessible. In an interview with The Times , he stated that the play's "twin themes of love and the total breakdown of understanding between two generations" had contemporary relevance. [lower-alpha 10] Recent performances often set the play in the contemporary world. For example, in 1986, the Royal Shakespeare Company set the play in modern Verona . Switchblades replaced swords, feasts and balls became drug-laden rock parties, and Romeo killed himself by hypodermic needle . Neil Bartlett's production of Romeo and Juliet themed the play very contemporary with a cinematic look which started its life at the Lyric Hammersmith, London then went to West Yorkshire Playhouse for an exclusive run in 1995. The cast included Emily Woof as Juliet, Stuart Bunce as Romeo, Sebastian Harcombe as Mercutio, Ashley Artus as Tybalt, Souad Faress as Lady Capulet and Silas Carson as Paris. In 1997, the Folger Shakespeare Theatre produced a version set in a typical suburban world. Romeo sneaks into the Capulet barbecue to meet Juliet, and Juliet discovers Tybalt's death while in class at school. The play is sometimes given a historical setting, enabling audiences to reflect on the underlying conflicts. For example, adaptations have been set in the midst of the Israeli–Palestinian conflict , in the apartheid era in South Africa, and in the aftermath of the Pueblo Revolt . Similarly, Peter Ustinov 's 1956 comic adaptation, Romanoff and Juliet , is set in a fictional mid-European country in the depths of the Cold War . A mock-Victorian revisionist version of Romeo and Juliet ' s final scene (with a happy ending, Romeo, Juliet, Mercutio, and Paris restored to life, and Benvolio revealing that he is Paris's love, Benvolia, in disguise) forms part of the 1980 stage-play The Life and Adventures of Nicholas Nickleby . Shakespeare's R&J , by Joe Calarco, spins the classic in a modern tale of gay teenage awakening. A recent comedic musical adaptation was The Second City 's Romeo and Juliet Musical: The People vs. Friar Laurence, the Man Who Killed Romeo and Juliet , set in modern times. In the 19th and 20th centuries, Romeo and Juliet has often been the choice of Shakespeare plays to open a classical theatre company, beginning with Edwin Booth 's inaugural production of that play in his theatre in 1869, the newly re-formed company of the Old Vic in 1929 with John Gielgud , Martita Hunt , and Margaret Webster , as well as the Riverside Shakespeare Company in its founding production in New York City in 1977, which used the 1968 film of Franco Zeffirelli 's production as its inspiration. In 2013, Romeo and Juliet ran on Broadway at Richard Rodgers Theatre from 19 September to 8 December for 93 regular performances after 27 previews starting on 24 August with Orlando Bloom and Condola Rashad in the starring roles. A production of the play starring Tom Holland and Francesca Amewudah-Rivers is scheduled to run at the Duke of York's Theatre in London 's West End from 11 May 2024 for a 12-week limited run. The production is to be directed by Jamie Lloyd . A production of the play starring Kit Connor and Rachel Zegler is scheduled to run on Broadway in Fall 2024. The production is to feature music by Jack Antonoff , direction by Sam Gold , and movement by Sonya Tayeh . The best-known ballet version is Prokofiev 's Romeo and Juliet . Originally commissioned by the Kirov Ballet , it was rejected by them when Prokofiev attempted a happy ending and was rejected again for the experimental nature of its music. It has subsequently attained an "immense" reputation, and has been choreographed by John Cranko (1962) and Kenneth MacMillan (1965) among others. In 1977, Michael Smuin 's production of one of the play's most dramatic and impassioned dance interpretations was debuted in its entirety by San Francisco Ballet . This production was the first full-length ballet to be broadcast by the PBS series " Great Performances : Dance in America"; it aired in 1978. Dada Masilo, a South African dancer and choreographer, reinterpreted Romeo and Juliet in a new modern light. She introduced changes to the story, notably that of presenting the two families as multiracial. "Romeo loved Juliet Juliet, she felt the same When he put his arms around her He said Julie, baby, you're my flame Thou givest fever ..." — Peggy Lee 's rendition of " Fever " At least 24 operas have been based on Romeo and Juliet. The earliest, Romeo und Julie in 1776, a Singspiel by Georg Benda , omits much of the action of the play and most of its characters and has a happy ending. It is occasionally revived. The best-known is Gounod 's 1867 Roméo et Juliette (libretto by Jules Barbier and Michel Carré ), a critical triumph when first performed and frequently revived today. Bellini's I Capuleti e i Montecchi is also revived from time to time, but has sometimes been judged unfavourably because of its perceived liberties with Shakespeare; however, Bellini and his librettist, Felice Romani , worked from Italian sources—principally Romani's libretto for Giulietta e Romeo by Nicola Vaccai —rather than directly adapting Shakespeare's play. Among later operas, there is Heinrich Sutermeister 's 1940 work Romeo und Julia and Pascal Dusapin 's first opera Roméo et Juliette ( fr ) on a libretto by Olivier Cadiot (1988). Roméo et Juliette by Berlioz is a "symphonie dramatique", a large-scale work in three parts for mixed voices, chorus, and orchestra, which premiered in 1839. Tchaikovsky 's Romeo and Juliet Fantasy-Overture (1869, revised 1870 and 1880) is a 20-minute symphonic poem , containing the famous melody known as the "love theme". Tchaikovsky's device of repeating the same musical theme at the ball, in the balcony scene, in Juliet's bedroom and in the tomb has been used by subsequent directors: for example, Nino Rota 's love theme is used in a similar way in the 1968 film of the play, as is Des'ree 's " Kissing You " in the 1996 film. Other classical composers influenced by the play include Henry Hugh Pearson ( Romeo and Juliet, overture for orchestra , Op. 86), Svendsen ( Romeo og Julie , 1876), Delius ( A Village Romeo and Juliet , 1899–1901), Stenhammar ( Romeo och Julia , 1922), and Kabalevsky ( Incidental Music to Romeo and Juliet , Op. 56, 1956). The play influenced several jazz works, including Peggy Lee 's " Fever ". Duke Ellington 's Such Sweet Thunder contains a piece entitled "The Star-Crossed Lovers" in which the pair are represented by tenor and alto saxophones: critics noted that Juliet's sax dominates the piece, rather than offering an image of equality. The play has frequently influenced popular music , including works by The Supremes , Bruce Springsteen , Tom Waits , Lou Reed , and Taylor Swift . The most famous such track is Dire Straits ' " Romeo and Juliet ". The most famous musical theatre adaptation is West Side Story with music by Leonard Bernstein and lyrics by Stephen Sondheim . It débuted on Broadway in 1957 and in the West End in 1958 and was twice adapted as popular films in 1961 and in 2021 . This version updated the setting to mid-20th-century New York City and the warring families to ethnic gangs. Other musical adaptations include Terrence Mann 's 1999 rock musical William Shakespeare's Romeo and Juliet , co-written with Jerome Korman; Gérard Presgurvic's 2001 Roméo et Juliette, de la Haine à l'Amour ; Riccardo Cocciante 's 2007 Giulietta & Romeo and Johan Christher Schütz ; and Johan Petterssons's 2013 adaptation Carnival Tale ( Tivolisaga ) , which takes place at a travelling carnival. Romeo and Juliet had a profound influence on subsequent literature. Before then, romance had not even been viewed as a worthy topic for tragedy. In Harold Bloom's words, Shakespeare "invented the formula that the sexual becomes the erotic when crossed by the shadow of death". Of Shakespeare's works, Romeo and Juliet has generated the most—and the most varied—adaptations, including prose and verse narratives, drama, opera, orchestral and choral music, ballet, film, television, and painting. [lower-alpha 11] The word "Romeo" has even become synonymous with "male lover" in English. Romeo and Juliet was parodied in Shakespeare's own lifetime: Henry Porter 's Two Angry Women of Abingdon (1598) and Thomas Dekker 's Blurt, Master Constable (1607) both contain balcony scenes in which a virginal heroine engages in bawdy wordplay. The play directly influenced later literary works . For example, the preparations for a performance form a major plot in Charles Dickens ' Nicholas Nickleby . Romeo and Juliet is one of Shakespeare's most-illustrated works. The first known illustration was a woodcut of the tomb scene, thought to be created by Elisha Kirkall , which appeared in Nicholas Rowe 's 1709 edition of Shakespeare's plays. Five paintings of the play were commissioned for the Boydell Shakespeare Gallery in the late 18th century, one representing each of the five acts of the play. Early in the 19th century, Henry Thomson painted Juliet after the Masquerade , an engraving . of which was published in The Literary Souvenir, 1828, with an accompanying poem by Letitia Elizabeth Landon . The 19th-century fashion for "pictorial" performances led to directors' drawing on paintings for their inspiration, which, in turn, influenced painters to depict actors and scenes from the theatre. In the 20th century, the play's most iconic visual images have derived from its popular film versions. David Blixt 's 2007 novel The Master Of Verona imagines the origins of the famous Capulet-Montague feud, combining the characters from Shakespeare's Italian plays with the historical figures of Dante's time. Blixt's subsequent novels Voice Of The Falconer (2010), Fortune's Fool (2012), and The Prince's Doom (2014) continue to explore the world, following the life of Mercutio as he comes of age. More tales from Blixt's Star-Cross'd series appear in Varnished Faces: Star-Cross'd Short Stories (2015) and the plague anthology, We All Fall Down (2020). Blixt also authored Shakespeare's Secrets: Romeo & Juliet (2018), a collection of essays on the history of Shakespeare's play in performance, in which Blixt asserts the play is structurally not a Tragedy, but a Comedy-Gone-Wrong. In 2014 Blixt and his wife, stage director Janice L Blixt, were guests of the city of Verona, Italy for the launch of the Italian language edition of The Master Of Verona , staying with Dante's descendants and filmmaker Anna Lerario, with whom Blixt collaborated on a film about the life of Veronese prince Cangrande della Scala . Lois Leveen 's 2014 novel Juliet's Nurse imagined the fourteen years leading up to the events in the play from the point of view of the nurse. The nurse has the third largest number of lines in the original play; only the eponymous characters have more lines. The play was the subject of a 2017 General Certificate of Secondary Education ( GCSE ) question by the Oxford, Cambridge and RSA Examinations board that was administered to c. 14000 students. The board attracted widespread media criticism and derision after the question appeared to confuse the Capulets and the Montagues, with exams regulator Ofqual describing the error as unacceptable. Romeo and Juliet was adapted into manga format by publisher UDON Entertainment's Manga Classics imprint and was released in May 2018. Romeo and Juliet may be the most-filmed play of all time. The most notable theatrical releases were George Cukor 's multi- Oscar -nominated 1936 production , Franco Zeffirelli 's 1968 version , and Baz Luhrmann 's 1996 MTV-inspired Romeo + Juliet . The latter two were both, in their time, the highest-grossing Shakespeare film ever. Romeo and Juliet was first filmed in the silent era, by Georges Méliès , although his film is now lost. The play was first heard on film in The Hollywood Revue of 1929 , in which John Gilbert recited the balcony scene opposite Norma Shearer . Shearer and Leslie Howard , with a combined age over 75, played the teenage lovers in George Cukor 's MGM 1936 film version . Neither critics nor the public responded enthusiastically. Cinema-goers considered the film too "arty", staying away as they had from Warner's A Midsummer Night's Dream a year before: leading to Hollywood abandoning the Bard for over a decade. Renato Castellani won the Grand Prix at the Venice Film Festival for his 1954 film of Romeo and Juliet . His Romeo, Laurence Harvey , was already an experienced screen actor. By contrast, Susan Shentall , as Juliet, was a secretarial student who was discovered by the director in a London pub and was cast for her "pale sweet skin and honey-blonde hair". [lower-alpha 12] Stephen Orgel describes Franco Zeffirelli 's 1968 Romeo and Juliet as being "full of beautiful young people, and the camera and the lush technicolour make the most of their sexual energy and good looks". Zeffirelli's teenage leads, Leonard Whiting and Olivia Hussey , had virtually no previous acting experience but performed capably and with great maturity. Zeffirelli has been particularly praised, [lower-alpha 13] for his presentation of the duel scene as bravado getting out-of-control. The film courted controversy by including a nude wedding-night scene while Olivia Hussey was only fifteen. Baz Luhrmann 's 1996 Romeo + Juliet and its accompanying soundtrack successfully targeted the " MTV Generation ": a young audience of similar age to the story's characters. Far darker than Zeffirelli's version, the film is set in the "crass, violent and superficial society" of Verona Beach and Sycamore Grove. Leonardo DiCaprio was Romeo and Claire Danes was Juliet. The play has been widely adapted for TV and film. In 1960, Peter Ustinov 's cold-war stage parody, Romanoff and Juliet was filmed. The 1961 film West Side Story —set among New York gangs—featured the Jets as white youths, equivalent to Shakespeare's Montagues, while the Sharks, equivalent to the Capulets, are Puerto Rican. In 2006, Disney's High School Musical made use of Romeo and Juliet ' s plot, placing the two young lovers in different high-school cliques instead of feuding families. Film-makers have frequently featured characters performing scenes from Romeo and Juliet . [lower-alpha 14] The conceit of dramatising Shakespeare writing Romeo and Juliet has been used several times, including John Madden 's 1998 Shakespeare in Love , in which Shakespeare writes the play against the backdrop of his own doomed love affair. An anime series produced by Gonzo and SKY Perfect Well Think , called Romeo x Juliet , was made in 2007 and the 2013 version is the latest English-language film based on the play. In 2013, Sanjay Leela Bhansali directed the Bollywood film Goliyon Ki Raasleela Ram-Leela , a contemporary version of the play which starred Ranveer Singh and Deepika Padukone in leading roles. The film was a commercial and critical success. In February 2014, BroadwayHD released a filmed version of the 2013 Broadway Revival of Romeo and Juliet . The production starred Orlando Bloom and Condola Rashad . In April and May 2010, the Royal Shakespeare Company and the Mudlark Production Company presented a version of the play, entitled Such Tweet Sorrow , as an improvised, real-time series of tweets on Twitter. The production used RSC actors who engaged with the audience as well each other, performing not from a traditional script but a "Grid" developed by the Mudlark production team and writers Tim Wright and Bethan Marlow. The performers also make use of other media sites such as YouTube for pictures and video. A Juliet balcony (or Juliette balcony) is a balustrade connected to the façade of a building. Two of Uranus 's moons, Juliet and Mab , are named for the play. Romeo and Juliet ranks with Hamlet as one of Shakespeare's most performed plays. Its many adaptations have made it one of his most enduring and famous stories. Even in Shakespeare's lifetime, it was extremely popular. Scholar Gary Taylor measures it as the sixth most popular of Shakespeare's plays, in the period after the death of Christopher Marlowe and Thomas Kyd but before the ascendancy of Ben Jonson during which Shakespeare was London's dominant playwright. [lower-alpha 6] The date of the first performance is unknown. The First Quarto, printed in 1597, reads "it hath been often (and with great applause) plaid publiquely", setting the first performance before that date. The Lord Chamberlain's Men were certainly the first to perform it. Besides their strong connections with Shakespeare, the Second Quarto actually names one of its actors, Will Kemp , instead of Peter, in a line in Act V. Richard Burbage was probably the first Romeo, being the company's chief tragedian; and Master Robert Goffe (a boy), the first Juliet. The premiere is likely to have been at The Theatre , with other early productions at the Curtain . Romeo and Juliet is one of the first Shakespeare plays to have been performed outside England: a shortened and simplified version was performed in Nördlingen in 1604. All theatres were closed down by the puritan government on 6 September 1642. Upon the restoration of the monarchy in 1660, two patent companies (the King's Company and the Duke's Company ) were established, and the existing theatrical repertoire was divided between them. Sir William Davenant of the Duke's Company staged a 1662 adaptation in which Henry Harris played Romeo, Thomas Betterton Mercutio, and Betterton's wife Mary Saunderson Juliet: she was probably the first woman to play the role professionally. Another version closely followed Davenant's adaptation and was also regularly performed by the Duke's Company. This was a tragicomedy by James Howard, in which the two lovers survive. Thomas Otway 's The History and Fall of Caius Marius , one of the more extreme of the Restoration adaptations of Shakespeare, debuted in 1680. The scene is shifted from Renaissance Verona to ancient Rome ; Romeo is Marius, Juliet is Lavinia, the feud is between patricians and plebeians; Juliet/Lavinia wakes from her potion before Romeo/Marius dies. Otway's version was a hit, and was acted for the next seventy years. His innovation in the closing scene was even more enduring, and was used in adaptations throughout the next 200 years: Theophilus Cibber 's adaptation of 1744, and David Garrick 's of 1748 both used variations on it. These versions also eliminated elements deemed inappropriate at the time. For example, Garrick's version transferred all language describing Rosaline to Juliet, to heighten the idea of faithfulness and downplay the love-at-first-sight theme. In 1750, a "Battle of the Romeos" began, with Spranger Barry and Susannah Maria Arne (Mrs. Theophilus Cibber) at Covent Garden versus David Garrick and George Anne Bellamy at Drury Lane . The earliest known production in North America was an amateur one: on 23 March 1730, a physician named Joachimus Bertrand placed an advertisement in the Gazette newspaper in New York, promoting a production in which he would play the apothecary. The first professional performances of the play in North America were those of the Hallam Company . Garrick's altered version of the play was very popular, and ran for nearly a century. Not until 1845 did Shakespeare's original return to the stage in the United States with the sisters Susan and Charlotte Cushman as Juliet and Romeo, respectively, and then in 1847 in Britain with Samuel Phelps at Sadler's Wells Theatre . Cushman adhered to Shakespeare's version, beginning a string of eighty-four performances. Her portrayal of Romeo was considered genius by many. The Times wrote: "For a long time Romeo has been a convention. Miss Cushman's Romeo is a creative, a living, breathing, animated, ardent human being." Queen Victoria wrote in her journal that "no-one would ever have imagined she was a woman". Cushman's success broke the Garrick tradition and paved the way for later performances to return to the original storyline. Professional performances of Shakespeare in the mid-19th century had two particular features: firstly, they were generally star vehicles , with supporting roles cut or marginalised to give greater prominence to the central characters. Secondly, they were "pictorial", placing the action on spectacular and elaborate sets (requiring lengthy pauses for scene changes) and with the frequent use of tableaux . Henry Irving 's 1882 production at the Lyceum Theatre (with himself as Romeo and Ellen Terry as Juliet) is considered an archetype of the pictorial style. In 1895, Sir Johnston Forbes-Robertson took over from Irving and laid the groundwork for a more natural portrayal of Shakespeare that remains popular today. Forbes-Robertson avoided the showiness of Irving and instead portrayed a down-to-earth Romeo, expressing the poetic dialogue as realistic prose and avoiding melodramatic flourish. American actors began to rival their British counterparts. Edwin Booth (brother to John Wilkes Booth ) and Mary McVicker (soon to be Edwin's wife) opened as Romeo and Juliet at the sumptuous Booth's Theatre (with its European-style stage machinery , and an air conditioning system unique in New York) on 3 February 1869. Some reports said it was one of the most elaborate productions of Romeo and Juliet ever seen in America; it was certainly the most popular, running for over six weeks and earning over $60,000 ( equivalent to $1,000,000 in 2023 ). [lower-alpha 7] [lower-alpha 8] The programme noted that: "The tragedy will be produced in strict accordance with historical propriety, in every respect, following closely the text of Shakespeare." [lower-alpha 9] The first professional performance of the play in Japan may have been George Crichton Miln's company's production, which toured to Yokohama in 1890. Throughout the 19th century, Romeo and Juliet had been Shakespeare's most popular play, measured by the number of professional performances. In the 20th century it would become the second most popular, behind Hamlet . In 1933, the play was revived by actress Katharine Cornell and her director husband Guthrie McClintic and was taken on a seven-month nationwide tour throughout the United States. It starred Orson Welles , Brian Aherne and Basil Rathbone . The production was a modest success, and so upon the return to New York, Cornell and McClintic revised it, and for the first time the play was presented with almost all the scenes intact, including the Prologue. The new production opened on Broadway in December 1934. Critics wrote that Cornell was "the greatest Juliet of her time", "endlessly haunting", and "the most lovely and enchanting Juliet our present-day theatre has seen". John Gielgud 's New Theatre production in 1935 featured Gielgud and Laurence Olivier as Romeo and Mercutio, exchanging roles six weeks into the run, with Peggy Ashcroft as Juliet. Gielgud used a scholarly combination of Q1 and Q2 texts and organised the set and costumes to match as closely as possible the Elizabethan period . His efforts were a huge success at the box office, and set the stage for increased historical realism in later productions. Olivier later compared his performance and Gielgud's: "John, all spiritual, all spirituality, all beauty, all abstract things; and myself as all earth, blood, humanity ... I've always felt that John missed the lower half and that made me go for the other ... But whatever it was, when I was playing Romeo I was carrying a torch, I was trying to sell realism in Shakespeare." Peter Brook 's 1947 version was the beginning of a different style of Romeo and Juliet performances. Brook was less concerned with realism, and more concerned with translating the play into a form that could communicate with the modern world. He argued, "A production is only correct at the moment of its correctness, and only good at the moment of its success." Brook excluded the final reconciliation of the families from his performance text. Throughout the century, audiences, influenced by the cinema, became less willing to accept actors distinctly older than the teenage characters they were playing. A significant example of more youthful casting was in Franco Zeffirelli 's Old Vic production in 1960, with John Stride and Judi Dench , which would serve as the basis for his 1968 film . Zeffirelli borrowed from Brook's ideas, altogether removing around a third of the play's text to make it more accessible. In an interview with The Times , he stated that the play's "twin themes of love and the total breakdown of understanding between two generations" had contemporary relevance. [lower-alpha 10] Recent performances often set the play in the contemporary world. For example, in 1986, the Royal Shakespeare Company set the play in modern Verona . Switchblades replaced swords, feasts and balls became drug-laden rock parties, and Romeo killed himself by hypodermic needle . Neil Bartlett's production of Romeo and Juliet themed the play very contemporary with a cinematic look which started its life at the Lyric Hammersmith, London then went to West Yorkshire Playhouse for an exclusive run in 1995. The cast included Emily Woof as Juliet, Stuart Bunce as Romeo, Sebastian Harcombe as Mercutio, Ashley Artus as Tybalt, Souad Faress as Lady Capulet and Silas Carson as Paris. In 1997, the Folger Shakespeare Theatre produced a version set in a typical suburban world. Romeo sneaks into the Capulet barbecue to meet Juliet, and Juliet discovers Tybalt's death while in class at school. The play is sometimes given a historical setting, enabling audiences to reflect on the underlying conflicts. For example, adaptations have been set in the midst of the Israeli–Palestinian conflict , in the apartheid era in South Africa, and in the aftermath of the Pueblo Revolt . Similarly, Peter Ustinov 's 1956 comic adaptation, Romanoff and Juliet , is set in a fictional mid-European country in the depths of the Cold War . A mock-Victorian revisionist version of Romeo and Juliet ' s final scene (with a happy ending, Romeo, Juliet, Mercutio, and Paris restored to life, and Benvolio revealing that he is Paris's love, Benvolia, in disguise) forms part of the 1980 stage-play The Life and Adventures of Nicholas Nickleby . Shakespeare's R&J , by Joe Calarco, spins the classic in a modern tale of gay teenage awakening. A recent comedic musical adaptation was The Second City 's Romeo and Juliet Musical: The People vs. Friar Laurence, the Man Who Killed Romeo and Juliet , set in modern times. In the 19th and 20th centuries, Romeo and Juliet has often been the choice of Shakespeare plays to open a classical theatre company, beginning with Edwin Booth 's inaugural production of that play in his theatre in 1869, the newly re-formed company of the Old Vic in 1929 with John Gielgud , Martita Hunt , and Margaret Webster , as well as the Riverside Shakespeare Company in its founding production in New York City in 1977, which used the 1968 film of Franco Zeffirelli 's production as its inspiration. In 2013, Romeo and Juliet ran on Broadway at Richard Rodgers Theatre from 19 September to 8 December for 93 regular performances after 27 previews starting on 24 August with Orlando Bloom and Condola Rashad in the starring roles. A production of the play starring Tom Holland and Francesca Amewudah-Rivers is scheduled to run at the Duke of York's Theatre in London 's West End from 11 May 2024 for a 12-week limited run. The production is to be directed by Jamie Lloyd . A production of the play starring Kit Connor and Rachel Zegler is scheduled to run on Broadway in Fall 2024. The production is to feature music by Jack Antonoff , direction by Sam Gold , and movement by Sonya Tayeh . The best-known ballet version is Prokofiev 's Romeo and Juliet . Originally commissioned by the Kirov Ballet , it was rejected by them when Prokofiev attempted a happy ending and was rejected again for the experimental nature of its music. It has subsequently attained an "immense" reputation, and has been choreographed by John Cranko (1962) and Kenneth MacMillan (1965) among others. In 1977, Michael Smuin 's production of one of the play's most dramatic and impassioned dance interpretations was debuted in its entirety by San Francisco Ballet . This production was the first full-length ballet to be broadcast by the PBS series " Great Performances : Dance in America"; it aired in 1978. Dada Masilo, a South African dancer and choreographer, reinterpreted Romeo and Juliet in a new modern light. She introduced changes to the story, notably that of presenting the two families as multiracial. "Romeo loved Juliet Juliet, she felt the same When he put his arms around her He said Julie, baby, you're my flame Thou givest fever ..." — Peggy Lee 's rendition of " Fever " At least 24 operas have been based on Romeo and Juliet. The earliest, Romeo und Julie in 1776, a Singspiel by Georg Benda , omits much of the action of the play and most of its characters and has a happy ending. It is occasionally revived. The best-known is Gounod 's 1867 Roméo et Juliette (libretto by Jules Barbier and Michel Carré ), a critical triumph when first performed and frequently revived today. Bellini's I Capuleti e i Montecchi is also revived from time to time, but has sometimes been judged unfavourably because of its perceived liberties with Shakespeare; however, Bellini and his librettist, Felice Romani , worked from Italian sources—principally Romani's libretto for Giulietta e Romeo by Nicola Vaccai —rather than directly adapting Shakespeare's play. Among later operas, there is Heinrich Sutermeister 's 1940 work Romeo und Julia and Pascal Dusapin 's first opera Roméo et Juliette ( fr ) on a libretto by Olivier Cadiot (1988). Roméo et Juliette by Berlioz is a "symphonie dramatique", a large-scale work in three parts for mixed voices, chorus, and orchestra, which premiered in 1839. Tchaikovsky 's Romeo and Juliet Fantasy-Overture (1869, revised 1870 and 1880) is a 20-minute symphonic poem , containing the famous melody known as the "love theme". Tchaikovsky's device of repeating the same musical theme at the ball, in the balcony scene, in Juliet's bedroom and in the tomb has been used by subsequent directors: for example, Nino Rota 's love theme is used in a similar way in the 1968 film of the play, as is Des'ree 's " Kissing You " in the 1996 film. Other classical composers influenced by the play include Henry Hugh Pearson ( Romeo and Juliet, overture for orchestra , Op. 86), Svendsen ( Romeo og Julie , 1876), Delius ( A Village Romeo and Juliet , 1899–1901), Stenhammar ( Romeo och Julia , 1922), and Kabalevsky ( Incidental Music to Romeo and Juliet , Op. 56, 1956). The play influenced several jazz works, including Peggy Lee 's " Fever ". Duke Ellington 's Such Sweet Thunder contains a piece entitled "The Star-Crossed Lovers" in which the pair are represented by tenor and alto saxophones: critics noted that Juliet's sax dominates the piece, rather than offering an image of equality. The play has frequently influenced popular music , including works by The Supremes , Bruce Springsteen , Tom Waits , Lou Reed , and Taylor Swift . The most famous such track is Dire Straits ' " Romeo and Juliet ". The most famous musical theatre adaptation is West Side Story with music by Leonard Bernstein and lyrics by Stephen Sondheim . It débuted on Broadway in 1957 and in the West End in 1958 and was twice adapted as popular films in 1961 and in 2021 . This version updated the setting to mid-20th-century New York City and the warring families to ethnic gangs. Other musical adaptations include Terrence Mann 's 1999 rock musical William Shakespeare's Romeo and Juliet , co-written with Jerome Korman; Gérard Presgurvic's 2001 Roméo et Juliette, de la Haine à l'Amour ; Riccardo Cocciante 's 2007 Giulietta & Romeo and Johan Christher Schütz ; and Johan Petterssons's 2013 adaptation Carnival Tale ( Tivolisaga ) , which takes place at a travelling carnival. Romeo and Juliet had a profound influence on subsequent literature. Before then, romance had not even been viewed as a worthy topic for tragedy. In Harold Bloom's words, Shakespeare "invented the formula that the sexual becomes the erotic when crossed by the shadow of death". Of Shakespeare's works, Romeo and Juliet has generated the most—and the most varied—adaptations, including prose and verse narratives, drama, opera, orchestral and choral music, ballet, film, television, and painting. [lower-alpha 11] The word "Romeo" has even become synonymous with "male lover" in English. Romeo and Juliet was parodied in Shakespeare's own lifetime: Henry Porter 's Two Angry Women of Abingdon (1598) and Thomas Dekker 's Blurt, Master Constable (1607) both contain balcony scenes in which a virginal heroine engages in bawdy wordplay. The play directly influenced later literary works . For example, the preparations for a performance form a major plot in Charles Dickens ' Nicholas Nickleby . Romeo and Juliet is one of Shakespeare's most-illustrated works. The first known illustration was a woodcut of the tomb scene, thought to be created by Elisha Kirkall , which appeared in Nicholas Rowe 's 1709 edition of Shakespeare's plays. Five paintings of the play were commissioned for the Boydell Shakespeare Gallery in the late 18th century, one representing each of the five acts of the play. Early in the 19th century, Henry Thomson painted Juliet after the Masquerade , an engraving . of which was published in The Literary Souvenir, 1828, with an accompanying poem by Letitia Elizabeth Landon . The 19th-century fashion for "pictorial" performances led to directors' drawing on paintings for their inspiration, which, in turn, influenced painters to depict actors and scenes from the theatre. In the 20th century, the play's most iconic visual images have derived from its popular film versions. David Blixt 's 2007 novel The Master Of Verona imagines the origins of the famous Capulet-Montague feud, combining the characters from Shakespeare's Italian plays with the historical figures of Dante's time. Blixt's subsequent novels Voice Of The Falconer (2010), Fortune's Fool (2012), and The Prince's Doom (2014) continue to explore the world, following the life of Mercutio as he comes of age. More tales from Blixt's Star-Cross'd series appear in Varnished Faces: Star-Cross'd Short Stories (2015) and the plague anthology, We All Fall Down (2020). Blixt also authored Shakespeare's Secrets: Romeo & Juliet (2018), a collection of essays on the history of Shakespeare's play in performance, in which Blixt asserts the play is structurally not a Tragedy, but a Comedy-Gone-Wrong. In 2014 Blixt and his wife, stage director Janice L Blixt, were guests of the city of Verona, Italy for the launch of the Italian language edition of The Master Of Verona , staying with Dante's descendants and filmmaker Anna Lerario, with whom Blixt collaborated on a film about the life of Veronese prince Cangrande della Scala . Lois Leveen 's 2014 novel Juliet's Nurse imagined the fourteen years leading up to the events in the play from the point of view of the nurse. The nurse has the third largest number of lines in the original play; only the eponymous characters have more lines. The play was the subject of a 2017 General Certificate of Secondary Education ( GCSE ) question by the Oxford, Cambridge and RSA Examinations board that was administered to c. 14000 students. The board attracted widespread media criticism and derision after the question appeared to confuse the Capulets and the Montagues, with exams regulator Ofqual describing the error as unacceptable. Romeo and Juliet was adapted into manga format by publisher UDON Entertainment's Manga Classics imprint and was released in May 2018. Romeo and Juliet may be the most-filmed play of all time. The most notable theatrical releases were George Cukor 's multi- Oscar -nominated 1936 production , Franco Zeffirelli 's 1968 version , and Baz Luhrmann 's 1996 MTV-inspired Romeo + Juliet . The latter two were both, in their time, the highest-grossing Shakespeare film ever. Romeo and Juliet was first filmed in the silent era, by Georges Méliès , although his film is now lost. The play was first heard on film in The Hollywood Revue of 1929 , in which John Gilbert recited the balcony scene opposite Norma Shearer . Shearer and Leslie Howard , with a combined age over 75, played the teenage lovers in George Cukor 's MGM 1936 film version . Neither critics nor the public responded enthusiastically. Cinema-goers considered the film too "arty", staying away as they had from Warner's A Midsummer Night's Dream a year before: leading to Hollywood abandoning the Bard for over a decade. Renato Castellani won the Grand Prix at the Venice Film Festival for his 1954 film of Romeo and Juliet . His Romeo, Laurence Harvey , was already an experienced screen actor. By contrast, Susan Shentall , as Juliet, was a secretarial student who was discovered by the director in a London pub and was cast for her "pale sweet skin and honey-blonde hair". [lower-alpha 12] Stephen Orgel describes Franco Zeffirelli 's 1968 Romeo and Juliet as being "full of beautiful young people, and the camera and the lush technicolour make the most of their sexual energy and good looks". Zeffirelli's teenage leads, Leonard Whiting and Olivia Hussey , had virtually no previous acting experience but performed capably and with great maturity. Zeffirelli has been particularly praised, [lower-alpha 13] for his presentation of the duel scene as bravado getting out-of-control. The film courted controversy by including a nude wedding-night scene while Olivia Hussey was only fifteen. Baz Luhrmann 's 1996 Romeo + Juliet and its accompanying soundtrack successfully targeted the " MTV Generation ": a young audience of similar age to the story's characters. Far darker than Zeffirelli's version, the film is set in the "crass, violent and superficial society" of Verona Beach and Sycamore Grove. Leonardo DiCaprio was Romeo and Claire Danes was Juliet. The play has been widely adapted for TV and film. In 1960, Peter Ustinov 's cold-war stage parody, Romanoff and Juliet was filmed. The 1961 film West Side Story —set among New York gangs—featured the Jets as white youths, equivalent to Shakespeare's Montagues, while the Sharks, equivalent to the Capulets, are Puerto Rican. In 2006, Disney's High School Musical made use of Romeo and Juliet ' s plot, placing the two young lovers in different high-school cliques instead of feuding families. Film-makers have frequently featured characters performing scenes from Romeo and Juliet . [lower-alpha 14] The conceit of dramatising Shakespeare writing Romeo and Juliet has been used several times, including John Madden 's 1998 Shakespeare in Love , in which Shakespeare writes the play against the backdrop of his own doomed love affair. An anime series produced by Gonzo and SKY Perfect Well Think , called Romeo x Juliet , was made in 2007 and the 2013 version is the latest English-language film based on the play. In 2013, Sanjay Leela Bhansali directed the Bollywood film Goliyon Ki Raasleela Ram-Leela , a contemporary version of the play which starred Ranveer Singh and Deepika Padukone in leading roles. The film was a commercial and critical success. In February 2014, BroadwayHD released a filmed version of the 2013 Broadway Revival of Romeo and Juliet . The production starred Orlando Bloom and Condola Rashad . In April and May 2010, the Royal Shakespeare Company and the Mudlark Production Company presented a version of the play, entitled Such Tweet Sorrow , as an improvised, real-time series of tweets on Twitter. The production used RSC actors who engaged with the audience as well each other, performing not from a traditional script but a "Grid" developed by the Mudlark production team and writers Tim Wright and Bethan Marlow. The performers also make use of other media sites such as YouTube for pictures and video. A Juliet balcony (or Juliette balcony) is a balustrade connected to the façade of a building.Two of Uranus 's moons, Juliet and Mab , are named for the play.

Wiki

Plague

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Bonaparte Visiting the Plague Victims of Jaffa

Bonaparte Visits the Plague Stricken in Jaffa ( French : Bonaparte visitant les pestiférés de Jaffa ) is an oil-on-canvas painting commissioned by Napoleon Bonaparte and painted in 1804 by Antoine-Jean Gros , portraying an event during the French invasion of Egypt . The scene shows Napoleon during a striking scene which is supposed to have occurred in Jaffa on 11 March 1799, depicting the French general making a visit to his ill soldiers at the Armenian Saint Nicholas Monastery . The commission was an attempt to embroider Bonaparte's mythology and quell reports that Napoleon had ordered fifty plague victims in Jaffa be given fatal doses of opium during his retreat from his Syrian expedition. It also served a propaganda purpose in countering reports of French atrocities during their capture of Jaffa . On 18 September 1804, the painting was exhibited at the Salon de Paris , between Napoleon's proclamation as emperor on 18 May and his coronation at Notre-Dame de Paris on 2 December. Dominique Vivant Denon , who participated in Bonaparte's expedition to Egypt and was now director of the musée du Louvre, acted as advisor to Gros on it. The painting now forms part of the collection of French paintings at the Louvre . The painting was ordered by the state after Napoleon had become emperor, and it had a clear propaganda purpose. As for eyewitnesses, in General Berthier 's campaign report there is no mention about such an event. Bourrienne , Bonaparte's private secretary, wrote only that the general crossed the lazaretto at a fast pace. However, Doctor Desgenettes (present in the painting between Napoleon and the patient with the raised arm) wrote that Bonaparte grabbed the sick and helped to transport them. It is now known that the plague is not transmitted by touch. The painting was also commissioned in part to counter reports of French atrocities during their capture of Jaffa . After two French messengers sent to parley with the Ottomans had been killed and their heads displayed on the city walls, Napoleon promised the troops under his command two days and nights to plunder the city. After the city capitulated on the fourth day, the French brutally sacked the city, "slaughtering Christians, Jews and Muslims indiscriminately." Napoleon also ordered the mass killing of 3,000 Ottoman prisoners in French captivity. News of such atrocities contradicted the French justification for their invasions of Ottoman-held Egypt and Syria, namely that it was a mission civilisatrice "that would bring enlightenment to the benighted lands of the East." The painting "thus had a very specific propagandist function." This painting uses elements of the composition of Jacques-Louis David 's 1784 Oath of the Horatii , also held at the Louvre, such as the three arcades from Oath , which defined three different worlds (the three sons making the oath in the left, the father brandishing the swords in the middle and the women abandoned to sadness in the right), a principle taken up in this painting as well. It is sometimes mistaken to be set in a mosque but is actually set in the Armenian Saint Nicholas Monastery , whose courtyard can be seen in the background. Further into the background are the walls of Jaffa , with a breached tower above that flies an oversized French flag . The smoke from a fire, or excessive cannon smoke, dominates the town. To the left, dominated by a typically Egyptian horseshoe arch , a man is richly dressed in the oriental manner hands out bread and is aided by a servant carrying a bread-basket. Behind them, two black men carry a stretcher on which is a form, probably a cadaver. The two-coloured arcade opens out on a gallery full of the sick. To the right, under two arcades, under a broken arch, is Napoleon, accompanied by his officers, touching the armpit bubo presented to him by one of the sick. In front of him, an Arab doctor is caring for another sick man, and a blind man struggles to approach the general. The bottom of the painting is occupied by prostrate and extended men. The light of the painting and the play of colours paint Bonaparte's gesture in the best possible light.The capture and the violent sack of Jaffa by the French army under Bonaparte on 7 March 1799 were rapidly followed by an outbreak of bubonic plague , identified by January 1799, which decimated the army. On 11 March, Bonaparte made a spectacular visit to his sick soldiers and touched them, [ dubious – discuss ] which was considered to be either magnificent or suicidal, according to one's point of view on the Napoleonic legend or of the terrors of an age of plagues. The Napoleonic army requested the help of the priests from the Armenian monastery, who provided medicine that was able to cure some of the soldiers. Napoleon personally thanked the Armenian patriarch and gifted him with his own tent and sword. [ citation needed ] The sick man with bandaged eyes on the right is suffering from blindness as well as plague. Since the army's arrival in Egypt in July 1798, several French had suffered serious eye problems because of the sand, dust and the extreme light of the sun. In 1804, there was no question of representing it as other than a daring deed by Bonaparte, but the officer behind Napoleon tries to stop him touching the bubo. The means by which bubonic plague spread were still unknown in the early 19th century, and the flea 's role in its transmission was unknown until Paul-Louis Simond found evidence for it in 1898. Touching a bubo with a bare hand was not particularly risky since all of the other actors in the scene are now known to be running exactly the same risk of transmission of the disease by fleas. The left-hand officer's action of holding something over his mouth and nose is not entirely unjustified, however, since certain cases of bubonic plague can evolve into a pulmonary plague, with a highly-elevated risk of infection from aerosols emitted by patients' coughs. Medical efforts to stop the plague, seen a little further to the right, were unchanged since the Middle Ages. An old doctor is incising the bubos to let the pus flow out, which is in fact inefficient in terms of treating the disease and weakens the patient. He has already operated on a bubo under the raised right arm of his patient, who holds a bloodied compress under his arm, and is wiping his blade ready to incise a second bubo. The doctor's assistant supports the patient during the operation. The bodies are sick and languishing, and the hero is less heroic for being surrounded by ordinary people. Idealism and classicism were abandoned in favour of a certain romanticism . In effect, it is suffering in painted form, which was a novelty since previously, only noble deaths were painted. On 23 April 1799, during the Siege of Acre , Bonaparte suggested to Desgenettes , the expedition's chief doctor, that the sick should be administered a fatal-level dose of opium . Desgenetted refused to perform euthanasia . On 27 May, Napoleon made a second visit to the plague victims. In the context of the Troubadour style , especially while Napoleon was becoming emperor, this episode evoked the tradition of the thaumaturgical royal touch which the French kings carried out with sufferers of scrofula . A longstanding question concerning the interpretation of the painting is the significance of the number "32" on the hat of one of the patients. Since Gros, the artist, was 32 years old at the time at the composition, the shy, naked prisoner behind the patient raising his arm in front of Napoleon may in fact be a hidden self-portrait. Alternatively, it could reflect the soldier's regiment since the 32e demi-brigade was one of the French units committed to the Egyptian campaign.A longstanding question concerning the interpretation of the painting is the significance of the number "32" on the hat of one of the patients. Since Gros, the artist, was 32 years old at the time at the composition, the shy, naked prisoner behind the patient raising his arm in front of Napoleon may in fact be a hidden self-portrait. Alternatively, it could reflect the soldier's regiment since the 32e demi-brigade was one of the French units committed to the Egyptian campaign.

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Plague

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The Rev

The Rev Jimmy Rathead Musician songwriter composer Drums vocals piano keyboards James Owen Sullivan (February 9, 1981 – December 28, 2009), also known by his stage name The Rev (shortened version of the Reverend Tholomew Plague ), was an American musician, best known as a founding member of the heavy metal band Avenged Sevenfold , where he played drums, piano and provided backing and co-lead vocals. He was also the lead vocalist/pianist in the avant-garde metal band Pinkly Smooth and drummer for the ska punk band Suburban Legends from 1998 to 1999. Sullivan was born on February 9, 1981, of Irish descent and raised Roman Catholic . [ citation needed ] He received his first pair of drumsticks at the age of five and his own drum set at the age of twelve. In high school, he started playing in bands. Before leaving to join Avenged Sevenfold as one of the band's founding members, Sullivan was the drummer for the third wave ska band Suburban Legends . At the age of 19, he recorded his first album with Avenged Sevenfold titled Sounding the Seventh Trumpet . His early influences included Frank Zappa and King Crimson . The Rev stated in an interview with Modern Drummer that he "was raised on that stuff as much as rock and metal." Later in life, he was influenced by drummers Vinnie Paul , Mike Portnoy (who would later be his fill-in with Avenged Sevenfold), Dave Lombardo , Lars Ulrich , and Terry Bozzio , stating "It's funny [...], of all my influences, Tommy Lee is a visual influence. I never thought I'd have one of those." Sullivan had a signature ability called "the double-ride thing" or "the Double Octopus", as the Rev called it, "just for lack of a better definition." "The double-ride thing" is a technique that can be heard on tracks such as " Almost Easy ", "Critical Acclaim", "Crossroads", and "Dancing Dead", in which Sullivan doubles up at a fast tempo between the double bass and ride cymbals . The Rev was the drummer, composer, songwriter, vocalist, and pianist for the band. His vocals are featured in several Avenged Sevenfold songs, including "Strength of the World", " Afterlife ", " A Little Piece of Heaven ", "Almost Easy", " Scream ", "Critical Acclaim", "Lost", "Brompton Cocktail", "Crossroads", "Flash of the Blade" ( Iron Maiden cover), "Art of Subconscious Illusion", "Save Me", and "Fiction". He also wrote and composed several songs for Avenged Sevenfold including "A Little Piece of Heaven", "Afterlife", "Almost Easy", "Unbound (The Wild Ride)", "Buried Alive", "Fiction", "Brompton Cocktail", "Welcome to the Family", "Save Me", among others. Avenged Sevenfold released a demo version of "Nightmare" featuring the Rev on an electronic drumset and providing some vocals. At the second annual Revolver Golden God Awards, the Rev won the award for "Best Drummer". His family members, and Avenged Sevenfold, received the posthumous honor on his behalf. In an Ultimate Guitar online readers' poll of the "Top Ten Greatest Drummers of All Time", the Rev appeared at No. 8, placing higher than Bill Ward of Black Sabbath and lower than Keith Moon of the Who . In 2017, he once again appeared in Ultimate Guitar's list of Top 25 Greatest Singing Drummers, at No. 5. Pinkly Smooth was an American heavy metal / avant-garde metal band. The band was formed in the summer of 2001 in Huntington Beach, California , as a side project of the Rev, and originally featured Rev (under the name "Rathead") on vocals, along with fellow Avenged Sevenfold member Synyster Gates on guitar and former Ballistico band members Buck Silverspur (under the name "El Diablo") on bass, as well as Derek Eglit (under the name "Super Loop") on drums. They released only one album, Unfortunate Snort , which featured former Avenged Sevenfold bassist Justin Meacham (under his stage name "Justin Sane") as a keyboard player.Pinkly Smooth was an American heavy metal / avant-garde metal band. The band was formed in the summer of 2001 in Huntington Beach, California , as a side project of the Rev, and originally featured Rev (under the name "Rathead") on vocals, along with fellow Avenged Sevenfold member Synyster Gates on guitar and former Ballistico band members Buck Silverspur (under the name "El Diablo") on bass, as well as Derek Eglit (under the name "Super Loop") on drums. They released only one album, Unfortunate Snort , which featured former Avenged Sevenfold bassist Justin Meacham (under his stage name "Justin Sane") as a keyboard player.On December 28, 2009, Sullivan was found unresponsive in his Huntington Beach home, and was pronounced dead upon arrival to the hospital. Police ruled out foul play and noted that his death appeared to be from natural causes. An autopsy performed on December 30, 2009, was inconclusive, but toxicology results revealed to the public in June that he died from an overdose of oxycodone ( Percocet ), oxymorphone (a metabolite of oxycodone), diazepam (Valium), nordiazepam (a metabolite of diazepam), and alcohol. The coroner noted an enlarged heart as a "significant condition" that may have played a role in Sullivan's death. On January 6, 2010, a private funeral was held for Sullivan. Shortly after his death, Avenged Sevenfold dedicated their fifth studio album Nightmare to him, as well as several songs, including " So Far Away ", which had been written by bandmate (and childhood friend) Synyster Gates , and "Fiction", which the Rev had written three days before his death. M. Shadows and Gates stated in an interview to Hard Drive Radio : "The eeriest thing about it is there is a song on the album called 'Fiction' [a nickname the Rev gave himself] which started out with the title 'Death.' And it was the last song The Rev wrote for the album, and when he handed it in, he said, 'That's it, that's the last song for this record.' And then, three days later, he died." The Rev's triple bass drum kit from the 2008 Taste of Chaos tour was donated for display at a Hard Rock Cafe in Las Vegas. It has since been taken down. Another drum kit he used is displayed in a Hard Rock Cafe in Gatlinburg, Tennessee . [ needs update ]Origin Edition (1999) Unfortunate Snort (2001) Fistfight at the Wafflehouse (2010)Origin Edition (1999)Unfortunate Snort (2001)Fistfight at the Wafflehouse (2010)

Wiki

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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Plague

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Saint Sebastian

Sebastian ( Latin : Sebastianus ; c. AD 255 – c. AD 288 ) was an early Christian saint and martyr . According to traditional belief, he was killed during the Diocletianic Persecution of Christians. He was initially tied to a post or tree and shot with arrows, though this did not kill him. He was, according to tradition, rescued and healed by Irene of Rome , which became a popular subject in 17th-century painting. In all versions of the story, shortly after his recovery he went to Diocletian to warn him about his sins, and as a result was clubbed to death. He is venerated in the Catholic Church and the Orthodox Church . The oldest record of the details of Sebastian's martyrdom is found in the Chronograph of 354 , which mentions him as a martyr, venerated on January 20. He is also mentioned in a sermon on Psalm 118 by 4th-century bishop Ambrose of Milan : in his sermon, Ambrose stated that Sebastian came from Milan and that he was already venerated there at that time. The full account of his martyrdom comes from the Passio Sancti Sebastiani , a 5th-century text written by an anonymous author, possibly Arnobius the Younger . Sebastian is a popular male saint, especially today among athletes. In medieval times, he was regarded as a saint with a special ability to intercede to protect from plague , and devotion to him greatly increased when plague was active.There is not much known about Saint Sebastian's early life, but the ancient source mentioning Sebastian is found in the Chronograph of 354 , a compilation of chronological and calendrical texts produced in 354 AD by the calligrapher and illustrator Furius Dionysius Filocalus , which mentions him as a martyr who was venerated on January 20. His cult is also mentioned by Ambrose of Milan in his Expositio in Psalmum CXVIII , a theological and exegetical commentary of Psalm 118 dated to 386–390 AD; Ambrose states that Sebastian came from Milan and that he was venerated as a saint there. The first surviving account of Sebastian's life and death is the Passio Sancti Sebastiani , long thought to have been written by Ambrose in the 4th century, but now regarded as a 5th-century account by an unknown author (possibly Arnobius the Younger ). This includes the "two martyrdoms", and the care by Irene in between, and other details that remained part of the story. According to Sebastian's 18th-century entry in Acta Sanctorum , still attributed to Ambrose by the 17th-century hagiographer Jean Bolland , and the briefer account in the 14th-century Legenda Aurea , he was a man of Gallia Narbonensis who was taught in Mediolanum ( Milan ). In 283, Sebastian entered the army in Rome under Emperor Carinus to assist the martyrs . Because of his courage he became one of the captains of the Praetorian Guards under Diocletian and Maximian , who were unaware that he was a Christian. According to tradition, Marcus and Marcellianus were twin brothers from a distinguished family and were deacons . Both brothers married, and they resided in Rome with their wives and children. The brothers refused to sacrifice to the Roman gods and were arrested. They were visited by their parents Tranquillinus and Martia in prison, who attempted to persuade them to renounce Christianity. Sebastian succeeded in converting Tranquillinus and Martia, as well as Tiburtius , the son of Chromatius, the local prefect. Another official, Nicostratus, and his wife Zoe were also converted. It has been said that Zoe had been a mute for six years; however, she made known to Sebastian her desire to be converted to Christianity. As soon as she had, her speech returned to her. Nicostratus then brought the rest of the prisoners; these 16 persons were converted by Sebastian. Chromatius and Tiburtius converted; Chromatius set all of his prisoners free from jail, resigned his position, and retired to the country in Campania . Marcus and Marcellianus, after being concealed by a Christian named Castulus , were later martyred, as were Nicostratus, Zoe, and Tiburtius. Sebastian had prudently concealed his faith, but in 286 it was detected. Diocletian reproached him for his supposed betrayal, and he commanded him to be led to a field and there to be bound to a stake so that the chosen archers from Mauretania would shoot arrows at him. "And the archers shot at him till he was as full of arrows as an urchin [Note 1] is full of pricks, and thus left him there for dead." Miraculously, the arrows did not kill him. The widow of Castulus, Irene of Rome , went to retrieve his body to bury it, and discovered he was still alive. She brought him back to her house and nursed him back to health. Sebastian later stood by a staircase where the emperor was to pass and harangued Diocletian for his cruelties against Christians. This freedom of speech, and from a person whom he supposed to have been dead, greatly astonished the emperor; but recovering from his surprise, he gave orders for Sebastian to be seized and beaten to death with cudgels , and his body thrown into the common sewer. A holy lady named Lucina, admonished by the martyr in a vision, privately removed the body and buried it in the catacombs at the entrance of the cemetery of Calixtus, where now stands the Basilica of St. Sebastian . Remains reputed to be those of Sebastian are housed in Rome in the Basilica Apostolorum , built by Pope Damasus I in 367 on the site of the provisional tomb of Saints Peter and Paul . The church, today called San Sebastiano fuori le mura , was rebuilt in the 1610s under the patronage of Scipione Borghese . Ado, Eginard, Sigebert, and other contemporary authors relate that, in the reign of Louis Debonnair , Pope Eugenius II gave the body of Sebastian to Hilduin, Abbot of St. Denys, who brought it into France , and it was deposited at Saint Medard Abbey , at Soissons , on 8 December, in 826. Sebastian's cranium was brought to the town of Ebersberg ( Germany ) in 934. A Benedictine abbey was founded there and became one of the most important pilgrimage sites in southern Germany. It is said the silver-encased cranium was used as a cup in which to present the consecrated wine of the Blessed Sacrament to the faithful during the feast of Saint Sebastian. Sebastian had prudently concealed his faith, but in 286 it was detected. Diocletian reproached him for his supposed betrayal, and he commanded him to be led to a field and there to be bound to a stake so that the chosen archers from Mauretania would shoot arrows at him. "And the archers shot at him till he was as full of arrows as an urchin [Note 1] is full of pricks, and thus left him there for dead." Miraculously, the arrows did not kill him. The widow of Castulus, Irene of Rome , went to retrieve his body to bury it, and discovered he was still alive. She brought him back to her house and nursed him back to health. Sebastian later stood by a staircase where the emperor was to pass and harangued Diocletian for his cruelties against Christians. This freedom of speech, and from a person whom he supposed to have been dead, greatly astonished the emperor; but recovering from his surprise, he gave orders for Sebastian to be seized and beaten to death with cudgels , and his body thrown into the common sewer. A holy lady named Lucina, admonished by the martyr in a vision, privately removed the body and buried it in the catacombs at the entrance of the cemetery of Calixtus, where now stands the Basilica of St. Sebastian . Remains reputed to be those of Sebastian are housed in Rome in the Basilica Apostolorum , built by Pope Damasus I in 367 on the site of the provisional tomb of Saints Peter and Paul . The church, today called San Sebastiano fuori le mura , was rebuilt in the 1610s under the patronage of Scipione Borghese . Ado, Eginard, Sigebert, and other contemporary authors relate that, in the reign of Louis Debonnair , Pope Eugenius II gave the body of Sebastian to Hilduin, Abbot of St. Denys, who brought it into France , and it was deposited at Saint Medard Abbey , at Soissons , on 8 December, in 826. Sebastian's cranium was brought to the town of Ebersberg ( Germany ) in 934. A Benedictine abbey was founded there and became one of the most important pilgrimage sites in southern Germany. It is said the silver-encased cranium was used as a cup in which to present the consecrated wine of the Blessed Sacrament to the faithful during the feast of Saint Sebastian. The belief that Saint Sebastian was a defense against the plague was a medieval addition to his reputation, which largely accounts for the enormous increase in his importance in the Late Middle Ages . The connection of the martyr shot with arrows with the plague is not an intuitive one. However, the hopeful example of Sebastian being able to recover from his "first martyrdom " (or "sagittation", as it is sometimes called) was relevant as the arrow-wounds can resemble the buboes that were symptoms of bubonic plague. Visually, "the arrow wounds call to God for mercy to us, as the symptoms of the infirm call for pity from the passerby", as Molanus put it. The chronicler Paul the Deacon relates that, in 680, Rome was freed from a raging pestilence by him. The Golden Legend transmits the episode of a great plague that afflicted the Lombards in the time of King Gumburt, which was stopped by the erection of an altar in honor of Sebastian in the Church of Saint Peter in the Province of Pavia .The earliest known representation of Sebastian is a mosaic in the Basilica of Sant'Apollinare Nuovo (Ravenna, Italy) dated between 527 and 565. The right lateral wall of the basilica contains large mosaics representing a procession of 26 martyrs, led by Saint Martin and including Sebastian. The martyrs are represented in Byzantine style, lacking any individuality, and all have identical expressions. Another early representation is in a mosaic in the Church of San Pietro in Vincoli in Rome, probably made in the year 682. It shows a grown, bearded man in court dress but contains no trace of an arrow. The archers and arrows begin to appear by 1000, and ever since have been far more commonly shown than the actual moment of his death by clubbing, so that there is a popular misperception that this is how he died. As protector of potential plague victims (a connection popularized by the Golden Legend ) and soldiers, Sebastian occupied an important place in the popular medieval mind. He was among the most frequently depicted of all saints by Late Gothic and Renaissance artists, in the period after the Black Death . The opportunity to show a semi-nude young male, often in a contorted pose, also made Sebastian a favorite subject. His shooting with arrows was the subject of the largest engraving by the Master of the Playing Cards in the 1430s, when there were few other current subjects with male nudes other than Christ. Sebastian appears in many other prints and paintings, although this was due to his popularity with the faithful. Among many others, Botticelli , Perugino , Titian , Pollaiuolo , Giovanni Bellini , Guido Reni (who painted the subject seven times), Mantegna (three times), Hans Memling , Gerrit van Honthorst , Luca Signorelli , El Greco , Honoré Daumier , John Singer Sargent and Louise Bourgeois all painted Saint Sebastians. An early work by the sculptor Gianlorenzo Bernini is of Saint Sebastian . The saint is ordinarily depicted as a handsome youth pierced by arrows. Predella scenes when required often depicted his arrest, confrontation with the Emperor, and final beheading. The illustration in the infobox is the Saint Sebastian of Il Sodoma , at the Pitti Palace , Florence. Hans Holbein the Elder created a statuette of Saint Sebastian "in silver and parcel-gilt", now in the Victoria and Albert Museum in London . A mainly 17th-century subject, though found in predella scenes as early as the 15th century, was Saint Sebastian Tended by Saint Irene , painted by Georges de La Tour , Trophime Bigot (four times), Jusepe de Ribera , Hendrick ter Brugghen (in perhaps his masterpiece ) and others. This may have been a deliberate attempt by the Church to get away from the single nude subject, which is already recorded in Vasari as sometimes arousing inappropriate thoughts among female and male churchgoers. The Baroque artists usually treated it as a nocturnal chiaroscuro scene, illuminated by a single candle, torch or lantern, in the style fashionable in the first half of the 17th century. There exist several cycles depicting the life of Sebastian. Among them are the frescos in the basilica church of San Sebastiano, Acireale in Sicily painted by Pietro Paolo Vasta . Egon Schiele , an Austrian Expressionist artist, painted a self-portrait as Saint Sebastian in 1915. In 1911, the Italian playwright Gabriele d'Annunzio in conjunction with Claude Debussy produced Le Martyre de saint Sébastien . The American composer Gian Carlo Menotti composed a ballet score for a Ballets Russes production which was first given in 1944. In his novella Death in Venice , Thomas Mann hails the "Sebastian-Figure" as the supreme emblem of Apollonian beauty, that is, the artistry of differentiated forms; beauty as measured by discipline, proportion, and luminous distinctions. This allusion to Sebastian's suffering, associated with the writerly professionalism of the novella's protagonist, Gustav Aschenbach, provides a model for the "heroism born of weakness", which characterizes poise amidst agonizing torment and plain acceptance of one's fate as, beyond mere patience and passivity, a stylized achievement and artistic triumph. Sebastian's death was depicted in the 1949 film Fabiola , in which he was played by Massimo Girotti . In 1976, the British director Derek Jarman made a film, Sebastiane , which caused controversy in its treatment of the martyr as a " homosexual icon ", according to a number of critics reflecting a subtext perceptible in the imagery since the Renaissance. Also in 1976, in the American horror film Carrie , a figure of Saint Sebastian (commonly misconstrued as a figure of the crucified Christ) appears in Carrie's prayer closet. Boxer Muhammad Ali was pictured in the iconography of a bound Saint Sebastian pierced by arrows, in the April 1968 issue of Esquire Magazine . The image was created by photographer George Lois and art director Carl Fischer. A depiction of Saint Sebastian in a fresco restoration in an isolated Italian village is the central motif and cryptic mystery of the 1976 giallo horror film The House with Laughing Windows . In her 1965 story " Everything That Rises Must Converge ", Flannery O'Connor 's character Julian feels as if he were the martyr while taking his mother to "reducing" classes at the Y. In 1997, the eighth episode of the second season of the television series Millennium , the protagonists search for the hand of Saint Sebastian. In 2007, artist Damien Hirst presented Saint Sebastian, Exquisite Pain from his Natural History series. The piece depicts a cow in formaldehyde, bound in metal cable and shot with arrows. British pop band Alt-J 's video for " Hunger of the Pine " contains references to the story of Saint Sebastian's death, adapted to fit the lyrics of the song. Tarsem Singh 's video for the R.E.M. song " Losing My Religion " makes use of imagery of Saint Sebastian, drawing particular inspiration from paintings by Guido Reni and Caravaggio . The indie folk band the Mountain Goats have a song called "Hail, St. Sebastian" that makes reference to his life. Scottish musician Momus has a song "Lucky like St Sebastian", featuring on his 1986 debut album Circus Maximus . Madonna 's song "I'm a Sinner" from her 2012 album MDNA has a segment resembling a litany , with one line saying, "St. Sebastian, don't you cry; let those poisoned arrows fly." The 2013–2018 Canadian drama series Forgive Me centres on a priest haunted by recurring visions of Saint Sebastian. The look of the character Gemino in the popular action-platform videogame Blasphemous is clearly inspired by Saint Sebastian. The family del Valle in Isabel Allende 's novel " House of the Spirits " attends Sunday mass in the Church of Saint Sebastian.The earliest known representation of Sebastian is a mosaic in the Basilica of Sant'Apollinare Nuovo (Ravenna, Italy) dated between 527 and 565. The right lateral wall of the basilica contains large mosaics representing a procession of 26 martyrs, led by Saint Martin and including Sebastian. The martyrs are represented in Byzantine style, lacking any individuality, and all have identical expressions. Another early representation is in a mosaic in the Church of San Pietro in Vincoli in Rome, probably made in the year 682. It shows a grown, bearded man in court dress but contains no trace of an arrow. The archers and arrows begin to appear by 1000, and ever since have been far more commonly shown than the actual moment of his death by clubbing, so that there is a popular misperception that this is how he died. As protector of potential plague victims (a connection popularized by the Golden Legend ) and soldiers, Sebastian occupied an important place in the popular medieval mind. He was among the most frequently depicted of all saints by Late Gothic and Renaissance artists, in the period after the Black Death . The opportunity to show a semi-nude young male, often in a contorted pose, also made Sebastian a favorite subject. His shooting with arrows was the subject of the largest engraving by the Master of the Playing Cards in the 1430s, when there were few other current subjects with male nudes other than Christ. Sebastian appears in many other prints and paintings, although this was due to his popularity with the faithful. Among many others, Botticelli , Perugino , Titian , Pollaiuolo , Giovanni Bellini , Guido Reni (who painted the subject seven times), Mantegna (three times), Hans Memling , Gerrit van Honthorst , Luca Signorelli , El Greco , Honoré Daumier , John Singer Sargent and Louise Bourgeois all painted Saint Sebastians. An early work by the sculptor Gianlorenzo Bernini is of Saint Sebastian . The saint is ordinarily depicted as a handsome youth pierced by arrows. Predella scenes when required often depicted his arrest, confrontation with the Emperor, and final beheading. The illustration in the infobox is the Saint Sebastian of Il Sodoma , at the Pitti Palace , Florence. Hans Holbein the Elder created a statuette of Saint Sebastian "in silver and parcel-gilt", now in the Victoria and Albert Museum in London . A mainly 17th-century subject, though found in predella scenes as early as the 15th century, was Saint Sebastian Tended by Saint Irene , painted by Georges de La Tour , Trophime Bigot (four times), Jusepe de Ribera , Hendrick ter Brugghen (in perhaps his masterpiece ) and others. This may have been a deliberate attempt by the Church to get away from the single nude subject, which is already recorded in Vasari as sometimes arousing inappropriate thoughts among female and male churchgoers. The Baroque artists usually treated it as a nocturnal chiaroscuro scene, illuminated by a single candle, torch or lantern, in the style fashionable in the first half of the 17th century. There exist several cycles depicting the life of Sebastian. Among them are the frescos in the basilica church of San Sebastiano, Acireale in Sicily painted by Pietro Paolo Vasta . Egon Schiele , an Austrian Expressionist artist, painted a self-portrait as Saint Sebastian in 1915. In 1911, the Italian playwright Gabriele d'Annunzio in conjunction with Claude Debussy produced Le Martyre de saint Sébastien . The American composer Gian Carlo Menotti composed a ballet score for a Ballets Russes production which was first given in 1944. In his novella Death in Venice , Thomas Mann hails the "Sebastian-Figure" as the supreme emblem of Apollonian beauty, that is, the artistry of differentiated forms; beauty as measured by discipline, proportion, and luminous distinctions. This allusion to Sebastian's suffering, associated with the writerly professionalism of the novella's protagonist, Gustav Aschenbach, provides a model for the "heroism born of weakness", which characterizes poise amidst agonizing torment and plain acceptance of one's fate as, beyond mere patience and passivity, a stylized achievement and artistic triumph. Sebastian's death was depicted in the 1949 film Fabiola , in which he was played by Massimo Girotti . In 1976, the British director Derek Jarman made a film, Sebastiane , which caused controversy in its treatment of the martyr as a " homosexual icon ", according to a number of critics reflecting a subtext perceptible in the imagery since the Renaissance. Also in 1976, in the American horror film Carrie , a figure of Saint Sebastian (commonly misconstrued as a figure of the crucified Christ) appears in Carrie's prayer closet. Boxer Muhammad Ali was pictured in the iconography of a bound Saint Sebastian pierced by arrows, in the April 1968 issue of Esquire Magazine . The image was created by photographer George Lois and art director Carl Fischer. A depiction of Saint Sebastian in a fresco restoration in an isolated Italian village is the central motif and cryptic mystery of the 1976 giallo horror film The House with Laughing Windows . In her 1965 story " Everything That Rises Must Converge ", Flannery O'Connor 's character Julian feels as if he were the martyr while taking his mother to "reducing" classes at the Y. In 1997, the eighth episode of the second season of the television series Millennium , the protagonists search for the hand of Saint Sebastian. In 2007, artist Damien Hirst presented Saint Sebastian, Exquisite Pain from his Natural History series. The piece depicts a cow in formaldehyde, bound in metal cable and shot with arrows. British pop band Alt-J 's video for " Hunger of the Pine " contains references to the story of Saint Sebastian's death, adapted to fit the lyrics of the song. Tarsem Singh 's video for the R.E.M. song " Losing My Religion " makes use of imagery of Saint Sebastian, drawing particular inspiration from paintings by Guido Reni and Caravaggio . The indie folk band the Mountain Goats have a song called "Hail, St. Sebastian" that makes reference to his life. Scottish musician Momus has a song "Lucky like St Sebastian", featuring on his 1986 debut album Circus Maximus . Madonna 's song "I'm a Sinner" from her 2012 album MDNA has a segment resembling a litany , with one line saying, "St. Sebastian, don't you cry; let those poisoned arrows fly." The 2013–2018 Canadian drama series Forgive Me centres on a priest haunted by recurring visions of Saint Sebastian. The look of the character Gemino in the popular action-platform videogame Blasphemous is clearly inspired by Saint Sebastian. The family del Valle in Isabel Allende 's novel " House of the Spirits " attends Sunday mass in the Church of Saint Sebastian.In the Roman Catholic Church , Sebastian is commemorated by an optional memorial on 20 January. In the Church of Greece , Sebastian's feast day is on 18 December. As a protector from the bubonic plague , Sebastian was formerly one of the Fourteen Holy Helpers . In Catholicism, Sebastian is the patron saint of archers, pin-makers, athletes (a modern association) and of a holy death. Sebastian is one of the patron saints of the city of Qormi in Malta Sebastian is the patron saint of Acireale, Caserta and Petilia Policastro in Italy , Melilli in Sicily , and San Sebastián as well as Palma de Mallorca , Lubrín and Huelva in Spain. He is the patron saint of Negombo , Sri Lanka and Rio de Janeiro , Brazil . Informally, in the tradition of the Afro-Brazilian syncretic religion Umbanda , Sebastian is often associated with Oxossi , especially in the state of Rio de Janeiro itself. In Lubrín , every year on 20 January, there is a festival in honor of Saint Sebastian. A statue of Saint Sebastian leads a procession around the village, and people hurl bread rolls from their balconies to the crowds following the saint in the streets below. The rolls have a hole in the middle and some people string them on a rope around their body. The festival is thought to have originated in the 14th century, after a plague of cholera hit the area. At this time, the wealthy were said to have thrown bread and money to the poor on the streets below, so as to avoid catching the disease. The San Sebastian 'bread festival' is so unusual that it has been declared a Fiesta of National Tourist Interest in Andalusia . King Sebastian I of Portugal , the only King to ever have this name, was so named for having been born on this saint's feast day. The Feast of St. Sebastian is celebrated among Catholic communities of Kerala in India. Churches are illuminated and decorated, with fireworks being a main event in Catholic homes to commemorate the saint. Every parish has its own date of celebration, especially in the districts of Thrissur , Ernakulam , St. Andrew's Basilica, Arthunkal and Kottayam . In Kanjoor Syro Malabar Church the feast is celebrated with the largest procession of golden crosses and decorated umbrellas in Asia. Besides this, many pilgrim centres, churches, shrines and many educational institutions too, throughout Kerala, bear the name of the saint. He is the patron of San Sebastian College – Recoletos in Manila , Philippines , which is adjacent to the Minor Basilica of San Sebastian, the all-steel church in the Philippines and in Asia administered by the Order of Augustinian Recollect (OAR). At the Catholic Newman Community at the University of Rochester , the St. Sebastian Society is an organization of campus-wide Christian athletes that works to serve the greater Rochester, New York , area through methods of restorative justice , special needs fundraising and community service . Sebastian is the patron saint of the Roman Catholic Diocese of Bacolod , in Negros Occidental , Philippines and Lipa City in Batangas , Philippines . Also, Sebastian is the patron saint of Leon City Mexico . A representation of the Saint in his martyrdom is present in the upper left corner of the city coat of arms. Sebastian is the patron of Knights of Columbus Council #4926 in the Roman Catholic Diocese of San Jose in California , serving the cities of Mountain View and Los Altos . Sebastian is the patron saint of the Catholic War Veterans of the United States of America. The highest award given by the CWV is the Honor Legion of the Order of St. Sebastian. In his 1906 Reminiscences , Carl Schurz recalls the annual "bird shoot" pageant of the Rhenish town of Liblar ( de ), sponsored by the Saint Sebastian Society, a club of sharpshooters and their sponsors to which nearly every adult member of the town belonged. The St. Sebastian River in the American state of Florida is named after him. The river is a tributary of the Indian River Lagoon and comprises part of the boundary between Indian River County and Brevard County . The adjacent city of Sebastian, Florida , and St. Sebastian River Preserve State Park are also named for Saint Sebastian. Within the Diocese of Central Florida, the nearby Episcopal Church on Melbourne Beaches is named St Sebastian-by-the-Sea.American author Richard A. Kaye wrote in 1996 that "Contemporary gay men have seen in Sebastian at once a stunning advertisement for homosexual desire (indeed, a homoerotic ideal ), and a prototypical portrait of tortured closet case ." Some religious images depicting Saint Sebastian have been adopted by the LGBT community. A combination of his strong, shirtless physique, the symbolism of the arrows penetrating his body, and the countenance of rapturous pain have intrigued artists (gay or otherwise) for centuries. In Yukio Mishima 's novel Confessions of a Mask , the protagonist Kochan has his first gay sexual experience while looking at a reproduction of Guido Reni 's Saint Sebastian . Kochan remarks: "It is an interesting coincidence that Hirschfeld should place 'pictures of St. Sebastian' in the first rank of those kinds of art works in which the invert takes special delight," referencing Magnus Hirschfeld 's belief that gay men have an inclination towards certain artistic subjects including Saint Sebastian.

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Plague

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Australian plague locust

Calataria coerulescens Sjöstedt, 1932 Calataria rubripes Sjöstedt, 1921 Calataria terminifera subsp. elegans Sjöstedt, 1921 Calataria terminifera subsp. fuscosanguinea Sjöstedt, 1936 Chortoicetes affinis J.A.G.Rehn, 1907 Chortoicetes yorketownensis Brancsik, 1896 Chortoicetes yorketownensis subsp. fuscus Brancsik, 1896 Epacromia terminifera F.Walker, 1870 The Australian plague locust ( Chortoicetes terminifera ) is a native Australian insect in the family Acrididae , and a significant agricultural pest . Adult Australian plague locusts range in size from 20 to 45 mm in length, and the colour varies from brown to green. In profile, the head is higher than the thorax , and the thorax has an X-shaped mark. The legs have a reddish shank and the wings are clear other than for a dark spot on the periphery. The locusts occur naturally in far northwestern New South Wales and the adjoining areas of Queensland and South Australia , as well as Western Australia . From these areas, the locusts can expand from time to time to be found in the agricultural areas of South Australia, New South Wales, including the Riverina , and Victoria . The locust can be found in a variety of grassland and open wooded habitats across the inland areas of the Australian mainland. Upper-level winds may occasionally carry locusts to coastal areas of the mainland and northern Tasmania and may establish populations in the eastern valleys of the Great Dividing Range ; these populations usually fail to establish themselves for more than a few generations. Climatic change is projected to influence spatial patterns of pest outbreaks, as climate change is a primary limiting factor for insect dispersal. The most commercially important locust species in Australia is the Australian plague locust, Chortoicetes terminifera. Invasions wreak havoc on agricultural crops and pastures on a massive scale.Adult locusts feeding on green shoots that follow rain within 24 to 48 hours in warmer months will mature and lay eggs within 5 to 7 days of a rain event. Using their ovipositors to drill a hole, locusts lay their eggs in the soil in a pod. Pods contain around 30 to 50 eggs and locusts lay two or three pods, 5 to 10 days apart. Egglaying often happens en masse , with as many as a million laid in a hectare of suitable soil. In good conditions (i.e. warm and moist), eggs take around two weeks to develop. After hatching, the nymphs take around 20–25 days to complete development in mid-summer. The locust has five instars , with the wings becoming more prominent with each moult. After the first and second instars, nymphs form aggregations known as bands; these tend to disperse by the fifth instar. Late-instar bands travel up to 500 m per day. Drier country has large bands congregating that are visible from the air, while in the agricultural regions, bands tend to be smaller. After its final moult—6 to 8 weeks after egglaying—the adult locust is called a fledgling. Fledglings have three development stages; a growth phase, where wings are strengthened and the exoskeleton hardened, a fat accumulation stage, and lastly, oocyte development. Gregarious populations of locusts form swarms , recurring in central Eastern Australia once every two or three years. The Australian plague locust is less gregarious than other locust species and swarms occur in a continuum from dense swarms through a range of densities down to scattered adults. Swarms may persist for days, dispersing and reforming while following the wind. Swarms may move up to 20 km in a day. Swarms can infest areas up to 50 km 2 (19 sq mi) , although typical infestations are less than 5 km 2 (1.9 sq mi) . Swarms can travel up to 800 km (500 mi) , tending to move with hot winds and generally towards the coast in most cases. When food and climatic conditions are favourable, huge swarms of locusts may develop. The first recorded swarm was in 1844, with further outbreaks from the 1870s onward. After 1900, the intensity and frequency of locust swarms increased, and since the 1920s, a pattern has developed of localised, high-density populations in some locations most years and less frequent major plagues over large areas persisting for one to two years. Infestations in Western Australia are less frequent. Widespread heavy inland rains, especially in summer, allow plague locusts to reach plague proportions with less regular rain maintaining these high-density populations. During these conditions, the lifecycle pattern may change to one in which the period from hatching to maturity is reduced to 2.5 months. Dry conditions reduce populations back to background levels. Due to its large range and frequent plagues, the Australian plague locust is the most damaging locust species in Australia. Damage is mainly confined to pasture , although crop damage can occur. Advanced winter crops have generally hardened off by early summer, when plague locusts become active and therefore are not favoured, but dry conditions and less advanced crops can be highly susceptible to locust infestation as can young autumn crops.Losses in a plague can amount to $ 3–4 million if protection barriers are ineffective. The Australian Plague Locust Commission is responsible for the monitoring and control of locust outbreaks using the control agent fipronil and growth regulators such as diflubenzuron in the juvenile nymphal stage. Two older-generation organophosphates , fenitrothion and chlorpyrifos , are also used occasionally for auxiliary, blanket spray runs, and the bioinsecticide 'Green Guard', made from a native fungal isolate of Metarhizium acridum . The latter is based on technology developed by CSIRO and the LUBILOSA programme, and now accounts for more than 12% of spray applications: for protected, organic farming, or environmentally susceptible areas such as water courses.

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Plague

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

David Brin

Astronomy Exobiology Glen David Brin (born October 6, 1950) is an American science fiction author. He has won the Hugo , Locus , Campbell and Nebula Awards . His novel The Postman was adapted into a 1997 feature film starring Kevin Costner . Brin was born in Glendale, California , in 1950 to Selma and Herb Brin . He graduated from the California Institute of Technology with a Bachelor of Science in astronomy , in 1973. At the University of California, San Diego , he earned a Master of Science in electrical engineering (optics) in 1978 and a Doctor of Philosophy degree in astronomy in 1981. From 1983 to 1986, he was a postdoctoral research fellow at the California Space Institute, of the University of California, at the San Diego campus in La Jolla . In 2010, Brin became a fellow of the Institute for Ethics and Emerging Technologies . He helped establish the Arthur C. Clarke Center for Human Imagination at UCSD. He serves on the advisory board of NASA 's Innovative and Advanced Concepts group and frequently does futurist consulting for corporations and government agencies. [ citation needed ] As of 2013, he served on the Board of Advisors for the Museum of Science Fiction . Brin has Polish Jewish ancestry, from the area around Konin . His grandfather was drafted into the Russian army and fought in the Russo-Japanese War of 1904–1905. As of 2022, Brin was living in San Diego County, California , with his wife and children. Most of Brin's fiction is categorized as hard science fiction , in that they apply some degree of plausible scientific or technological change as important plot elements. About half of Brin's works are in his Uplift Universe . These have twice won the Hugo Award for Best Novel . Much of Brin's work outside the Uplift series focuses on technology's effects on human society, a common theme of contemporary North American science fiction.The Uplift novels are: Short stories: Contacting Aliens: An Illustrated Guide to David Brin's Uplift Universe (2002), ISBN 978-0553377965 is co-written by Brin and Kevin Lenagh Stand-alone novels: Graphic novels: His short fiction has been collected in: Other works by Brin include his addition to Asimov's Foundation Universe : and his addition to Eric Flint's 1632-verse : Brin designed the game Tribes , published in 1998 by Steve Jackson Games , and wrote the storyline for the 2000 Dreamcast video game Ecco the Dolphin: Defender of the Future . Ongoing: Books:The Uplift novels are: Short stories: Contacting Aliens: An Illustrated Guide to David Brin's Uplift Universe (2002), ISBN 978-0553377965 is co-written by Brin and Kevin Lenagh Stand-alone novels: Graphic novels: His short fiction has been collected in: Other works by Brin include his addition to Asimov's Foundation Universe : and his addition to Eric Flint's 1632-verse : Brin designed the game Tribes , published in 1998 by Steve Jackson Games , and wrote the storyline for the 2000 Dreamcast video game Ecco the Dolphin: Defender of the Future .The Uplift novels are: Short stories: Contacting Aliens: An Illustrated Guide to David Brin's Uplift Universe (2002), ISBN 978-0553377965 is co-written by Brin and Kevin LenaghStand-alone novels: Graphic novels: His short fiction has been collected in: Other works by Brin include his addition to Asimov's Foundation Universe : and his addition to Eric Flint's 1632-verse : Brin designed the game Tribes , published in 1998 by Steve Jackson Games , and wrote the storyline for the 2000 Dreamcast video game Ecco the Dolphin: Defender of the Future .Ongoing: Books:

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Plague

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

Anazapta

26 July 2002 ( 2002-07-26 ) (Germany) Anazapta is a 2002 British mystery thriller film directed by Alberto Sciamma and starring Jason Flemyng , Lena Headey , Christopher Fairbank , Ian McNeice , Jeff Nuttall . In the US the film was released as Black Plague . The film is set in England in 1348. While the Hundred Years War rages on between England and France, a detachment of soldiers returns to the estate of the beautiful English noblewoman Lady Matilda ( Lena Headey ) with news that her husband, Sir Walter de Mellerby ( Jon Finch ), was captured and remains hostage in France. Meanwhile, the soldiers led by her husband's nephew Nicholas ( Jason Flemyng ) have brought with them a prisoner, Jacques de Saint Amant ( David La Haye ), the son of the one holding her husband. He can be exchanged for Sir Walter and for an additional ransom, which will save her estate from bankruptcy, as they are deeply in debt to the bishop. When Lady Matilda asks the bishop ( Ian McNeice ) for time to get the ransom, he informs her that he will expect sexual favors from her if the money does not arrive. After some time, however, the inhabitants of the manor begin to die, one by one, a mysterious and painful death. Lady Matilda starts suspecting that the prisoner, whom she has come to care for, is not the one he claims to be.

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Rift Valley fever

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Rift Valley fever

Rift Valley fever ( RVF ) is a viral disease of humans and livestock that can cause mild to severe symptoms. The mild symptoms may include: fever , muscle pains , and headaches which often last for up to a week. The severe symptoms may include: loss of sight beginning three weeks after the infection, infections of the brain causing severe headaches and confusion , and bleeding together with liver problems which may occur within the first few days. Those who have bleeding have a chance of death as high as 50%. The disease is caused by the RVF virus . It is spread by either touching infected animal blood, breathing in the air around an infected animal being butchered , drinking raw milk from an infected animal, or the bite of infected mosquitoes . Animals such as cows, sheep, goats, and camels may be affected. In these animals it is spread mostly by mosquitoes. It does not appear that one person can infect another person. The disease is diagnosed by finding antibodies against the virus or the virus itself in the blood. Prevention of the disease in humans is accomplished by vaccinating animals against the disease. This must be done before an outbreak occurs because if it is done during an outbreak it may worsen the situation. Stopping the movement of animals during an outbreak may also be useful, as may decreasing mosquito numbers and avoiding their bites. There is a human vaccine ; however, as of 2010 it is not widely available. There is no specific treatment and medical efforts are supportive. Outbreaks of the disease have only occurred in Africa and Arabia . Outbreaks usually occur during periods of increased rain which increase the number of mosquitoes. The disease was first reported among livestock in Rift Valley of Kenya in the early 1900s, and the virus was first isolated in 1931. In humans, the virus can cause several syndromes. Usually, they have either no symptoms or only a mild illness with fever, headache , muscle pains , and liver abnormalities. In a small percentage of cases (< 2%), the illness can progress to hemorrhagic fever syndrome, meningoencephalitis (inflammation of the brain and tissues lining the brain ), or affect the eye. Patients who become ill usually experience fever, generalised weakness, back pain, dizziness, and weight loss at the onset of the illness. Typically, people recover within two to seven days after onset. About 1% of people with the disease die of it. In livestock, the fatality level is significantly higher. Pregnant livestock infected with RVF abort virtually 100% of foetuses. An epizootic (animal disease epidemic) of RVF is usually first indicated by a wave of unexplained abortions. [ citation needed ] Other signs in livestock include vomiting and diarrhea, respiratory disease, fever, lethargy, anorexia and sudden death in young animals. The virus belongs to the Bunyavirales order. This is an order of enveloped negative single stranded RNA viruses. All Bunyaviruses have an outer lipid envelope with two glycoproteins —G(N) and G(C)—required for cell entry. They deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane . [ citation needed ] The virus' G(C) protein has a class II membrane fusion protein architecture similar to that found in flaviviruses and alphaviruses . This structural similarity suggests that there may be a common origin for these viral families. [ citation needed ] The virus' 11.5 kb tripartite genome is composed of single-stranded RNA . As a Phlebovirus , it has an ambisense genome. Its L and M segments are negative-sense, but its S segment is ambisense. These three genome segments code for six major proteins: L protein ( viral polymerase ), the two glycoproteins G(N) and G(C), the nucleocapsid N protein, and the nonstructural NSs and NSm proteins. The virus is transmitted through mosquito vectors , as well as through contact with the tissue of infected animals. Two species— Culex tritaeniorhynchus and Aedes vexans —are known to transmit the virus. Other potential vectors include Aedes caspius , Aedes mcintosh , Aedes ochraceus , Culex pipiens , Culex antennatus , Culex perexiguus , Culex zombaensis and Culex quinquefasciatus . Contact with infected tissue is considered to be the main source of human infections. The virus has been isolated from two bat species: the Peter's epauletted fruit bat ( Micropteropus pusillus ) and the aba roundleaf bat ( Hipposideros abae ), which are believed to be reservoirs for the virus. The virus belongs to the Bunyavirales order. This is an order of enveloped negative single stranded RNA viruses. All Bunyaviruses have an outer lipid envelope with two glycoproteins —G(N) and G(C)—required for cell entry. They deliver their genome into the host-cell cytoplasm by fusing their envelope with an endosomal membrane . [ citation needed ] The virus' G(C) protein has a class II membrane fusion protein architecture similar to that found in flaviviruses and alphaviruses . This structural similarity suggests that there may be a common origin for these viral families. [ citation needed ] The virus' 11.5 kb tripartite genome is composed of single-stranded RNA . As a Phlebovirus , it has an ambisense genome. Its L and M segments are negative-sense, but its S segment is ambisense. These three genome segments code for six major proteins: L protein ( viral polymerase ), the two glycoproteins G(N) and G(C), the nucleocapsid N protein, and the nonstructural NSs and NSm proteins. The virus is transmitted through mosquito vectors , as well as through contact with the tissue of infected animals. Two species— Culex tritaeniorhynchus and Aedes vexans —are known to transmit the virus. Other potential vectors include Aedes caspius , Aedes mcintosh , Aedes ochraceus , Culex pipiens , Culex antennatus , Culex perexiguus , Culex zombaensis and Culex quinquefasciatus . Contact with infected tissue is considered to be the main source of human infections. The virus has been isolated from two bat species: the Peter's epauletted fruit bat ( Micropteropus pusillus ) and the aba roundleaf bat ( Hipposideros abae ), which are believed to be reservoirs for the virus. Although many components of the RVFV's RNA play an important role in the virus' pathology, the nonstructural protein encoded on the S segment (NSs) is the only component that has been found to directly affect the host. NSs is hostile and combative against the host interferon (IFNs) antiviral response. IFNs are essential in order for the immune system to fight off viral infections in a host. This inhibitory mechanism is believed to be due to a number of reasons, the first being, competitive inhibition of the formation of the transcription factor. On this transcription factor, NSs interacts with and binds to a subunit that is needed for RNA polymerase I and II. This interaction cause competitive inhibition with another transcription factor component and prevents the assembly process of the transcription factor complex, which results in the suppression of the host antiviral response. Transcription suppression is believed to be another mechanism of this inhibitory process. This occurs when an area of NSs interacts with and binds to the host's protein, SAP30 and forms a complex. This complex causes histone acetylation to regress, which is needed for transcriptional activation of the IFN promoter. This causes IFN expression to be obstructed. Lastly, NSs has also been known to affect regular activity of double-stranded RNA-dependent protein kinase R. This protein is involved in cellular antiviral responses in the host. When RVFV is able to enter the host's DNA, NSs forms a filamentous structure in the nucleus. This allows the virus to interact with specific areas of the host's DNA that relates to segregation defects and induction of chromosome continuity. This increases host infectivity and decreases the host's antiviral response. Diagnosis relies on viral isolation from tissues, or serological testing with an ELISA . Other methods of diagnosis include Nucleic Acid Testing (NAT), cell culture , and IgM antibody assays. As of September 2016, the Kenya Medical Research Institute (KEMRI) has developed a product called Immunoline, designed to diagnose the disease in humans much faster than in previous methods. A person's chances of becoming infected can be reduced by taking measures to decrease contact with blood, body fluids, or tissues of infected animals and protection against mosquitoes and other bloodsucking insects. Use of mosquito repellents and bed nets are two effective methods. For persons working with animals in RVF-endemic areas, wearing protective equipment to avoid any exposure to blood or tissues of animals that may potentially be infected is an important protective measure. Potentially, establishing environmental monitoring and case surveillance systems may aid in the prediction and control of future RVF outbreaks. No vaccines are currently available for humans. While a vaccines have been developed for humans, it has only been used experimentally for scientific personnel in high-risk environments. Trials of a number of vaccines, such as NDBR-103 and TSI-GSD 200, are ongoing. Different types of vaccines for veterinary use are available. The killed vaccines are not practical in routine animal field vaccination because of the need of multiple injections. Live vaccines require a single injection but are known to cause birth defects and abortions in sheep and induce only low-level protection in cattle. The live-attenuated vaccine, MP-12, has demonstrated promising results in laboratory trials in domesticated animals, but more research is needed before the vaccine can be used in the field. The live-attenuated clone 13 vaccine was recently registered and used in South Africa. Alternative vaccines using molecular recombinant constructs are in development and show promising results. A vaccine has been conditionally approved for use in animals in the US. It has been shown that knockout of the NSs and NSm nonstructural proteins of this virus produces an effective vaccine in sheep as well. RVF outbreaks occur across sub-Saharan Africa , with outbreaks occurring elsewhere infrequently. Outbreaks of this disease usually correspond with the warm phases of the EI Niño/Southern Oscillation. During this time there is an increase in rainfall, flooding and greenness of vegetation index , which leads to an increase in mosquito vectors. RVFV can be transmitted vertically in mosquitos, meaning that the virus can be passed from the mother to her offspring. During dry conditions, the virus can remain viable for a number of years in the egg. Mosquitos lay their eggs in water, where they eventually hatch. As water is essential for mosquito eggs to hatch, rainfall and flooding cause an increase in the mosquito population and an increased potential for the virus. The first documented outbreak was identified in Kenya in 1931, in sheep, cattle and humans; another severe outbreak in the country in 1950–1951 involved 100,000 deaths in livestock and an unrecorded number of humans with fever. An outbreak occurred in South Africa in 1974–1976, with more than 500,000 infected animals and the first deaths in humans. In Egypt in 1977–78, an estimated 200,000 people were infected and there were at least 594 deaths. In Kenya in 1998, the virus killed more than 400 people. [ citation needed ] Since then, there have been outbreaks in Saudi Arabia and Yemen (2000), [ citation needed ] East Africa (2006–2007) , Sudan (2007), South Africa (2010), Uganda (2016), Kenya (2018), and Mayotte (2018–2019). 2020–2021 in Kenya, in 2022 an outbreak is ongoing in Burundi.Rift Valley fever was one of more than a dozen agents that the United States researched as potential biological weapons before the nation suspended its biological weapons program in 1969. The disease is one of several identified by WHO as a likely cause of a future epidemic in a new plan developed after the Ebola epidemic for urgent research and development toward new diagnostic tests, vaccines and medicines.

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Rift Valley fever

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Great Rift Valley

The Great Rift Valley ( Swahili : Bonde la ufa ) is a series of contiguous geographic trenches , approximately 7,000 kilometres (4,300 mi) in total length, that runs from Lebanon in Asia to Mozambique in Southeast Africa . While the name continues in some usages, it is rarely used in geology as it is considered an imprecise merging of separate though related rift and fault systems. This valley extends northward for 5,950 km through the eastern part of Africa, through the Red Sea , and into Western Asia . Several deep, elongated lakes, called ribbon lakes , exist on the floor of this rift valley: Lake Malawi and Lake Tanganyika are examples of such lakes. The region has a unique ecosystem and contains a number of Africa's wildlife parks. The term Great Rift Valley is most often used to refer to the valley of the East African Rift , the divergent plate boundary which extends from the Afar Triple Junction southward through eastern Africa , and is in the process of splitting the African Plate into two new and separate plates. Geologists generally refer to these evolving plates as the Nubian Plate and the Somali Plate .Today these rifts and faults are seen as distinct, although connected, but originally, the Great Rift Valley was thought to be a single feature that extended from Lebanon in the north to Mozambique in the south, where it constitutes one of two distinct physiographic provinces of the East African mountains . It included what today is called the Lebanese section of the Dead Sea Transform , the Jordan Rift Valley , Red Sea Rift and the East African Rift . These rifts and faults were formed 35 million years ago.The northernmost part of the Rift corresponds to the central section of what is called today the Dead Sea Transform (DST) or Rift. This midsection of the DST forms the Beqaa Valley in Lebanon, separating the Mount Lebanon range from the Anti-Lebanon Mountains . Further south it is known as the Hula Valley separating the Galilee mountains and the Golan Heights . The Jordan River begins here and flows southward through Lake Hula into the Sea of Galilee in Israel . The Rift then continues south through the Jordan Rift Valley into the Dead Sea on the Israeli - Jordanian border. From the Dead Sea southwards, the Rift is occupied by the Wadi Arabah , then the Gulf of Aqaba , and then the Red Sea . Off the southern tip of Sinai in the Red Sea, the Dead Sea Transform meets the Red Sea Rift which runs the length of the Red Sea. The Red Sea Rift comes ashore to meet the East African Rift and the Aden Ridge in the Afar Depression of East Africa. The junction of these three rifts is called the Afar Triple Junction . The East African Rift follows the Red Sea to the end before turning inland into the Ethiopian highlands , dividing the country into two large and adjacent but separate mountainous regions. In Kenya, Uganda, and the fringes of South Sudan, the Great Rift runs along two separate branches that are joined to each other only at their southern end, in Southern Tanzania along its border with Zambia . The two branches are called the Western Rift Valley and the Eastern Rift Valley . The Western Rift, also called the Albertine Rift , is bordered by some of the highest mountains in Africa, including the Virunga Mountains , Mitumba Mountains , and Ruwenzori Range . It contains the Rift Valley lakes , which include some of the deepest lakes in the world (up to 1,470 metres (4,820 ft) deep at Lake Tanganyika ). Much of this area lies within the boundaries of national parks such as Virunga National Park in the Democratic Republic of Congo , Rwenzori National Park and Queen Elizabeth National Park in Uganda, and Volcanoes National Park in Rwanda . Lake Victoria is considered to be part of the rift valley system although it actually lies between the two branches. All of the African Great Lakes were formed as the result of the rift, and most lie in territories within the rift. In Kenya , the valley is deepest to the north of Nairobi . As the lakes in the Eastern Rift have no outlet to the sea and tend to be shallow, they have a high mineral content as the evaporation of water leaves the salts behind. For example, Lake Magadi has high concentrations of soda ( sodium carbonate ) and Lake Elmenteita , Lake Bogoria , and Lake Nakuru are all strongly alkaline , while the freshwater springs supplying Lake Naivasha are essential to support its current biological variety. The southern section of the Rift Valley includes Lake Malawi , the third-deepest freshwater body in the world, which reaches 706 metres (2,316 ft) in depth and separates the Nyassa plateau of Northern Mozambique from Malawi. The rift extends southwards from Lake Malawi as the valley of the Shire River , which flows from the lake into the Zambezi River. The rift continues south of the Zambezi as the Urema Valley of central Mozambique. Some people would wonder how long will the rift remain stable.

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Rift Valley fever

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List of Rift Valley fever outbreaks

Rift Valley fever (RVF) outbreaks affecting humans and livestock occur across sub-Saharan Africa , with outbreaks occurring elsewhere infrequently. Outbreaks usually correspond with the El Niño , associated with increased rainfall and flooding, causing increases in the mosquito population, which act as vector for the virus. The earliest documented outbreak was identified in livestock in Kenya in 1931, and RVF is believed to have been circulating in the country earlier in the 20th century. The first recorded human deaths occurred in 1974 in South Africa.While RVF may well have been circulating at least as early as 1912 or 1913 when along with a variety of other livestock diseases were described, a series of unexplained deaths were also described that had occurred in lambs in Kenya , the first documented outbreak was identified in Kenya in 1931. While the initial set of Kenyan cases in this 1931 outbreak were identified because of sudden death in a large number of lambs, the disease was also found in cattle as well as in humans including scientists, veterinarians, and farmers working with those animals leading to a total of over 5,000 deaths, all limited to livestock. While no cases were reported in Kenya from 1936 to 1950, another severe outbreak in 1950 and 1951 resulted in 500,000 cases and 100,000 deaths in livestock and an undetermined numbers of humans with fever symptoms, but no human deaths. After heavy rain and flooding in South Africa , a Rift Valley fever outbreak, which ultimately extended from 1974 to 1976, infected more than 500,000 animals. Significantly, during this outbreak, in 1974, the first human deaths were reported from the Rift Valley Fever Virus. In total during this outbreak, there were 110 human cases and seven deaths. The first cases of Rift Valley fever recorded outside of sub-Saharan Africa were in an outbreak that began in Egypt in 1977. Livestock trade along the Nile irrigation system was blamed for its introduction. The fever may have been introduced via sheep that were imported from Sudan or imported from Zimbabwe. The outbreak lasted from 1977 to 1979 and significantly damaged the Egyptian economy resulting in, for the first time, a significant numbers of human deaths.   In total, there were an estimated 200,000 people infected and at least 594 deaths. From late October 1997 to early January 1998, Kenya received 60 to 100 times the normal rainfall resulting in an outbreak of Rift Valley fever. By early 1998, farmers reported deaths of as many as 70% of their sheep and goats and 20 to 30% of their cattle and camels. By 1998, reports were in that more than 400 people had died. Later estimates suggested that as many as 27,500 people were infected within a single district in Kenya, making it the largest outbreak in East Africa. In 2000, there was an outbreak of Rift Valley fever in Saudi Arabia and Yemen again tied to excessive rainfall. Critically, this was the initial outbreak outside of the African continent, and was thought to have spread from the 1997-1998 Kenyan outbreak. The Saudi government blamed the problem on livestock imported from East Africa, and Saudi Arabia and other Gulf states placed a ban on imports from the region, which greatly affected East Africa's livestock sector. In animals, there were over 10,000 infected and 1,000 deaths in Saudi Arabia and 22,000 infections and 6,000 deaths in Yemen [KK].  In humans, there were 886 cases in Saudi Arabia and 1328 cases in Yemen with 123 and 166 deaths, respectively. In November 2006, a Rift Valley fever outbreak started in Kenya . The cases were from the North Eastern Province and Coast Province of Kenya, which had received heavy rain, causing floods and creating breeding grounds for mosquitoes , which spread the virus of the fever from infected livestock to humans. By 7 January 2007, about 75 people had died and another 183 were infected. The outbreak forced the closure of livestock markets in the North Eastern Province, affecting the economy of the region. The outbreak was subsequently reported to have moved into Maragua and Kirinyaga districts of Central Province of Kenya. On 20 January 2007, the outbreak was reported to have crossed into Somalia from Kenya and killed 14 people in the Lower Jubba region. As of 23 January 2007, cases had started to crop up at the Kenyan capital, Nairobi . Businesses were suffering large losses, as customers were shunning the common meat joints for the popular nyama choma (roast meat), as it was believed to be spreading the fever. In December 2006 and again in January 2007, Taiwan International Health Action (Taiwan IHA) began operating missions in Kenya consisting of medical experts assisting in training laboratory and health facility personnel, and included donations of supplies, such as mosquito sprays. The United States Centers for Disease Control also set up an assistance mission and laboratory in Kenya. By the end of January, 2007, some 148 people had died since the outbreak began in December. On 14 March 2007, the Kenyan government declared RVF cases to be diminished after spending an estimated $2.5 million in vaccine and deployment costs. It also lifted the ban on cattle movement in the affected areas. The final death toll in this outbreak was more than 150 people. However, on 8 June 2018, the Ministry of Health in Kenya declared another outbreak of RVF. As of 2 November 2007, 125 cases, including 60 deaths, had been reported from more than 10 localities of White Nile , Sinnar , and Gezira states in Sudan. Young adult males were predominantly affected. More than 25 human samples have been found positive for RVF by PCR or ELISA. During two consecutive seasons of heavy rains in 2008 and 2009, there were two separate outbreaks in Madagascar resulting in 712 suspected human cases and 26 deaths. Studies showed the Rift Valley fever virus strains found in Madagascar were similar to those found in the 2006-2007 outbreak in Kenya. There were minor outbreaks in 2008 and 2009 in South Africa , followed by an extensive outbreak of infections in 2010. As of 8 April 2010, the Ministry of Health South Africa had reported 87 human cases infected with Rift Valley fever (RVF), including two deaths in Free State, Eastern Cape and Northern Cape provinces. Most of these cases reported direct contact with RVFV-infected livestock and or were linked to farms with confirmed animal cases of RVF. The human cases were among farmers, veterinarians and farm workers. All cases were confirmed with RVF by test conducted at the National Institute of Communicable Diseases (NICD) in Johannesburg, South Africa. An outbreak of Rift Valley fever virus (RVFV) infection affected sheep, goats, cattle and wildlife on farms within Free State, Eastern Cape, Northern Cape, Western Cape, Mpumalanga, North West, and Gauteng provinces. As of 29 March 2010, about 78 farms reported laboratory-confirmed animal cases, with extensive livestock deaths. By 2011, at least 20,000 animal infections and 8,851 deaths, and 302 human infections and 25 deaths had been reported. Before this outbreak, sporadic cases of RVFV infection in animals had been documented in South Africa. The last major outbreak of the disease in humans occurred between 1974 and 1976, where an estimated 10,000 to 20,000 cases were recorded. On 19 October 2011, a case of Rift Valley fever contracted in Zimbabwe was reported in a Caucasian female traveler who returned to France after a 26-day stay in Marondera , Mashonaland East Province during July and August, 2011 but later classified as "not confirmed." In September, 2012, there was a human case of Rift Valley fever reported in southern Mauritania . There were a total of 34 cases reported including 17 deaths, and in each case, there was documented contact between the identified cases and animals. The first outbreak of Rift Valley fever in Niger occurred in 2016, with a total of as many as 266 suspected human cases, and included significant loss of cattle as well as 33 human deaths including 17 that were confirmed cases. In March 2016, a male butcher from Kabale District in western Uganda reported to a local hospital with symptoms of headache, fever, fatigue and bleeding, subsequently testing positive for Rift Valley fever . The CDC sent epidemiologists to the District to assist the Ugandan Ministry of Health with the epidemiologic investigation of this small, localized outbreak of 3 confirmed and 2 probable cases. Working with the Uganda Virus Research Institute (UVRI) and the Uganda Ministry of Health, the CDC team conducted a serologic study in animals and humans and also assessed residents' knowledge, attitudes, and practices related to Rift Valley Fever. The team collected samples from cows, goats and sheep, and interviewed and tested 650 district residents. A coordinated educational campaign targeting the general population, farmers, herders, and butchers was initiated and informational posters were created targeting these groups. In January 2018, three human cases of RVF were confirmed in three separate Ugandan districts. By July 2018, an outbreak was declared with 6 confirmed cases and 3 deaths in 5 different districts. By September 2018, an additional 19 people had died with many of the deaths blamed on eating infected livestock. In December 2019, 2 human deaths in two different regions of Uganda were reported. On 3 June 2018, an outbreak of Rift Valley fever began in northern Kenya , and by 6 June 2018, there were 26 suspected human cases including 6 deaths in Wajir County (24 cases) and Marsabit County (2 cases); 7 cases had been confirmed. There were also numerous deaths and abortions in camels, goats and other livestock across a wider area of the country. Despite vaccination of 250,000 livestock in the first two weeks of July, by 12 Jul 2018, there were 120 human cases reported with at least ten deaths. While multiple cattle markets were closed and plans were underway to vaccinate an additional 70,000 cattle, by August, 2018, 500 livestock had died. In July and August alone, there were ten outbreaks reported in livestock and/or humans, and by the end of 2018, 26 people had died. A smaller outbreak, caused by contact with infected animals while grazing or drinking, began in cattle and sheep in January, 2019, followed by several human cases. An outbreak of Rift Valley Virus in the French Mayotte Islands , part of the Comoro group off Mozambique , began with the first human case showing symptoms on 22 November 2018. The outbreak led to restrictions on the sale of uncooked milk, as well as the sale and export of cattle and uncooked meat. While the WHO noted that mosquito transmission should have decreased as the rainy season ended in April, rain provided by Cyclone Kenneth prolonged the outbreak, and the last reported case did not occur until August, 2019. During the outbreak, there were a total of 143 confirmed human cases, as well as 126 cases in livestock. On 5 August 2019, the first confirmed human case ever of RVF in Bangui, Central African Republic, was identified; seven additional potentially infected individuals were also identified. Heavy rains leading to massive flooding from August through October 2019, led to spread of the disease including to Eastern Africa, and, in September 2019, three suspected cases appeared in three separate regions of Sudan with 44 additional cases by 10 October 2019 including 2 deaths. In Sudan, by mid-November, 2019, there were 293 suspected RVF cases identified in humans, including 11 deaths, and more than 75 sheep and goats, including 12 deaths. Massive vaccination efforts extending to 120,000 cattle, goats, and sheep, in neighboring Egypt prevented spread into that country.Likely because of illegally transporting of infected animals, a small animal outbreak began in Libya in mid-December 2019 and was ongoing in 2020 with 30 cases and 4 deaths. As of 22 October 2020, no human infections were reported. In an ongoing outbreak, as of 1 October 2020, three deaths have been reported by the Mauritanian government. In an ongoing outbreak in Sudan , as of 15 October 2020, there have been 79 deaths and 1,962 cases reported from Rift Valley fever . An outbreak started in Sericho, Isiolo county in Kenya on around 19 November 2020, and was confirmed in December. As of 4 February 2021, there have been 32 cases in humans (14 confirmed) in Isiolo and Mandera , of whom 11 have died. Many of the cases have been among herders and other people who work with livestock, and the disease has also affected livestock, including sheep, goats and camels, in Isiolo, Mandera, Murang'a and Garissa . The outbreak appears to be associated with flooding of the Dawa and Ewaso rivers. It is ongoing as of February 2021.

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Rift Valley fever

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Viral hemorrhagic fever

Viral hemorrhagic fevers ( VHFs ) are a diverse group of animal and human illnesses . VHFs may be caused by five distinct families of RNA viruses : the families Filoviridae , Flaviviridae , Rhabdoviridae , and several member families of the Bunyavirales order such as Arenaviridae , and Hantaviridae . All types of VHF are characterized by fever and bleeding disorders and all can progress to high fever, shock and death in many cases. Some of the VHF agents cause relatively mild illnesses, such as the Scandinavian nephropathia epidemica (a hantavirus ), while others, such as Ebola virus , can cause severe, life-threatening disease.Signs and symptoms of VHFs include (by definition) fever and bleeding: The severity of symptoms varies with the type of virus. The "VHF syndrome" (capillary leak, bleeding diathesis , and circulatory compromise leading to shock) appears in a majority of people with filoviral hemorrhagic fevers (e.g., Ebola and Marburg virus ), Crimean–Congo hemorrhagic fever (CCHF), and the South American hemorrhagic fevers caused by arenaviruses , but only in a small minority of patients with dengue or Rift Valley fever .Five families of RNA viruses have been recognised as being able to cause hemorrhagic fevers. [ citation needed ] The pathogen that caused the cocoliztli epidemics in Mexico of 1545 and 1576 is still unknown, and the 1545 epidemic may have been bacterial rather than viral. Different hemorrhagic fever viruses act on the body in different ways, resulting in different symptoms. In most VHFs, it is likely that several mechanisms contribute to symptoms, including liver damage, disseminated intravascular coagulation (DIC), and bone marrow dysfunction. In DIC, small blood clots form in blood vessels throughout the body, removing platelets necessary for clotting from the bloodstream and reducing clotting ability. DIC is thought to cause bleeding in Rift Valley, Marburg, and Ebola fevers. For filoviral hemorrhagic fevers, there are four general mechanisms of pathogenesis. The first mechanism is dissemination of virus due to suppressed responses by macrophages and dendritic cell (antigen presenting cells). The second mechanism is prevention of antigen specific immune response. The third mechanism is apoptosis of lymphocytes. The fourth mechanism is when infected macrophages interact with toxic cytokines , leading to diapedesis and coagulation deficiency. From the vascular perspective, the virus will infect vascular endothelial cells, leading to the reorganization of the VE-cadherin catenin complex (a protein important in cell adhesion). This reorganization creates intercellular gaps in endothelial cells. The gaps lead to increased endothelial permeability and allow blood to escape from the vascular circulatory system. [ citation needed ] The reasons for variation among patients infected with the same virus are unknown but stem from a complex system of virus-host interactions. Dengue fever becomes more virulent during a second infection by means of antibody-dependent enhancement . After the first infection, macrophages display antibodies on their cell membranes specific to the dengue virus. By attaching to these antibodies, dengue viruses from a second infection are better able to infect the macrophages, thus reducing the immune system's ability to fight off infection. [ citation needed ]Definitive diagnosis is usually made at a reference laboratory with advanced biocontainment capabilities. The findings of laboratory investigation vary somewhat between the viruses but in general, there is a decrease in the total white cell count (particularly the lymphocytes ), a decrease in the platelet count, an increase in the blood serum liver enzymes , and reduced blood clotting ability measured as an increase in both the prothrombin (PT) and activated partial thromboplastin times (PTT). The hematocrit may be elevated. The serum urea and creatine may be raised but this is dependent on the hydration status of the patient. The bleeding time tends to be prolonged. [ citation needed ]With the exception of yellow fever vaccine and Ebola vaccines , vaccines for VHF-associated viruses are generally not available. Post-exposure prophylactic (preventive) ribavirin may be effective for some bunyavirus and arenavirus infections. VHF isolation guidelines dictate that all VHF patients (with the exception of dengue patients) should be cared for using strict contact precautions, including hand hygiene, double gloves, gowns, shoe and leg coverings, and face shield or goggles. Lassa, CCHF, Ebola, and Marburg viruses may be particularly prone to nosocomial (hospital-based) spread. Airborne precautions should be utilized including, at a minimum, a fit-tested , HEPA filter-equipped respirator (such as an N95 mask ), a battery-powered, air-purifying respirator, or a positive pressure supplied air respirator to be worn by personnel coming within 1.8 meter (six feet) of a VHF patient. Groups of patients should be cohorted (sequestered) to a separate building or a ward with an isolated air-handling system. Environmental decontamination is typically accomplished with hypochlorite (e.g. bleach) or phenolic disinfectants . Medical management of VHF patients may require intensive supportive care. Antiviral therapy with intravenous ribavirin may be useful in Bunyaviridae and Arenaviridae infections (specifically Lassa fever, RVF, CCHF, and HFRS due to Old World Hantavirus infection) and can be used only under an experimental protocol as IND approved by the U.S. Food and Drug Administration (FDA). Interferon may be effective in Argentine or Bolivian hemorrhagic fevers (also available only as IND). [ citation needed ]The VHF viruses are spread in a variety of ways. Some may be transmitted to humans through a respiratory route. [ citation needed ] The virus is considered by military medical planners to have a potential for aerosol dissemination, weaponization, or likelihood for confusion with similar agents that might be weaponized.

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Rift Valley fever

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2006–2007 East Africa Rift Valley fever outbreak

East Africa had a regional outbreak of Rift Valley fever in late 2006 that affected Kenya , Somalia , and Tanzania . During outbreak, 1062 people were infected with Rift Valley fever and 394 people died between December 2006 and December 2007. Rift Valley fever (RVF) is caused by a phlebovirus in the Bunyavirales order which is transmitted by mosquito bite and contact with infected animal blood; it mainly infects livestock that come into infectious contact with a viral reservoir but human beings can also be infected. The outbreak began after a heavy El Niño rain season across East Africa left greater than usual breeding ground for Aedes aegypti mosquitos, with particularly heavy rainfall over eastern Kenya, central Tanzania, and southern Somalia. While most people infected with the virus experience a relatively mild, flu-like illness without hospitalization, around 8% will develop a severe illness that can include eye disease , encephalitis , hemorrhagic fever and death. During this outbreak, of the 1,062 hospitalized, laboratory-confirmed RVF cases (via anti-RVF ImG ) assays, 37% died.Unusually heavy rains in Kenya's eastern and coastal regions caused widespread flooding in October 2006 and provided extensive breeding grounds for mosquitos capable of transmitting Rift Valley fever. On 30 November 2006 a man identified as the RVF index case began to show symptoms in Kenya's Garissa County , and he checked into a hospital the next day. By mid-December, the Ministry of Health had received reports of deaths from an illness featuring fever and generalized bleeding. Mild cases had likely gone undetected for weeks before the region's mosquito populations climbed after one of the area's heaviest recorded rain seasons. 11 deaths from RVF were reported in Garissa by December 20. Cases of began to cluster in Garissa and Baringo counties areas that had been having high livestock mortality and morbidity rates, which attracted the Kenya Ministry of Health's attention. The WHO alerted the Global Outbreak and Response Network (GOARN) on December 22 and, in response to a January 2 request for help, sent an 11-member team from GOARNS partners to assist the Ministry of Health in addition regional, provincial governments. The outbreak peaked on December 27, when Garissa's authorities issued a ban on slaughtering livestock. Other county's began to follow suit with their own bans on the slaughtering of animals, wary of transmission from slaughtered animals. The Baringo district experienced a total of 169 cases of RVF. A ban on the slaughtering of animals was imposed by the Kenyan Ministry of Health. Heavy rainstorms over southern Somalia in December brought about and influx of mosquitos that quickly spread the disease among domestic herds. By late December, 3 cases had been confirmed in Lower Juba and dozens of other cases were suspected across Somalia's southern regions. On 20 February 2007, 51 deaths were reported in Somalia. Cases of RVF were first reported in livestock on 18 January 2007, with the first human case being confirmed in the Arusha region in mid-February. By mid-March, new clusters of the disease were detected in the Dodoma and Morogoro regions. By 3 May 2007, 264 cases and 109 deaths had been confirmed by authorities. Unusually heavy rains in Kenya's eastern and coastal regions caused widespread flooding in October 2006 and provided extensive breeding grounds for mosquitos capable of transmitting Rift Valley fever. On 30 November 2006 a man identified as the RVF index case began to show symptoms in Kenya's Garissa County , and he checked into a hospital the next day. By mid-December, the Ministry of Health had received reports of deaths from an illness featuring fever and generalized bleeding. Mild cases had likely gone undetected for weeks before the region's mosquito populations climbed after one of the area's heaviest recorded rain seasons. 11 deaths from RVF were reported in Garissa by December 20. Cases of began to cluster in Garissa and Baringo counties areas that had been having high livestock mortality and morbidity rates, which attracted the Kenya Ministry of Health's attention. The WHO alerted the Global Outbreak and Response Network (GOARN) on December 22 and, in response to a January 2 request for help, sent an 11-member team from GOARNS partners to assist the Ministry of Health in addition regional, provincial governments. The outbreak peaked on December 27, when Garissa's authorities issued a ban on slaughtering livestock. Other county's began to follow suit with their own bans on the slaughtering of animals, wary of transmission from slaughtered animals. The Baringo district experienced a total of 169 cases of RVF. A ban on the slaughtering of animals was imposed by the Kenyan Ministry of Health. Heavy rainstorms over southern Somalia in December brought about and influx of mosquitos that quickly spread the disease among domestic herds. By late December, 3 cases had been confirmed in Lower Juba and dozens of other cases were suspected across Somalia's southern regions. On 20 February 2007, 51 deaths were reported in Somalia. Cases of RVF were first reported in livestock on 18 January 2007, with the first human case being confirmed in the Arusha region in mid-February. By mid-March, new clusters of the disease were detected in the Dodoma and Morogoro regions. By 3 May 2007, 264 cases and 109 deaths had been confirmed by authorities. In Kenya the CDC Atlanta-Special Pathogens Branch began training staff for the Ministry of Livestock and Fisheries Development in Polymerase Chain Reaction ( PCR ) testing, sending them a PCR testing machine and reagents for detecting RVF in samples. The United Nations Emergency Coordination group send funding and equipment to Tanzania, while the WHO sent teams to train Tanzania's clinicians in patient care and diagnostic testing. Virologists collected over 296,000 mosquitos and tested over 72,000 for Rift Valley Fever via reverse transcription polymerase chain reaction , with positive results from mosquitos in the Aedes , Anopheles , Culex , and Masonia species. The virus was also observed for the first time to be infecting Ae. pembaensis , Cx. univitattus , and Cx. bitaeniorhynchus mosquitos. Most human cases were the result of viraemic exposure to animal tissue. The last case of RVF was confirmed in the Rift Valley Province and died in the Baringo District on 9 March 2007. At least 394 hospital confirmed cases of RVF were ultimately fatal. The outbreak highlighted the necessity of monitoring livestock for RVF before disease can become widespread enough in herds to significantly spread to humans. Even though animals in Baringo County had shown signs of disease since December 2006, the first human case was not reported until 25 January 2007. The CDC in partnership with the University of Edinburgh began establishing surveillance teams to monitor emerging pneumonias, diarrheal disease, and febrile illnesses West Kenya's domestic animal herds, with the goal of such increased surveillance being to detect future outbreaks in animals before they reach humans.

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Rift Valley fever

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Coalition for Epidemic Preparedness Innovations

The Coalition for Epidemic Preparedness Innovations ( CEPI ) is a foundation that takes donations from public, private, philanthropic, and civil society organisations, to finance independent research projects to develop vaccines against emerging infectious diseases (EID). CEPI is focused on the World Health Organization 's (WHO) " blueprint priority diseases ", which include: the Middle East respiratory syndrome-related coronavirus ( MERS-CoV ), the Severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2 ), the Nipah virus , the Lassa fever virus , and the Rift Valley fever virus, as well as the Chikungunya virus and the hypothetical, unknown pathogen " Disease X ". CEPI investment also requires "equitable access" to the vaccines during outbreaks , although subsequent CEPI policy changes may have compromised this criterion. In 2022, CEPI adopted a vision for the world to be able to respond to a pandemic threat with a new vaccine within 100 days. CEPI was conceived in 2015 and formally launched in 2017 at the World Economic Forum (WEF) in Davos , Switzerland. It was co-founded and co-funded with US$460 million from the Bill and Melinda Gates Foundation , the Wellcome Trust , and the governments of India and Norway , and was later joined by the European Union (2019) and the United Kingdom (2020). CEPI is headquartered in Oslo , Norway. The concept for CEPI was outlined in a July 2015 paper in The New England Journal of Medicine , titled "Establishing a Global Vaccine-Development Fund", co-authored by British medical researcher Jeremy Farrar (a director of Wellcome Trust ), American physician Stanley A. Plotkin (co-discoverer of the Rubella vaccine), and American expert in infectious diseases Adel Mahmoud (developer of the HPV vaccine and rotavirus vaccine ). Their concept was further expanded at the 2016 WEF in Davos, where it was discussed as a solution to the problems encountered in developing and distributing a vaccine for the Western African Ebola virus epidemic . Co-founder and funder, Bill Gates said: "The market is not going to solve this problem because epidemics do not come along very often — and when they do you are not allowed to charge some huge premium price for the tools involved". CEPI's creation was also supported and co-funded by the pharmaceutical industry including GlaxoSmithKline (GSK), with CEO Sir Andrew Witty explaining at the WEF, "It is super-disruptive when the red phone rings in our vaccine division because of a health emergency. People do not realise that there's no spare capacity in the world's vaccine production system today". CEPI was formally launched at the 2017 WEF in Davos, with an initial investment of US$460 million by a consortium that included the governments of Norway, Japan, and Germany, The Wellcome Trust, and the Gates Foundation ; India joined a short time afterwards. In a launch interview with the Financial Times (FT), Gates said that a key goal was to reduce the time to develop vaccines from 10 years to less than 12 months. The initial targets were the six EID viruses with known potential to cause major epidemics, being: MERS , Lassa fever , Nipah virus , Ebola , Marburg fever and Zika . The FT reported CEPI would "build the scientific and technological infrastructure for developing vaccines quickly against pathogens that emerge from nowhere to cause a global health crisis, such as Sars in 2002/03 and Zika in 2015/16", and fund research papers on the costs and process of vaccine development. Town & Country listed it as one of the top-10 newsworthy moments from the 2017 Davos. At launch, Norwegian physician John-Arne Røttingen , who led the steering committee for Ebola vaccine trials, served as interim CEO, and CEPI was based at the Norwegian Institute of Public Health in Oslo. In April 2017, Richard J. Hatchett, former director of the U.S. government's Biomedical Advanced Research and Development Authority (BARDA), became the full-time CEO. Hatchett was also a member of the United States Homeland Security Council under George W. Bush , and the United States National Security Council , under Barack Obama . Also in April 2017, CEPI opened an additional office in London, and in October 2017, a further office was opened in Washington, D.C. Nature later stated, "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". In 2020, CEPI was identified by several media outlets as a "key player in the race to develop a vaccine" for coronavirus disease 2019 . At its launch in 2017, CEPI announced five-year financial pledges from its founders that amounted to US$460 million and came from the sovereign governments of Japan (US$125 million), Norway (US$120 million), and Germany (US$10.6 million in 2017 alone, and which later became US$90 million), and from global foundations of the Gates Foundation (US$100 million), and the Wellcome Trust (US$100 million); India was finalising their financial commitment, which was made shortly afterward. A funding target of US$1 billion was set for the first 5 years of operation (i.e. by January 2022). The journal Nature said of the amount raised that: "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". As part of its funding structure, CEPI has used "vaccine bonds" to "frontload" multi-year sovereign funding pledges. In 2019, the International Finance Facility for Immunisation (IFFIm) issued NOK 600 million in vaccine bonds to front-load the commitment by Norway, through Gavi, the Vaccine Alliance , to CEPI. In March 2019, the European Commission granted access to CEPI into the EU's Horizon 2020 programme, and a longer-term financial funding programme. CEPI note presentations that the EU's financial commitment amounts to US$200 million, which when added to the seed amount (including the full German commitment), came to US$740 million. By February 2020, Bloomberg News reported that CEPI had raised a total of US$760 million with additional donations from the governments of Australia, Belgium, Canada, and the U.K. Bloomberg said that "CEPI solves what economists call a 'coordination problem'. It can help pair boutique research and development companies with big vaccine manufacturers, work with regulators to streamline approval processes and resolve patent disputes on the spot. Its scientific advisory committee has executives from Pfizer, Johnson & Johnson, and Japan's Takeda Pharmaceutical, among others". In March 2020, the British government pledged £210 million in funding to CEPI to specifically focus on a vaccine for the coronavirus; making Britain CEPI's largest individual donor. In January 2022, The Wellcome Trust and the Bill & Melinda Gates Foundation pledged $300 million to CEPI. This is part of CEPI's effort to enable the world to reduce vaccine development timelines to 100 days. The founding mission of CEPI was "equitable access" in pandemics: selling vaccines to developing nations at affordable prices. Affordable access to existing patented vaccines had long been a concern for the medical community, and concern mounted in the wake of the struggle to get access to vaccine in the 2013–2016 Ebola epidemic . Averting a repetition of this crisis was the motivating factor behind founding CEPI. CEPI's original policy contained specific measures to prevent some of these market problems. All vaccine-manufacturing contracts would need initial approval by a public review board. The policy also stated that vaccine prices would be set at levels affordable to those needing vaccines and sustainable to the manufacturer. Trade secrets would not be funded by the CEPI. Companies had to share all research data developed with CEPI funds. While CEPI would, controversially, not retain and license the intellectual property developed with CEPI funds (allowing the groups awarded funding to own it), the CEPI retained "step-in" rights: the right to license and use intellectual property developed with CEPI funds for vaccine production, even if the company that had received the funding and taken ownership of the IP later withdrew from the agreement with CEPI. The original policy also required that funded parties pre-register any trials in a clinical trials registry , publish results within a year of study completion (except with compelling reason and permission of CEPI), publish results in open-access articles, and have mechanisms for securely sharing underlying data and results, including negative results, in a way that preserves trial volunteer privacy (see AllTrials for further information). Pharmaceutical corporations, including Johnson & Johnson , Pfizer , and Takeda , objected to the original policy, and these provisions were removed in December 2018, after the CEPI had obtained significant funding. The policy changes met with strong criticism, led by Médecins Sans Frontières . CEPI was also criticized for not following its own policies on transparency, and for removing the requirement that CEPI's board review CEPI's contracts. The CEPI stated that its vaccines would continue to be affordable and available, and published an article discussing the changes, saying that the old policy "while reflective of the idealism that inspired the creation of CEPI, was felt by others not to be pragmatic or reflect the business realities confronted by vaccine developers". It said that several unnamed vaccine manufacturers had declared that they could not work with the CEPI under the original policy. It said that the policy change did not reflect a change in commitment to access, and CEPI would still retain the right to do research and development using intellectual property it had funded, if the old partner was unable to continue. It also said that the CEPI would retain the right to find a new manufacturer if the old manufacturer could not continue, provided the old manufacturer agrees to the transfer of the information and intellectual property to the new one. The New York Times said that CEPI had made a "failed effort to get large pharmaceutical firms to agree to be partners without insisting on substantial profits or proprietary rights to research that CEPI helped to finance and produce," and had replaced specific implementation measures with lip service to its funding mission. The coalition was nominated for the 2021 Nobel Peace Prize by Norwegian MP Carl-Erik Grimstad . The concept for CEPI was outlined in a July 2015 paper in The New England Journal of Medicine , titled "Establishing a Global Vaccine-Development Fund", co-authored by British medical researcher Jeremy Farrar (a director of Wellcome Trust ), American physician Stanley A. Plotkin (co-discoverer of the Rubella vaccine), and American expert in infectious diseases Adel Mahmoud (developer of the HPV vaccine and rotavirus vaccine ). Their concept was further expanded at the 2016 WEF in Davos, where it was discussed as a solution to the problems encountered in developing and distributing a vaccine for the Western African Ebola virus epidemic . Co-founder and funder, Bill Gates said: "The market is not going to solve this problem because epidemics do not come along very often — and when they do you are not allowed to charge some huge premium price for the tools involved". CEPI's creation was also supported and co-funded by the pharmaceutical industry including GlaxoSmithKline (GSK), with CEO Sir Andrew Witty explaining at the WEF, "It is super-disruptive when the red phone rings in our vaccine division because of a health emergency. People do not realise that there's no spare capacity in the world's vaccine production system today". CEPI was formally launched at the 2017 WEF in Davos, with an initial investment of US$460 million by a consortium that included the governments of Norway, Japan, and Germany, The Wellcome Trust, and the Gates Foundation ; India joined a short time afterwards. In a launch interview with the Financial Times (FT), Gates said that a key goal was to reduce the time to develop vaccines from 10 years to less than 12 months. The initial targets were the six EID viruses with known potential to cause major epidemics, being: MERS , Lassa fever , Nipah virus , Ebola , Marburg fever and Zika . The FT reported CEPI would "build the scientific and technological infrastructure for developing vaccines quickly against pathogens that emerge from nowhere to cause a global health crisis, such as Sars in 2002/03 and Zika in 2015/16", and fund research papers on the costs and process of vaccine development. Town & Country listed it as one of the top-10 newsworthy moments from the 2017 Davos. At launch, Norwegian physician John-Arne Røttingen , who led the steering committee for Ebola vaccine trials, served as interim CEO, and CEPI was based at the Norwegian Institute of Public Health in Oslo. In April 2017, Richard J. Hatchett, former director of the U.S. government's Biomedical Advanced Research and Development Authority (BARDA), became the full-time CEO. Hatchett was also a member of the United States Homeland Security Council under George W. Bush , and the United States National Security Council , under Barack Obama . Also in April 2017, CEPI opened an additional office in London, and in October 2017, a further office was opened in Washington, D.C. Nature later stated, "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". In 2020, CEPI was identified by several media outlets as a "key player in the race to develop a vaccine" for coronavirus disease 2019 . At its launch in 2017, CEPI announced five-year financial pledges from its founders that amounted to US$460 million and came from the sovereign governments of Japan (US$125 million), Norway (US$120 million), and Germany (US$10.6 million in 2017 alone, and which later became US$90 million), and from global foundations of the Gates Foundation (US$100 million), and the Wellcome Trust (US$100 million); India was finalising their financial commitment, which was made shortly afterward. A funding target of US$1 billion was set for the first 5 years of operation (i.e. by January 2022). The journal Nature said of the amount raised that: "It is by far the largest vaccine development initiative ever against viruses that are potential epidemic threats". As part of its funding structure, CEPI has used "vaccine bonds" to "frontload" multi-year sovereign funding pledges. In 2019, the International Finance Facility for Immunisation (IFFIm) issued NOK 600 million in vaccine bonds to front-load the commitment by Norway, through Gavi, the Vaccine Alliance , to CEPI. In March 2019, the European Commission granted access to CEPI into the EU's Horizon 2020 programme, and a longer-term financial funding programme. CEPI note presentations that the EU's financial commitment amounts to US$200 million, which when added to the seed amount (including the full German commitment), came to US$740 million. By February 2020, Bloomberg News reported that CEPI had raised a total of US$760 million with additional donations from the governments of Australia, Belgium, Canada, and the U.K. Bloomberg said that "CEPI solves what economists call a 'coordination problem'. It can help pair boutique research and development companies with big vaccine manufacturers, work with regulators to streamline approval processes and resolve patent disputes on the spot. Its scientific advisory committee has executives from Pfizer, Johnson & Johnson, and Japan's Takeda Pharmaceutical, among others". In March 2020, the British government pledged £210 million in funding to CEPI to specifically focus on a vaccine for the coronavirus; making Britain CEPI's largest individual donor. In January 2022, The Wellcome Trust and the Bill & Melinda Gates Foundation pledged $300 million to CEPI. This is part of CEPI's effort to enable the world to reduce vaccine development timelines to 100 days.The founding mission of CEPI was "equitable access" in pandemics: selling vaccines to developing nations at affordable prices. Affordable access to existing patented vaccines had long been a concern for the medical community, and concern mounted in the wake of the struggle to get access to vaccine in the 2013–2016 Ebola epidemic . Averting a repetition of this crisis was the motivating factor behind founding CEPI. CEPI's original policy contained specific measures to prevent some of these market problems. All vaccine-manufacturing contracts would need initial approval by a public review board. The policy also stated that vaccine prices would be set at levels affordable to those needing vaccines and sustainable to the manufacturer. Trade secrets would not be funded by the CEPI. Companies had to share all research data developed with CEPI funds. While CEPI would, controversially, not retain and license the intellectual property developed with CEPI funds (allowing the groups awarded funding to own it), the CEPI retained "step-in" rights: the right to license and use intellectual property developed with CEPI funds for vaccine production, even if the company that had received the funding and taken ownership of the IP later withdrew from the agreement with CEPI. The original policy also required that funded parties pre-register any trials in a clinical trials registry , publish results within a year of study completion (except with compelling reason and permission of CEPI), publish results in open-access articles, and have mechanisms for securely sharing underlying data and results, including negative results, in a way that preserves trial volunteer privacy (see AllTrials for further information). Pharmaceutical corporations, including Johnson & Johnson , Pfizer , and Takeda , objected to the original policy, and these provisions were removed in December 2018, after the CEPI had obtained significant funding. The policy changes met with strong criticism, led by Médecins Sans Frontières . CEPI was also criticized for not following its own policies on transparency, and for removing the requirement that CEPI's board review CEPI's contracts. The CEPI stated that its vaccines would continue to be affordable and available, and published an article discussing the changes, saying that the old policy "while reflective of the idealism that inspired the creation of CEPI, was felt by others not to be pragmatic or reflect the business realities confronted by vaccine developers". It said that several unnamed vaccine manufacturers had declared that they could not work with the CEPI under the original policy. It said that the policy change did not reflect a change in commitment to access, and CEPI would still retain the right to do research and development using intellectual property it had funded, if the old partner was unable to continue. It also said that the CEPI would retain the right to find a new manufacturer if the old manufacturer could not continue, provided the old manufacturer agrees to the transfer of the information and intellectual property to the new one. The New York Times said that CEPI had made a "failed effort to get large pharmaceutical firms to agree to be partners without insisting on substantial profits or proprietary rights to research that CEPI helped to finance and produce," and had replaced specific implementation measures with lip service to its funding mission. CEPI's original policy contained specific measures to prevent some of these market problems. All vaccine-manufacturing contracts would need initial approval by a public review board. The policy also stated that vaccine prices would be set at levels affordable to those needing vaccines and sustainable to the manufacturer. Trade secrets would not be funded by the CEPI. Companies had to share all research data developed with CEPI funds. While CEPI would, controversially, not retain and license the intellectual property developed with CEPI funds (allowing the groups awarded funding to own it), the CEPI retained "step-in" rights: the right to license and use intellectual property developed with CEPI funds for vaccine production, even if the company that had received the funding and taken ownership of the IP later withdrew from the agreement with CEPI. The original policy also required that funded parties pre-register any trials in a clinical trials registry , publish results within a year of study completion (except with compelling reason and permission of CEPI), publish results in open-access articles, and have mechanisms for securely sharing underlying data and results, including negative results, in a way that preserves trial volunteer privacy (see AllTrials for further information). Pharmaceutical corporations, including Johnson & Johnson , Pfizer , and Takeda , objected to the original policy, and these provisions were removed in December 2018, after the CEPI had obtained significant funding. The policy changes met with strong criticism, led by Médecins Sans Frontières . CEPI was also criticized for not following its own policies on transparency, and for removing the requirement that CEPI's board review CEPI's contracts. The CEPI stated that its vaccines would continue to be affordable and available, and published an article discussing the changes, saying that the old policy "while reflective of the idealism that inspired the creation of CEPI, was felt by others not to be pragmatic or reflect the business realities confronted by vaccine developers". It said that several unnamed vaccine manufacturers had declared that they could not work with the CEPI under the original policy. It said that the policy change did not reflect a change in commitment to access, and CEPI would still retain the right to do research and development using intellectual property it had funded, if the old partner was unable to continue. It also said that the CEPI would retain the right to find a new manufacturer if the old manufacturer could not continue, provided the old manufacturer agrees to the transfer of the information and intellectual property to the new one. The New York Times said that CEPI had made a "failed effort to get large pharmaceutical firms to agree to be partners without insisting on substantial profits or proprietary rights to research that CEPI helped to finance and produce," and had replaced specific implementation measures with lip service to its funding mission. The coalition was nominated for the 2021 Nobel Peace Prize by Norwegian MP Carl-Erik Grimstad . CEPI is incorporated under Norwegian law . As of March 2020, a full-time staff of 68 that runs the organisation under the direction of a chief executive officer, Richard Hatchett. In October 2018, CEPI scientists estimated that the costs of developing at least one vaccine for each of the diseases that could escalate into global humanitarian crises was between US$2.8 billion and US$3.7 billion. In November 2019, CEPI discussed its target portfolio was on the WHO 's " blueprint priority diseases ", that included: MERS-CoV, Nipah virus, Lassa fever virus, and Rift Valley fever virus, as well as Chikungunya virus , and the WHO's Disease X . CEPI outlined its projects to update CEPI priorities for establishment of technical and regulatory pathways for vaccine development, develop sustainable manufacturing solutions for vaccine candidates nearing completion, and create investigatory stockpiles of its vaccine candidates for use in emergency situations.

Wiki

Rift Valley fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Rift_valley_(disambiguation)/html

Rift valley (disambiguation)

A rift valley is a linear lowland formed by the action of a geologic rift. Rift Valley may also refer to:

Wiki

Rift Valley fever

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

Symptomatic treatment

Symptomatic treatment , supportive care, supportive therapy, or palliative treatment is any medical therapy of a disease that only affects its symptoms , not the underlying cause . It is usually aimed at reducing the signs and symptoms for the comfort and well-being of the patient, but it also may be useful in reducing organic consequences and sequelae of these signs and symptoms of the disease. In many diseases, even in those whose etiologies are known (e.g., most viral diseases , such as influenza and Rift Valley fever ), symptomatic treatment is the only treatment available so far. For more detail, see supportive therapy . For conditions like cancer , arthritis, neuropathy , tendinopathy , and injury, it can be useful to distinguish treatments that are supportive/palliative and cannot alter the natural history of the disease ( disease modifying treatments ).Examples of symptomatic treatments:When the etiology (the cause, set of causes, or manner of causation of a disease or condition) for the disease is known, then specific treatment may be instituted, but it is generally associated with symptomatic treatment, as well. Symptomatic treatment is not always recommended, and in fact, it may be dangerous, because it may mask the presence of an underlying etiology which will then be forgotten or treated with great delay. Examples: Finally, symptomatic treatment is not exempt from adverse effects , and may be a cause of iatrogenic consequences (i.e., ill effects caused by the treatment itself), such as allergic reactions , stomach bleeding , central nervous system effects ( nausea , dizziness , etc.).

Wiki

Rift Valley fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Mosquito-borne_disease/html

Mosquito-borne disease

Mosquito-borne diseases or mosquito-borne illnesses are diseases caused by bacteria, viruses or parasites transmitted by mosquitoes . Nearly 700 million people get a mosquito-borne illness each year, resulting in over 725,000 deaths. Diseases transmitted by mosquitoes include malaria , dengue , West Nile virus , chikungunya , yellow fever , filariasis , tularemia , dirofilariasis , Japanese encephalitis , Saint Louis encephalitis , Western equine encephalitis , Eastern equine encephalitis , Venezuelan equine encephalitis , Ross River fever , Barmah Forest fever , La Crosse encephalitis , and Zika fever , as well as newly detected Keystone virus and Rift Valley fever . In January 2024, an Australian research group proved that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer is transmitted by mosquitos. This is the first described mosquito-borne transmission of a bacterial disease. There is no evidence as of April 2020 that COVID-19 can be transmitted by mosquitoes, and it is extremely unlikely this could occur. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ] Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ] The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. The female mosquito of the genus Anopheles may carry the malaria parasite . Four different species of protozoa cause malaria: Plasmodium falciparum , Plasmodium malariae , Plasmodium ovale and Plasmodium vivax (see Plasmodium ). Worldwide, malaria is a leading cause of premature mortality, particularly in children under the age of five, with an estimated 207 million cases and more than half a million deaths in 2012, according to the World Malaria Report 2013 published by the World Health Organization (WHO). The death toll increased to one million as of 2018 according to the American Mosquito Control Association. In January 2024, a publication by an Australian research group demonstrated significant genetic similarity between Mycobacterium ulcerans in humans and possums, compared to PCR screening of M. ulcerans from trapped Aedes notoscriptus mosquitoes, and concluded that Mycobacterium ulcerans , the causative pathogen of Buruli ulcer , is transmitted by mosquitos. Botflies are known to parasitize humans or other mammalians, causing myiasis , and to use mosquitoes as intermediate vector agents to deposit eggs on a host. The human botfly Dermatobia hominis attaches its eggs to the underside of a mosquito, and when the mosquito takes a blood meal from a human or an animal, the body heat of the mammalian host induces hatching of the larvae. [ citation needed ]Some species of mosquito can carry the filariasis worm, a parasite that causes a disfiguring condition (often referred to as elephantiasis ) characterized by a great swelling of several parts of the body; worldwide, around 40 million people are living with a filariasis disability. [ citation needed ]The viral diseases yellow fever , dengue fever , Zika fever and chikungunya are transmitted mostly by Aedes aegypti mosquitoes. [ citation needed ] Other viral diseases like epidemic polyarthritis , Rift Valley fever , Ross River fever , St. Louis encephalitis , West Nile fever , Japanese encephalitis , La Crosse encephalitis and several other encephalitic diseases are carried by several different mosquitoes. Eastern equine encephalitis (EEE) and Western equine encephalitis (WEE) occur in the United States where they cause disease in humans, horses, and some bird species. Because of the high mortality rate, EEE and WEE are regarded as two of the most serious mosquito-borne diseases in the United States. Symptoms range from mild flu-like illness to encephalitis, coma, and death. Viruses carried by arthropods such as mosquitoes or ticks are known collectively as arboviruses . West Nile virus was accidentally introduced into the US in 1999 and by 2003 had spread to almost every state with over 3,000 cases in 2006. Other species of Aedes as well as Culex and Culiseta are also involved in the transmission of disease. [ citation needed ] Myxomatosis is spread by biting insects, including mosquitoes. A mosquito's period of feeding is often undetected; the bite only becomes apparent because of the immune reaction it provokes. When a mosquito bites a human, it injects saliva and anti-coagulants . With the initial bite to an individual, there is no reaction, but with subsequent bites, the body's immune system develops antibodies . The bites become inflamed and itchy within 24 hours. This is the usual reaction in young children. With more bites, the sensitivity of the human immune system increases, and an itchy red hive appears in minutes where the immune response has broken capillary blood vessels and fluid has collected under the skin. This type of reaction is common in older children and adults. Some adults can become desensitized to mosquitoes and have little or no reaction to their bites, while others can become hyper-sensitive with bites causing blistering, bruising, and large inflammatory reactions, a response known as skeeter syndrome . One study found Dengue virus and Zika virus altered the skin bacteria of rats in a way that caused their body odor to be more attractive to mosquitoes. Symptoms of illness are specific to the type of viral infection and vary in severity, based on the individuals infected. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Symptoms vary in severity, from mild unnoticeable symptoms to more common symptoms like fever, rash, headache, achy muscle and joints, and conjunctivitis. Symptoms can last several days to weeks, but death resulting from this infection is rare. Most people infected with the West Nile virus usually do not develop symptoms. However, some individuals can develop cases of severe fatigue, weakness, headaches, body aches, joint and muscle pain, vomiting, diarrhea, and rash, which can last for weeks or months. More serious symptoms have a greater risk of appearing in people over 60 years of age, or those with cancer, diabetes, hypertension, and kidney disease. Dengue fever is mostly characterized by high fever, headaches, joint pain, and rash. However, more severe instances can lead to hemorrhagic fever, internal bleeding, and breathing difficulty, which can be fatal. People infected with this virus can develop sudden onset fever along with debilitating joint and muscle pain, rash, headache, nausea, and fatigue. Symptoms can last a few days or be prolonged to weeks and months. Although patients can recover completely, there have been cases in which joint pain has persisted for several months and can extend beyond that for years. Other people can develop heart complications, eye problems, and even neurological complications. Mosquitoes carrying such arboviruses stay healthy because their immune systems recognizes the virions as foreign particles and "chop off" the virus' genetic coding, rendering it inert. Human infection with a mosquito-borne virus occurs when a female mosquito bites someone while its immune system is still in the process of destroying the virus's harmful coding. [ clarification needed ] It is not completely known how mosquitoes handle eukaryotic parasites to carry them without being harmed. Data has shown that the malaria parasite Plasmodium falciparum alters the mosquito vector's feeding behavior by increasing frequency of biting in infected mosquitoes, thus increasing the chance of transmitting the parasite. The mechanism of transmission of this disease starts with the injection of the parasite into the victim's blood when malaria-infected female Anopheles mosquitoes bite into a human being. The parasite uses human liver cells as hosts for maturation where it will continue to replicate and grow, moving into other areas of the body via the bloodstream. The spread of this infection cycle then continues when other mosquitoes bite the same individual. The result will cause that mosquito to ingest the parasite and allow it to transmit the Malaria disease into another person through the same mode of bite injection. Flaviviridae viruses transmissible via vectors like mosquitoes include West Nile virus and yellow fever virus, which are single stranded, positive-sense RNA viruses enveloped in a protein coat. Once inside the host's body, the virus will attach itself to a cell's surface through receptor-mediated endocytosis. This essentially means that the proteins and DNA material of the virus are ingested into the host cell. The viral RNA material will undergo several changes and processes inside the host's cell so that it can release more viral RNA that can then be replicated and assembled to infect neighboring host cells. Mosquito-borne flaviviruses also encode viral antagonists to the innate immune system in order to cause persistent infection in mosquitoes and a broad spectrum of diseases in humans. The data on transmissibility via insect vectors of hepatitis C virus, also belonging to family Flaviviridae (as well as for hepatitis B virus, belonging to family Hepadnaviridae ) are inconclusive. WHO states that "There is no insect vector or animal reservoir for HCV", while there are experimental data supporting at least the presence of [PCR]-detectable hepatitis C viral RNA in Culex mosquitoes for up to 13 days. Currently, there are no specific vaccine therapies for West Nile virus approved for humans; however, vaccines are available and some show promise for animals, as a means to intervene with the mechanism of spreading such pathogens. Doctors can typically identify a mosquito bite by sight. A doctor will perform a physical examination and ask about medical history as well as any travel history. Be ready to give details on any international trips, including the dates you were traveling, the countries you visited and any contact you had with mosquitoes. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. Diagnosing dengue fever can be difficult, as its symptoms often overlap with many other diseases such as malaria and typhoid fever . Laboratory tests can detect evidence of the dengue viruses, however the results often come back too late to assist in directing treatment. Medical testing can confirm the presence of West Nile fever or a West Nile-related illness, such as meningitis or encephalitis. If infected, a blood test may show a rising level of antibodies to the West Nile virus. A lumbar puncture (spinal tap) is the most common way to diagnose meningitis, by analyzing the cerebrospinal fluid surrounding your brain and spinal cord. The fluid sample may show an elevated white cell count and antibodies to the West Nile virus if you were exposed. In some cases, an electroencephalography (EEG) or magnetic resonance imaging (MRI) scan can help detect brain inflammation. A Zika virus infection might be suspected if symptoms are present and an individual has traveled to an area with known Zika virus transmission. Zika virus can only be confirmed by a laboratory test of body fluids, such as urine or saliva, or by blood test. Laboratory blood tests can identify evidence of chikungunya or other similar viruses such as dengue and Zika. Blood test may confirm the presence of IgM and IgG anti-chikungunya antibodies. IgM antibodies are highest 3 to 5 weeks after the beginning of symptoms and will continue be present for about 2 months. There is a re-emergence of mosquito vectored viruses (arthropod-borne viruses) called arboviruses carried by the Aedes aegypti mosquito. Examples are the Zika virus, chikungunya virus, yellow fever and dengue fever. The re-emergence of the viruses has been at a faster rate, and over a wider geographic area, than in the past. The rapid re-emergence is due to expanding global transportation networks, the mosquito's increasing ability to adapt to urban settings, the disruption of traditional land use and the inability to control expanding mosquito populations. Like malaria, arboviruses do not have a vaccine. (The only exception is yellow fever.) Prevention is focused on reducing the adult mosquito populations, controlling mosquito larvae and protecting individuals from mosquito bites. Depending on the mosquito vector, and the affected community, a variety of prevention methods may be deployed at one time. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. The use of insecticide treated mosquito nets (ITNs) are at the forefront of preventing mosquito bites that cause malaria. The prevalence of ITNs in sub-Saharan Africa has grown from 3% of households to 50% of households from 2000 to 2010 with over 254 million insecticide treated nets distributed throughout sub-Saharan Africa for use against the mosquito vectors Anopheles gambiae and Anopheles funestus which carry malaria. Because the Anopheles gambiae feeds indoors (endophagic) and rests indoors after feeding (endophilic), insecticide treated nets (ITNs) interrupt the mosquito's feeding pattern. The ITNs continue to offer protection, even after there are holes in the nets, because of their excito-repellency properties which reduce the number of mosquitoes that enter the home. The World Health Organization (WHO) recommends treating ITNs with the pyrethroid class of insecticides. There is an emerging concern of mosquito resistance to insecticides used in ITNs. Twenty-seven (27) sub-Saharan African countries have reported Anopheles vector resistance to pyrethroid insecticides. Indoor spraying of insecticides is another prevention method widely used to control mosquito vectors. To help control the Aedes aegypti mosquito, homes are sprayed indoors with residual insecticide applications. Indoor residual spraying (IRS) reduces the female mosquito population and mitigates the risk of dengue virus transmission. Indoor residual spraying is completed usually once or twice a year. Mosquitoes rest on walls and ceilings after feeding and are killed by the insecticide. Indoor spraying can be combined with spraying the exterior of the building to help reduce the number of mosquito larvae and subsequently, the number of adult mosquitoes. There are other methods that an individual can use to protect themselves from mosquito bites. Limiting exposure to mosquitoes from dusk to dawn when the majority of mosquitoes are active and wearing long sleeves and long pants during the period mosquitoes are most active. Placing screens on windows and doors is a simple and effective means of reducing the number of mosquitoes indoors. Anticipating mosquito contact and using a topical mosquito repellant with icaridin or DEET is also recommended. Draining or covering water receptacles, both indoor and outdoors, is also a simple but effective prevention method. Removing debris and tires, cleaning drains, and cleaning gutters help larval control and reduce the number of adult mosquitoes. There is a vaccine for yellow fever which was developed in the 1930s, the yellow 17D vaccine , and it is still in use today. The initial yellow fever vaccination provides lifelong protection for most people and provides immunity within 30 days of the vaccine. Reactions to the yellow fever vaccine have included mild headache and fever, and muscle aches. There are rare cases of individuals presenting with symptoms that mirror the disease itself. The risk of complications from the vaccine are greater for individuals over 60 years of age. In addition, the vaccine is not usually administered to babies under nine months of age, pregnant women, people with allergies to egg protein, and individuals living with AIDS/HIV . The World Health Organization (WHO) reports that 105 million people have been vaccinated for yellow fever in West Africa from 2000 to 2015. To date, there are relatively few vaccines against mosquito-borne diseases, this is due to the fact that most viruses and bacteria caused by mosquitos are highly mutatable. The National Institute of Allergy and Infectious Disease (NIAID) began Phase 1 clinical trials of a new vaccine that would be nearly universal in protecting against the majority of mosquito-borne diseases. The arboviruses have expanded their geographic range and infected populations that had no recent community knowledge of the diseases carried by the Aedes aegypti mosquito. Education and community awareness campaigns are necessary for prevention to be effective. Communities are educated on how the disease is spread, how they can protect themselves from infection and the symptoms of infection. Community health education programs can identify and address the social/economic and cultural issues that can hinder preventative measures. Community outreach and education programs can identify which preventative measures a community is most likely to employ. Leading to a targeted prevention method that has a higher chance of success in that particular community. Community outreach and education includes engaging community health workers and local healthcare providers, local schools and community organizations to educate the public on mosquito vector control and disease prevention. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector). Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Numerous drugs have been used to treat yellow fever disease with minimal satisfaction to date. Patients with multisystem organ involvement will require critical care support such as possible hemodialysis or mechanical ventilation . Rest, fluids, and acetaminophen are also known to relieve milder symptoms of fever and muscle pain. Due to hemorrhagic complications, aspirin should be avoided. Infected individuals should avoid mosquito exposure by staying indoors or using a mosquito net . Dengue infection's therapeutic management is simple, cost effective and successful in saving lives by adequately performing timely institutionalized interventions. Treatment options are restricted, while no effective antiviral drugs for this infection have been accessible to date. Patients in the early phase of the dengue virus may recover without hospitalization. However, ongoing clinical research is in the works to find specific anti-dengue drugs. Dengue fever occurs via Aedes aegypti mosquito (it acts as a vector).Zika virus vaccine clinical trials are to be conducted and established. There are efforts being put toward advancing antiviral therapeutics against zika virus for swift control. Present day Zika virus treatment is symptomatic through antipyretics and analgesics . Currently there are no publications regarding viral drug screening. Nevertheless, therapeutics for this infection have been used. There are no treatment modalities for acute and chronic chikungunya that currently exist. Most treatment plans use supportive and symptomatic care like analgesics for pain and anti-inflammatories for inflammation caused by arthritis . In acute stages of this virus, rest, antipyretics and analgesics are used to subside symptoms. Most use non-steroidal anti-inflammatory drugs (NSAIDs). In some cases, joint pain may resolve from treatment but stiffness remains. The sterile insect technique (SIT) uses irradiation to sterilize insect pests before releasing them in large numbers to mate with wild females. Since they do not produce any offspring, the population, and consequently the disease incidence, is reduced over time. Used successfully for decades to combat fruit flies and livestock pests such as screwworm and tsetse flies , the technique can be adapted also for some disease-transmitting mosquito species. Pilot projects are being initiated or are under way in different parts of the world. Mosquito-borne diseases, such as dengue fever and malaria , typically affect developing countries and areas with tropical climates. Mosquito vectors are sensitive to climate changes and tend to follow seasonal patterns. Between years there are often dramatic shifts in incidence rates. The occurrence of this phenomenon in endemic areas makes mosquito-borne viruses difficult to treat. Dengue fever is caused by infection through viruses of the family Flaviviridae. The illness is most commonly transmitted by Aedes aegypti mosquitoes in tropical and subtropical regions. Dengue virus has four different serotypes, each of which are antigenically related but have limited cross-immunity to reinfection. Although dengue fever has a global incidence of 50–100 million cases, only several hundreds of thousands of these cases are life-threatening. The geographic prevalence of the disease can be examined by the spread of Aedes aegypti . Over the last twenty years, there has been a geographic spread of the disease. Dengue incidence rates have risen sharply within urban areas which have recently become endemic hot spots for the disease. The recent spread of Dengue can also be attributed to rapid population growth, increased coagulation in urban areas, and global travel. Without sufficient vector control, the dengue virus has evolved rapidly over time, posing challenges to both government and public health officials. [ citation needed ] Malaria is caused by a protozoan called Plasmodium falciparum . P. falciparum parasites are transmitted mainly by the Anopheles gambiae complex in rural Africa. In just this area, P. falciparum infections comprise an estimated 200 million clinical cases and 1 million annual deaths. 75% of individuals affected in this region are children. As with dengue, changing environmental conditions have led to novel disease characteristics. Due to increased illness severity, treatment complications, and mortality rates, many public health officials concede that malaria patterns are rapidly transforming in Africa. Scarcity of health services, rising instances of drug resistance, and changing vector migration patterns are factors that public health officials believe contribute to malaria's dissemination. Climate heavily affects mosquito vectors of malaria and dengue. Climate patterns influence the lifespan of mosquitos as well as the rate and frequency of reproduction. Climate change impacts have been of great interest to those studying these diseases and their vectors. Additionally, climate impacts mosquito blood feeding patterns as well as extrinsic incubation periods. Climate consistency gives researchers an ability to accurately predict annual cycling of the disease but recent climate unpredictability has eroded researchers' ability to track the disease with such precision.In many insect species, such as Drosophila melanogaster , researchers found that a natural infection with the bacteria strain Wolbachia pipientis increases the fitness of the host by increasing resistance to RNA viral infections. Robert L. Glaser and Mark A. Meola investigated Wolbachia -induced resistance to West Nile virus (WNV) in Drosophila melanogaster (fruit flies). Two groups of fruit flies were naturally infected with Wolbachia . Glaser and Meola then cured one group of fruit flies of Wolbachia using tetracycline. Both the infected group and the cured groups were then infected with WNV. Flies infected with Wolbachia were found to have a changed phenotype that caused resistance to WNV. The phenotype was found to be caused by a "dominant, maternally transmitted, cytoplasmic factor". The WNV-resistance phenotype was then reversed by curing the fruit flies of Wolbachia . Since Wolbachia is also maternally transmitted, it was found that the WNV-resistant phenotype is directly related to the Wolbachia infection. West Nile virus is transmitted to humans and animals through the Southern house mosquito, Culex quinquefasciatus . Glaser and Meola knew vector compatibility could be reduced through Wolbachia infection due to studies done with other species of mosquitoes, mainly, Aedes aegypti . Their goal was to transfer WNV resistance to Cx. quinquefasciatus by inoculating the embryos of the mosquito with the same strain of Wolbachia that naturally occurred in the fruit flies. Upon infection, Cx. quinquefasciatus showed an increased resistance to WNV that was transferable to offspring. The ability to genetically modify mosquitoes in the lab and then have the infected mosquitoes transmit it to their offspring showed that it was possible to transmit the bacteria to wild populations to decrease human infections. [ citation needed ] In 2011, Ary Hoffmann and associates produced the first case of Wolbachia -induced arbovirus resistance in wild populations of Aedes aegypti through a small project called Eliminate Dengue: Our Challenge. This was made possible by an engineered strain of Wolbachia termed w Mel that came from D. melanogaster . The transfer of w Mel from D. melanogaster into field-caged populations of the mosquito Aedes aegypti induced resistance to dengue, yellow fever, and chikungunya viruses. Although other strains of Wolbachia also reduced susceptibility to dengue infection, they also put a greater demand on the fitness of Ae. aegypti . w Mel was different in that it was thought to only cost the organism a small portion of its fitness. w Mel-infected Ae. aegypti were released into two residential areas in the city of Cairns, Australia over a 14-week period. Hoffmann and associates, released a total of 141,600 infected adult mosquitoes in Yorkeys Knob suburb and 157,300 in Gordonvale suburb. After release, the populations were monitored for three years to record the spread of w Mel. Population monitoring was gauged by measuring larvae laid in traps. At the beginning of the monitoring period but still within the release period, it was found that w Mel-infected Ae. aegypti had doubled in Yorkeys Knob and increased 1.5-fold in Gordonvale. Uninfected Ae. aegypti populations were in decline. By the end of the three years, w Mel-infected Ae. aegypti had stable populations of about 90%. However, these populations were isolated to the Yorkeys Knob and Gordonvale suburbs due to unsuitable habitat surrounding the neighborhoods. Although populations flourished in these areas with nearly 100% transmission, no signs of spread were noted, proving disappointing for some. Following this experiment, Tom L. Schmidt and his colleagues conducted an experiment releasing Wolbachia -infected Aedes aegypti using different site selection methods occurred in different areas of Cairns during 2013. The release sites were monitored over two years. This time the release was done in urban areas that were adjacent to adequate habitat to encourage mosquito dispersal. Over the two years, the population doubled, and spatial spread was also increased, unlike the first release, giving ample satisfactory results. By increasing the spread of the Wolbachia -infected mosquitoes, the researchers were able to establish that population of a large city was possible if the mosquitoes were given adequate habitat to spread into upon release in different local locations throughout the city. In both of these studies, no adverse effects on public health or the natural ecosystem occurred. This made it an extremely attractive alternative to traditional insecticide methods given the increased pesticide resistance occurring from heavy use. From the success seen in Australia, the researchers were able to begin operating in more threatened portions of the world. The Eliminate Dengue program spread to 10 countries throughout Asia, Latin America, and the Western Pacific blooming into the non-profit organization, World Mosquito Program, as of September 2017. They still use the same technique of infecting wild populations of Ae. aegypti as they did in Australia, but their target diseases now include Zika, chikungunya and yellow fever as well as dengue. Although not alone in their efforts to use Wolbachia- infected mosquitoes to reduce mosquito-borne disease, the World Mosquito Program method is praised for being self-sustaining in that it causes permanent phenotype change rather than reducing mosquito populations through cytoplasmic incompatibility through male-only dispersal.

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Rift Valley fever

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Arbovirus

Arbovirus is an informal name for any virus that is transmitted by arthropod vectors . The term arbovirus is a portmanteau word ( ar thropod- bo rne virus ). Tibovirus ( ti ck- bo rne virus ) is sometimes used to more specifically describe viruses transmitted by ticks , a superorder within the arthropods. Arboviruses can affect both animals (including humans) and plants. In humans, symptoms of arbovirus infection generally occur 3–15 days after exposure to the virus and last three or four days. The most common clinical features of infection are fever , headache , and malaise , but encephalitis and viral hemorrhagic fever may also occur. The incubation period – the time between when infection occurs and when symptoms appear – varies from virus to virus, but is usually limited between 2 and 15 days for arboviruses. The majority of infections, however, are asymptomatic. Among cases in which symptoms do appear, symptoms tend to be non-specific, resembling a flu-like illness , and are not indicative of a specific causative agent. These symptoms include fever, headache, malaise, rash and fatigue. Rarely, vomiting and hemorrhagic fever may occur. The central nervous system can also be affected by infection, as encephalitis and meningitis are sometimes observed. Prognosis is good for most people, but is poor in those who develop severe symptoms, with up to a 20% mortality rate in this population depending on the virus. The very young, elderly, pregnant women, and people with immune deficiencies are more likely to develop severe symptoms. [ citation needed ]Arboviruses maintain themselves in nature by going through a cycle between a host , an organism that carries the virus, and a vector , an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts. Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia , a condition in which there are large numbers of virions present in the blood. The abundance of virions in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector. An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals , humans are considered a dead-end host. Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions , organ transplantation , and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission , or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations. Arboviruses are a polyphyletic group , belonging to various viral genera and therefore exhibiting different virologic characteristics.Arboviruses maintain themselves in nature by going through a cycle between a host , an organism that carries the virus, and a vector , an organism that carries and transmits the virus to other organisms. For arboviruses, vectors are commonly mosquitoes, ticks, sandflies and other arthropods that consume the blood of vertebrates for nutritious or developmental purposes. Vertebrates which have their blood consumed act as the hosts, with each vector generally having an affinity for the blood of specific species, making those species the hosts. Transmission between the vector and the host occurs when the vector feeds on the blood of the vertebrate, wherein the virus that has established an infection in the salivary glands of the vector comes into contact with the host's blood. While the virus is inside the host, it undergoes a process called amplification, where the virus replicates at sufficient levels to induce viremia , a condition in which there are large numbers of virions present in the blood. The abundance of virions in the host's blood allows the host to transmit the virus to other organisms if its blood is consumed by them. When uninfected vectors become infected from feeding, they are then capable of transmitting the virus to uninfected hosts, resuming amplification of virus populations. If viremia is not achieved in a vertebrate, the species can be called a "dead-end host", as the virus cannot be transmitted back to the vector. An example of this vector-host relationship can be observed in the transmission of the West Nile virus. Female mosquitoes of the genus Culex prefer to consume the blood of passerine birds, making them the hosts of the virus. When these birds are infected, the virus amplifies, potentially infecting multiple mosquitoes that feed on its blood. These infected mosquitoes may go on to further transmit the virus to more birds. If the mosquito is unable to find its preferred food source, it will choose another. Human blood is sometimes consumed, but since the West Nile virus does not replicate that well in mammals , humans are considered a dead-end host. Person-to-person transmission of arboviruses is not common, but can occur. Blood transfusions , organ transplantation , and the use of blood products can transmit arboviruses if the virus is present in the donor's blood or organs. Because of this, blood and organs are often screened for viruses before being administered. Rarely, vertical transmission , or mother-to-child transmission, has been observed in infected pregnant and breastfeeding women. Exposure to used needles may also transmit arboviruses if they have been used by an infected person or animal. This puts intravenous drug users and healthcare workers at risk for infection in regions where the arbovirus may be spreading in human populations. Arboviruses are a polyphyletic group , belonging to various viral genera and therefore exhibiting different virologic characteristics.Preliminary diagnosis of arbovirus infection is usually based on clinical presentations of symptoms, places and dates of travel, activities, and epidemiological history of the location where infection occurred. Definitive diagnosis is typically made in a laboratory by employing some combination of blood tests , particularly immunologic , serologic and/or virologic techniques such as ELISA , complement fixation , polymerase chain reaction , neutralization test , and hemagglutination-inhibition test . In the past, arboviruses were organized into one of four groups: A, B, C, and D. Group A denoted members of the genus Alphavirus , Group B were members of the genus Flavivirus , and Group C remains as the Group C serogroup of the genus Orthobunyavirus . Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus . Currently, viruses are jointly classified according to Baltimore classification and a virus-specific system based on standard biological classification . With the exception of the African swine fever virus , which belongs to the Asfarviridae family of viruses, all major clinically important arboviruses belong to one of the following four groups: [ citation needed ]In the past, arboviruses were organized into one of four groups: A, B, C, and D. Group A denoted members of the genus Alphavirus , Group B were members of the genus Flavivirus , and Group C remains as the Group C serogroup of the genus Orthobunyavirus . Group D was renamed in the mid-1950s to the Guama group and is currently the Guama serogroup in the genus Orthobunyavirus . Currently, viruses are jointly classified according to Baltimore classification and a virus-specific system based on standard biological classification . With the exception of the African swine fever virus , which belongs to the Asfarviridae family of viruses, all major clinically important arboviruses belong to one of the following four groups: [ citation needed ]Vector control measures, especially mosquito control , are essential to reducing the transmission of disease by arboviruses. Habitat control involves draining swamps and removal of other pools of stagnant water (such as old tires, large outdoor potted plants, empty cans, etc.) that often serve as breeding grounds for mosquitoes. Insecticides can be applied in rural and urban areas, inside houses and other buildings, or in outdoor environments. They are often quite effective for controlling arthropod populations, though use of some of these chemicals is controversial, and some organophosphates and organochlorides (such as DDT ) have been banned in many countries. Infertile male mosquitoes have been introduced in some areas in order to reduce the breeding rate of relevant mosquito species. Larvicides are also used worldwide in mosquito abatement programs. Temefos is a common mosquito larvicide. People can also reduce the risk of getting bitten by arthropods by employing personal protective measures such as sleeping under mosquito nets , wearing protective clothing , applying insect repellents such as permethrin and DEET to clothing and exposed skin, and (where possible) avoiding areas known to harbor high arthropod populations. Arboviral encephalitis can be prevented in two major ways: personal protective measures and public health measures to reduce the population of infected mosquitoes. Personal measures include reducing time outdoors particularly in early evening hours, wearing long pants and long sleeved shirts and applying mosquito repellent to exposed skin areas. Public health measures often require spraying of insecticides to kill juvenile (larvae) and adult mosquitoes. Vaccines are available for the following arboviral diseases: Vaccines are in development for the following arboviral diseases:Vaccines are available for the following arboviral diseases: Vaccines are in development for the following arboviral diseases:Because the arboviral encephalitides are viral diseases, antibiotics are not an effective form of treatment and no effective antiviral drugs have yet been discovered. Treatment is supportive, attempting to deal with problems such as swelling of the brain, loss of the automatic breathing activity of the brain and other treatable complications like bacterial pneumonia . The WHO caution against the use of aspirin and ibuprofen as they can increase the risk of bleeding. Most arboviruses are located in tropical areas, however as a group they have a global distribution. The warm climate conditions found in tropical areas allows for year-round transmission by the arthropod vectors. Other important factors determining geographic distribution of arthropod vectors include rainfall, humidity, and vegetation. Mapping methods such as GIS and GPS have allowed for spatial and temporal analyses of arboviruses. Tagging cases or breeding sites geographically has allowed for deeper examination of vector transmission. To see the epidemiology of specific arboviruses, the following resources hold maps, fact sheets, and reports on arboviruses and arboviral epidemics. The WHO also hosts DengueNet, a database which can be queried about Dengue cases. Arboviruses were not known to exist until the rise of modern medicine , with the germ theory and an understanding that viruses were distinct from other microorganisms . The connection between arthropods and disease was not postulated until 1881 when Cuban doctor and scientist Carlos Finlay proposed that yellow fever may be transmitted by mosquitoes instead of human contact, a reality that was verified by Major Walter Reed in 1901. The primary vector, Aedes aegypti , had spread globally from the 15th to the 19th centuries as a result of globalization and the slave trade . This geographic spreading caused dengue fever epidemics throughout the 18th and 19th centuries, and later, in 1906, transmission by the Aedes mosquitoes was confirmed, making yellow fever and dengue fever the first two diseases known to be caused by viruses. Thomas Milton Rivers published the first clear description of a virus as distinct from a bacterium in 1927. The discovery of the West Nile virus came in 1937, and has since been found in Culex populations causing epidemics throughout Africa , the Middle East , and Europe . The virus was introduced into the Western Hemisphere in 1999, sparking a series of epidemics. During the latter half of the 20th century, Dengue fever reemerged as a global disease, with the virus spreading geographically due to urbanization , population growth , increased international travel, and global warming , and continues to cause at least 50 million infections per year, making Dengue fever the most common and clinically important arboviral disease. Yellow fever , alongside malaria , was a major obstacle in the construction of the Panama Canal . French supervision of the project in the 1880s was unsuccessful because of these diseases, forcing the abandonment of the project in 1889. During the American effort to construct the canal in the early 1900s, William C. Gorgas , the Chief Sanitary Officer of Havana , was tasked with overseeing the health of the workers. He had past success in eradicating the disease in Florida and Havana by reducing mosquito populations through draining nearby pools of water, cutting grass, applying oil to the edges of ponds and swamps to kill larvae , and capturing adult mosquitoes that remained indoors during the daytime. Joseph Augustin LePrince , the Chief Sanitary Inspector of the Canal Zone , invented the first commercial larvicide , a mixture of carbolic acid , resin , and caustic soda , to be used throughout the Canal Zone . The combined implementation of these sanitation measures led to a dramatic decline in the number of workers dying and the eventual eradication of yellow fever in the Canal Zone as well as the containment of malaria during the 10-year construction period. Because of the success of these methods at preventing disease, they were adopted and improved upon in other regions of the world.

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Rift Valley fever

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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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Rift Valley fever

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Bunyaviridae nonstructural S proteins

Bunyaviridae nonstructural S proteins (NSs) are synthesized by viral DNA/RNA and do not play a role in the replication or the viral protein coating. The nonstructural S segment (NSs) created by Bunyaviridae virus family , are able to interact with the human immune system , in order to increase their replication in infected cells. Understanding this mechanism can have global health impacts. Within the Bunyaviridae virus family, specifically phlebovirus genus, there has been multiple pathways of the inhibition of the immune response. NSs proteins are able to interact with interferon (INF) pathways , but the mechanism varies from virus to virus. The NSs protein in different viruses have been shown to differ in amino acid sequence by up to 85%. NSs protein is distributed throughout the cytoplasm and nucleus of the infected cell. The protein created fiber-like substances within the nucleus. NSs in RVFV to the SAP30 region of DNA in the nucleus of the cell, which is an important promotor region of INF-b. Many other NSs proteins in the Bunyaviridae virus family do not function in this same way. Although the exact target of the SFTSV is unknown, many believe that the virus attacks human hemopoietic cells. It has been shown that upstream molecules of INFs are unchanged in infected cells, such as MAVS, TRAF6 and TRAF3. This suggests that INFs are still being produced, but they have no effect and are undetectable in people's blood serum. The NSs protein in SFTSV has been shown to interfere with TBK1 which is needed in the activation of both IRF and NF-κB pathways. UUKV is a non-human pathogen that still creates a NSs protein. The NSs protein has only been shown to weakly interact with the 40s subunit of ribosomes and MAVS. AMTV is another non-human pathogen and its NSs protein is quickly degraded by proteasomes, and therefor doesn't cause infection in humans. NSs protein is distributed throughout the cytoplasm and nucleus of the infected cell. The protein created fiber-like substances within the nucleus. NSs in RVFV to the SAP30 region of DNA in the nucleus of the cell, which is an important promotor region of INF-b. Many other NSs proteins in the Bunyaviridae virus family do not function in this same way. Although the exact target of the SFTSV is unknown, many believe that the virus attacks human hemopoietic cells. It has been shown that upstream molecules of INFs are unchanged in infected cells, such as MAVS, TRAF6 and TRAF3. This suggests that INFs are still being produced, but they have no effect and are undetectable in people's blood serum. The NSs protein in SFTSV has been shown to interfere with TBK1 which is needed in the activation of both IRF and NF-κB pathways. UUKV is a non-human pathogen that still creates a NSs protein. The NSs protein has only been shown to weakly interact with the 40s subunit of ribosomes and MAVS. AMTV is another non-human pathogen and its NSs protein is quickly degraded by proteasomes, and therefor doesn't cause infection in humans.

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Rift Valley fever

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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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Rift Valley fever

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Bunyavirales

Bunyavirales is an order of segmented negative-strand RNA viruses with mainly tripartite genomes. Member viruses infect arthropods , plants , protozoans , and vertebrates . It is the only order in the class Ellioviricetes . The name Bunyavirales derives from Bunyamwera , where the original type species Bunyamwera orthobunyavirus was first discovered. Ellioviricetes is named in honor of late virologist Richard M. Elliott for his early work on bunyaviruses. Bunyaviruses belong to the fifth group of the Baltimore classification system , which includes viruses with a negative-sense , single-stranded RNA genome. They have an enveloped , spherical virion. Though generally found in arthropods or rodents, certain viruses in this order occasionally infect humans. Some of them also infect plants. In addition, there is a group of bunyaviruses whose replication is restricted to arthropods and is known as insect-specific bunyaviruses. A majority of bunyaviruses are vector-borne. With the exception of Hantaviruses and Arenaviruses , all viruses in the Bunyavirales order are transmitted by arthropods (mosquitos, tick, or sandfly). Hantaviruses are transmitted through contact with rodent feces. Incidence of infection is closely linked to vector activity, for example, mosquito-borne viruses are more common in the summer. Human infections with certain members of Bunyavirales , such as Crimean-Congo hemorrhagic fever orthonairovirus , are associated with high levels of morbidity and mortality, consequently handling of these viruses is done in biosafety level 4 laboratories. They are also the cause of severe fever with thrombocytopenia syndrome . Hantaviruses are another medically important member of the order Bunyvirales . They are found worldwide, and are relatively common in Korea , Scandinavia (including Finland ), Russia , western North America and parts of South America. Hantavirus infections are associated with high fever, lung edema, and pulmonary failure. The mortality rate varies significantly depending on the form, being up to 50% in New World hantaviruses (the Americas), up to 15% in Old World hantaviruses (Asia and Europe), and as little as 0.1% in Puumala virus (mostly Scandinavia). The antibody reaction plays an important role in decreasing levels of viremia .Bunyavirus morphology is somewhat similar to that of the Paramyxoviridae family; Bunyavirales form enveloped, spherical virions with diameters of 80–120 nm . These viruses contain no matrix proteins. Instead, the viral surface glycoproteins which form a continuous layer on the virion surface are thought to play a role in the formation of new virions by budding from a cell membrane. Bunyaviruses have bi- or tripartite genomes consisting of a large (L) and small(s), or large (L), medium (M), and small (S) RNA segment. These RNA segments are single-stranded, and exist in a helical formation within the virion. Besides, they exhibit a pseudo-circular structure due to each segment's complementary ends. The L segment encodes the RNA-dependent RNA polymerase , necessary for viral RNA replication and mRNA synthesis. The M segment encodes the viral glycoproteins , which project from the viral surface and aid the virus in attaching to and entering the host cell. The S segment encodes the nucleocapsid protein (N). Most bunyaviruses have a negative-sense L and M segment. The S segment of the genus Phlebovirus , and both M and S segment of the genus Tospovirus are ambisense . Ambisense means that some of the genes on the RNA strand are negative sense and others are positive sense. The ambisense S segment codes for the viral nucleoprotein (N) in the negative sense and a nonstructural protein (NSs) in the positive sense. The ambisense M segment codes for glycoprotein (GP) in the negative sense and a nonstructural protein (NSm) in the positive sense. The total genome size ranges from 10.5 to 22.7 kbp . The ambisense genome requires two rounds of transcription to be carried out. First, the negative-sense RNA is transcribed to produce mRNA and a full-length replicative intermediate. From this intermediate, a subgenomic mRNA encoding the small segment nonstructural protein is produced while the polymerase produced following the first round of transcription can now replicate the full-length RNA to produce viral genomes. [ citation needed ] Bunyaviruses replicate in the cytoplasm , while the viral proteins transit through the ER and Golgi apparatus . Mature virions bud from the Golgi apparatus into vesicles which are transported to the cell surface. [ citation needed ] Bunyaviruses infect arthropods , plants , protozoans , and vertebrates . Plants can host bunyaviruses from the families Tospoviridae and Fimoviridae (e.g. tomato, pigeonpea, melon, wheat, raspberry, redbud, and rose). Members of some families are insect-specific, for example the phasmavirids, first isolated from phantom midges , and since identified in diverse insects including moths , wasps and bees , and other true flies .Bunyavirus morphology is somewhat similar to that of the Paramyxoviridae family; Bunyavirales form enveloped, spherical virions with diameters of 80–120 nm . These viruses contain no matrix proteins. Instead, the viral surface glycoproteins which form a continuous layer on the virion surface are thought to play a role in the formation of new virions by budding from a cell membrane. Bunyaviruses have bi- or tripartite genomes consisting of a large (L) and small(s), or large (L), medium (M), and small (S) RNA segment. These RNA segments are single-stranded, and exist in a helical formation within the virion. Besides, they exhibit a pseudo-circular structure due to each segment's complementary ends. The L segment encodes the RNA-dependent RNA polymerase , necessary for viral RNA replication and mRNA synthesis. The M segment encodes the viral glycoproteins , which project from the viral surface and aid the virus in attaching to and entering the host cell. The S segment encodes the nucleocapsid protein (N). Most bunyaviruses have a negative-sense L and M segment. The S segment of the genus Phlebovirus , and both M and S segment of the genus Tospovirus are ambisense . Ambisense means that some of the genes on the RNA strand are negative sense and others are positive sense. The ambisense S segment codes for the viral nucleoprotein (N) in the negative sense and a nonstructural protein (NSs) in the positive sense. The ambisense M segment codes for glycoprotein (GP) in the negative sense and a nonstructural protein (NSm) in the positive sense. The total genome size ranges from 10.5 to 22.7 kbp . The ambisense genome requires two rounds of transcription to be carried out. First, the negative-sense RNA is transcribed to produce mRNA and a full-length replicative intermediate. From this intermediate, a subgenomic mRNA encoding the small segment nonstructural protein is produced while the polymerase produced following the first round of transcription can now replicate the full-length RNA to produce viral genomes. [ citation needed ] Bunyaviruses replicate in the cytoplasm , while the viral proteins transit through the ER and Golgi apparatus . Mature virions bud from the Golgi apparatus into vesicles which are transported to the cell surface. [ citation needed ]Bunyaviruses infect arthropods , plants , protozoans , and vertebrates . Plants can host bunyaviruses from the families Tospoviridae and Fimoviridae (e.g. tomato, pigeonpea, melon, wheat, raspberry, redbud, and rose). Members of some families are insect-specific, for example the phasmavirids, first isolated from phantom midges , and since identified in diverse insects including moths , wasps and bees , and other true flies .There are 477 virus species recognised in this order. The phylogenetic tree diagram provides a full list of member species and the hosts which they infect. The order is organized into the following 12 families: Bunyaviruses that cause disease in humans include: [ citation needed ] Bunyaviruses have segmented genomes, making them capable of rapid reassortment and increasing the risk of outbreak. The bunyavirus that causes severe fever with thrombocytopenia syndrome can undergo recombination both by reassortment of genome segments and by intragenic homologous recombination . Bunyaviridae are transmitted by hematophagous arthropods including mosquitoes, midges, flies, and ticks. The viral incubation period is about 48 hours. Symptomatic infection typically causes non-specific flu-like symptoms with fever lasting for about three days. Because of their non-specific symptoms , Bunyavirus infections are frequently mistaken for other illnesses. For example, Bwamba fever is often mistaken for malaria. Prevention depends on the reservoir, amplifying hosts and how the viruses are transmitted, i.e. the vector, whether ticks or mosquitoes and which animals are involved. Preventive measures include general hygiene, limiting contact with vector saliva, urine, feces, or bedding. There is no licensed vaccine for bunyaviruses. As precautions Cache Valley virus and Hantavirus research are conducted in BSL-2 (or higher), Rift Valley Fever virus research is conducted in BSL-3 (or higher), Congo-Crimean Hemorrhagic Fever virus research is conducted in BSL-4 laboratories. [ citation needed ]1940s: Crimean–Congo hemorrhagic fever is discovered in Russia 1951: 3,000 cases of Hantavirus were reported in South Korea in 1951, a time when UN forces were fighting on the 38th parallel during the Korean War 1956: Cache Valley virus isolated in Culiseta inornata mosquitoes in Utah 1960: La Crosse virus was first recognized in a fatal case of encephalitis in La Crosse, Wisconsin 1977: Rift Valley Fever virus caused approximately 200,000 cases and 598 deaths in Egypt 2017: Bunyavirales order is created

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Rift Valley fever

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Dengue fever

Dengue fever is a mosquito-borne tropical disease caused by dengue virus . It is frequently asymptomatic ; if symptoms appear they typically begin 3 to 14 days after infection. These may include a high fever , headache , vomiting , muscle and joint pains , and a characteristic skin itching and skin rash . Recovery generally takes two to seven days. In a small proportion of cases, the disease develops into severe dengue (previously known as dengue hemorrhagic fever or dengue shock syndrome) with bleeding , low levels of blood platelets , blood plasma leakage, and dangerously low blood pressure . Dengue virus has four confirmed serotypes ; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. The symptoms of dengue resemble many other diseases including malaria , influenza , and Zika . Blood tests are available to confirm the diagnosis including detecting viral RNA , or antibodies to the virus. There is no specific treatment for dengue fever. In mild cases, treatment is focused on treating pain symptoms. Severe cases of dengue require hospitalisation; treatment of acute dengue is supportive and includes giving fluid either by mouth or intravenously . Dengue is spread by several species of female mosquitoes of the Aedes genus , principally Aedes aegypti . Infection can be prevented by mosquito elimination and the prevention of bites. Two types of dengue vaccine have been approved and are commercially available. Dengvaxia became available in 2016 but it is only recommended to prevent re-infection in individuals who have been previously infected. The second vaccine, Qdenga, became available in 2022 and is suitable for adults, adolescents and children from four years of age. The earliest descriptions of a dengue outbreak date from 1779; its viral cause and spread were understood by the early 20th century. Already endemic in more than one hundred countries, dengue is spreading from tropical and subtropical regions to the Iberian Peninsula and the southern states of the US, partly attributed to climate change. It is classified as a neglected tropical disease . During 2023, more than 5 million infections were reported, with more than 5,000 dengue-related deaths. As most cases are asymptomatic or mild, the actual numbers of dengue cases and deaths are under-reported. Typically, people infected with dengue virus are asymptomatic (80%) or have only mild symptoms such as an uncomplicated fever. Others have more severe illness (5%), and in a small proportion it is life-threatening. The incubation period (time between exposure and onset of symptoms) ranges from 3 to 14 days, but most often it is 4 to 7 days. The characteristic symptoms of mild dengue are sudden-onset fever, headache (typically located behind the eyes), muscle and joint pains, nausea, vomiting, swollen glands and a rash. If this progresses to severe dengue the symptoms are severe abdominal pain, persistent vomiting, rapid breathing, bleeding gums or nose, fatigue, restlessness, blood in vomit or stool, extreme thirst, pale and cold skin, and feelings of weakness. The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . The course of infection is divided into three phases: febrile, critical, and recovery. The febrile phase involves high fever (40 °C/104 °F), and is associated with generalized pain and a headache; this usually lasts two to seven days. There may also be nausea, vomiting, a rash, and pains in the muscle and joints. Most people recover within a week or so. In about 5% of cases, symptoms worsen and can become life-threatening. This is called severe dengue , (formerly called dengue hemorrhagic fever or dengue shock syndrome ). Severe dengue can lead to shock, internal bleeding, organ failure and even death. Warning signs include severe stomach pain, vomiting, difficulty breathing, and blood in the nose, gums, vomit or stools. During this period, there is leakage of plasma from the blood vessels, together with a reduction in platelets . This may result in fluid accumulation in the chest and abdominal cavity as well as depletion of fluid from the circulation and decreased blood supply to vital organs . The recovery phase usually lasts two to three days. The improvement is often striking, and can be accompanied with severe itching and a slow heart rate . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Complications following severe dengue include fatigue, somnolence, headache, concentration impairment and memory impairment. A pregnant woman who develops dengue is at higher risk of miscarriage , low birth weight birth, and premature birth . Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. Dengue virus (DENV) is an RNA virus of the family Flaviviridae ; genus Flavivirus . Other members of the same genus include yellow fever virus , West Nile virus , and Zika virus . Dengue virus genome (genetic material) contains about 11,000 nucleotide bases , which code for the three structural protein molecules (C, prM and E) that form the virus particle and seven other protein molecules that are required for replication of the virus. There are four confirmed strains of the virus, called serotypes , referred to as DENV-1, DENV-2, DENV-3 and DENV-4. The distinctions between the serotypes are based on their antigenicity . Dengue virus is most frequently transmitted by the bite of mosquitos in the Aedes genus, particularly A. aegypti . They prefer to feed at dusk and dawn, but they may bite and thus spread infection at any time of day. Other Aedes species that may transmit the disease include A. albopictus , A. polynesiensis and A. scutellaris . Humans are the primary host of the virus, but it also circulates in nonhuman primates , and can infect other mammals. An infection can be acquired via a single bite. For 2 to 10 days after becoming newly infected, a person's bloodstream will contain a high level of virus particles (the viremic period). A female mosquito that takes a blood meal from the infected host then propagates the virus in the cells lining its gut. Over the next few days, the virus spreads to other tissues including the mosquito's salivary glands and is released into its saliva. Next time the mosquito feeds, the infectious saliva will be injected into the bloodstream of its victim, thus spreading the disease. The virus seems to have no detrimental effect on the mosquito, which remains infected for life. Dengue can also be transmitted via infected blood products and through organ donation . Vertical transmission (from mother to child) during pregnancy or at birth has been reported. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent ( DEET being the most effective). Chronic diseases – such as asthma, sickle cell anemia, and diabetes mellitus – increase the risk of developing a severe form of the disease. Other risk factors for severe disease include female sex, and high body mass index , Infection with one serotype is thought to produce lifelong immunity to that type, but only short-term protection against the other three. Subsequent re-infection with a different serotype increases the risk of severe complications due to phenomenon known as antibody-dependent enhancement (ADE). The exact mechanism of ADE is not fully understood. It appears that ADE occurs when the antibodies generated during an immune response recognize and bind to a pathogen, but they fail to neutralize it. Instead, the antibody-virus complex has an enhanced ability to bind to the Fcγ receptors of the target immune cells, enabling the virus to infect the cell and reproduce itself. When a mosquito carrying dengue virus bites a person, the virus enters the skin together with the mosquito's saliva. The virus infects nearby skin cells called keratinocytes , as well as specialized immune cell located in the skin, called a Langerhans cells . The Langerhans cells migrate to the lymph nodes , where the infection spreads to white blood cells , and reproduces inside the cells while they move throughout the body. The white blood cells respond by producing several signaling proteins, such as cytokines and interferons , which are responsible for many of the symptoms, such as the fever, the flu-like symptoms, and the severe pains. In severe infection, the virus production inside the body is greatly increased, and many more organs (such as the liver and the bone marrow ) can be affected. Fluid from the bloodstream leaks through the wall of small blood vessels into body cavities due to increased capillary permeability . As a result, blood volume decreases, and the blood pressure becomes so low that it cannot supply sufficient blood to vital organs. The spread of the virus to the bone marrow leads to reduced numbers of platelets, which are necessary for effective blood clotting; this increases the risk of bleeding, the other major complication of dengue fever. The principal risk for infection with dengue is the bite of an infected mosquito. This is more probable in areas where the disease is endemic, especially where there is high population density, poor sanitation, and standing water where mosquitoes can breed. It can be mitigated by taking steps to avoid bites such as by wearing clothing that fully covers the skin, using mosquito netting while resting, and/or the application of insect repellent (DEET being the most effective); it's also advisable to treat clothing, nets and tents with 0.5% permethrin . Protection of the home can be achieved with door and window screens, by using air conditioning, and by regularly emptying and cleaning all receptacles both indoors and outdoors which may accumulate water (such as buckets, planters, pools or trashcans). The primary method of controlling A. aegypti is by eliminating its habitats . This is done by eliminating open sources of water, or if this is not possible, by adding insecticides or biological control agents to these areas. Generalized spraying with organophosphate or pyrethroid insecticides, while sometimes done, is not thought to be effective. Reducing open collections of water through environmental modification is the preferred method of control, given the concerns of negative health effects from insecticides and greater logistical difficulties with control agents. Ideally, mosquito control would be a community activity, e.g. when all members of a community clear blocked gutters and street drains and keep their yards free of containers with standing water. If residences have direct water connections this eliminates the need for wells or street pumps and water-carrying containers. As of March 2024, there are two vaccines to protect against dengue infection; Dengvaxia and Qdenga . Dengvaxia (formerly CYD-TDV) became available in 2015, and is approved for use in the US, EU and in some Asian and Latin American countries. It is an attenuated virus, is suitable for individuals aged 6–45 years and protects against all four serotypes of dengue. Due to safety concerns about antibody-dependent enhancement (ADE), it should only be given to individuals who have previously been infected with dengue, in order to protect them from reinfection. It is given subcutaneously as three doses at six month intervals. Qdenga (formerly TAK-003) completed clinical trials in 2022 and was approved for use in the European Union in December 2022; it has been approved by a number of other countries including Indonesia and Brazil, and has been recommended by the SAGE committee of the World Health Organization. It is indicated for the prevention of dengue disease in individuals four years of age and older, and can be administered to people who have not been previously infected with dengue. It is a live attenuated vaccine containing the four serotypes of dengue virus, administered subcutaneously as two doses three months apart. The World Health Organization 's International Classification of Diseases divides dengue fever into two classes: uncomplicated and severe. Severe dengue is defined as that associated with severe bleeding, severe organ dysfunction, or severe plasma leakage. Severe dengue can develop suddenly, sometimes after a few days as the fever subsides. Leakage of plasma from the capillaries results in extreme low blood pressure and hypovolemic shock ; Patients with severe plasma leakage may have fluid accumulation in the lungs or abdomen , insufficient protein in the blood , or thickening of the blood . Severe dengue is a medical emergency which can cause damage to organs, leading to multiple organ failure and death. Mild cases of dengue fever can easily be confused with several common diseases including Influenza , measles , chikungunya , and zika . Dengue, chikungunya and zika share the same mode of transmission ( Aedes mosquitoes) and are often endemic in the same regions, so that it is possible to be infected simultaneously by more than one disease. For travellers, dengue fever diagnosis should be considered in anyone who develops a fever within two weeks of being in the tropics or subtropics . Warning symptoms of severe dengue include abdominal pain, persistent vomiting, odema, bleeding, lethargy, and liver enlargement. Once again, these symptoms can be confused with other diseases such as malaria, gastroenteritis, leptospirosis, and typhus. Blood tests can be used to confirm a diagnosis of dengue. During the first few days of infection, enzyme-linked immunosorbent assay ( ELISA ) can be used to detect the NS1 antigen ; however this antigen is produced by all flaviviruses. Four or five days into the infection, it is possible to reliably detect anti-dengue IgM antibodies, but this does not determine the serotype. Nucleic acid amplification tests provide the most reliable method of diagnosis. As of March 2024, there is no specific antiviral treatment available for dengue fever. Most cases of dengue fever have mild symptoms, and recovery takes place in a few days. No treatment is required for these cases. Acetaminophen (Paracetamol, Tylenol ) may be used to relieve mild fever or pain. Other common pain relievers, including aspirin , ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve) should be avoided as they can increase the risk of bleeding complications. For moderate illness, those who can drink, are passing urine, have no warning signs and are otherwise reasonably healthy can be monitored carefully at home. Supportive care with analgesics, fluid replacement, and bed rest are recommended. Severe dengue is a life-threatening emergency, requiring hospitalization and potentially intensive care. Warning signs include dehydration , decreasing platelets and increasing hematocrit . Treatment modes include intravenous fluids, and transfusion with platelets or plasma. Most people with dengue recover without any ongoing problems. The risk of death among those with severe dengue is 0.8% to 2.5%, and with adequate treatment this is less than 1%. However, those who develop significantly low blood pressure may have a fatality rate of up to 26%. The risk of death among children less than five years old is four times greater than among those over the age of 10. Elderly people are also at higher risk of a poor outcome. As of March 2023, dengue is endemic in more than 100 countries with cases reported in every continent with the exception of Antarctica. The Americas, Southeast Asia and the Western Pacific regions are the most seriously affected. It is difficult to estimate the full extent of the disease, as many cases are mild and not correctly diagnosed. WHO currently estimates that 3.9 billion people are at risk of dengue infection. In 2013, it was estimated that 390 million dengue infections occur every year, with 500,000 of these developing severe symptoms and 25,000 deaths. Generally, areas where dengue is endemic have only one serotype of the virus in circulation. The disease is said to be hyperendemic in areas where more than one serotype is circulating; this increases the risk of severe disease on a second or subsequent infection. Infections are most commonly acquired in urban environments where the virus is primarily transmitted by the mosquito species Aedes aegypti . This species has adapted to the urban environment, is generally found close to human habitation, prefers humans as its host, and takes advantage of small bodies of standing water (such as tanks and buckets) in which to breed. In rural settings the virus is transmitted to humans by A. aegypti and other related mosquitoes such as Aedes albopictus . Both these species have expanding ranges. Dengue has increased in incidence in recent decades, with WHO recording a ten fold increase between 2010 and 2019 (from 500,000 to 5 million recorded cases). This increase is tied closely to the increasing range of Aedes mosquitoes, which is attributed to a combination of urbanization , population growth, and an increasingly warm climate . In endemic areas, dengue infections peak when rainfall is optimal for mosquito breeding. The disease infects all races, sexes, and ages equally. In endemic areas, the infection is most commonly seen in children who then acquire a lifelong partial immunity. The first historical record of a case of probable dengue fever is in a Chinese medical encyclopedia from the Jin Dynasty (266–420) which referred to a "water poison" associated with flying insects. The principal mosquito vector of dengue, Aedes aegypti , spread out of Africa in the 15th to 19th centuries due to the slave trade and consequent expansion of international trading. There have been descriptions of epidemics of dengue-like illness in the 17th century, and it is likely that epidemics in Jakarta , Cairo , and Philadelphia during the 18th century were caused by dengue. It is assumed that dengue was constantly present in many tropical urban centres throughout the 19th and early 20th centuries, even though significant outbreaks were infrequent. The marked spread of dengue during and after the Second World War has been attributed partly to disruption caused by the war, and partly to subsequent urbanisation in south-east Asia. As novel serotypes were introduced to regions already endemic with dengue, outbreaks of severe disease followed. The severe hemorrhagic form of the disease was first reported in the Philippines in 1953; by the 1970s, it had become recognised as a major cause of child mortality in Southeast Asia. In Central and South America, the Aedes mosquito had been eradicated in the 1950s; however the eradication program was discontinued in the 1970s and the diesase re-established itself in the region during the 1980s, becoming hyperendemic and causing significant epidemics. Dengue has continued to increase in prevalence during the 21st century, as the mosquito vector continues to expand its range. This is attributed partly to continuing urbanisation, and partly to the impact of a warmer climate. The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". The name came into English in the early 19th century from West Indian Spanish, which borrowed it from the Kiswahili term dinga (in full kidingapopo , "disease caused by an evil spirit"). The borrowed term changed to dengue in Spanish due to this word existing in Spanish with the meaning "fastidiousness" and this folk etymology referring to the dislike of movement by affected patients. Slaves in the West Indies having contracted dengue were said to have the posture and gait of a dandy , and the disease was known as "dandy fever". The term break-bone fever was applied by physician and United States Founding Father Benjamin Rush , in a 1789 report of the 1780 epidemic in Philadelphia , due to the associated muscle and joint pains. In the report title he uses the more formal term "bilious remitting fever". The term dengue fever came into general use only after 1828. Other historical terms include "breakheart fever" and "la dengue". Terms for severe disease include "infectious thrombocytopenic purpura" and "Philippine", "Thai", or "Singapore hemorrhagic fever". Research directions include dengue pathogenesis (the process by which the disease develops in humans), as well as the biology, ecology and behaviour of the mosquito vector. Improved diagnostics would enable faster and more appropriate treatment. Attempts are ongoing to develop an antiviral medicine targeting the NS3 or NS5 proteins. In addition to the two vaccines which are already available, several vaccine candidates are in development. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion. Outbreaks of dengue fever increase the need for blood products while decreasing the number of potential blood donors due to potential infection with the virus. Someone who has a dengue infection is typically not allowed to donate blood for at least the next six months. International Anti-Dengue Day is observed every year on 15 June in a number of countries. The idea was first agreed upon in 2010 with the first event held in Jakarta , Indonesia, in 2011. Further events were held in 2012 in Yangon , Myanmar, and in 2013 in Vietnam . Goals are to increase public awareness about dengue, mobilize resources for its prevention and control and, to demonstrate the Southeast Asian region's commitment in tackling the disease. Efforts are ongoing as of 2019 to make it a global event. The Philippines has an awareness month in June since 1998. A National Dengue Day is held in India annually on 16 May. A study estimate that the global burden of dengue in 2013 amounted to US$8·9 billion.

Wiki

Rift Valley fever

https://api.wikimedia.org/core/v1/wikipedia/en/page/Mansonia_(fly)/html

Mansonia (fly)

Mansonia Mansonioides Mansonia mosquitoes are big, black or brown mosquitoes with sparkling on their wings and legs. They breed in ponds and lakes containing certain aquatic plants , especially the floating type like Pistia stratiotes and water hyacinth . The eggs are laid in star-shaped clusters on the undersurface of leaves of these plants. The larvae and pupae are found attached to the rootlets of these plants by their siphons . They obtain their air supply from these rootlets. When about to become adult, these pupae come to the surface of water and the fully formed adults emerge and escape. The control of Mansonia mosquitoes is easy by removal or destruction of the aquatic host plants by herbicides . A study published in 2013 determined that the species Mansonia dyari Belkin, Heinemann, and Page should be considered a potential vector of Rift Valley fever virus and would need to be controlled if the virus were introduced into an area where it occurs. These 27 species belong to the genus Mansonia : Data sources: i = ITIS, c = Catalogue of Life, g = GBIF, b = Bugguide.net

Wiki

Rift Valley fever

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

Marburg virus disease

Marburg virus disease ( MVD ; formerly Marburg hemorrhagic fever ) is a viral hemorrhagic fever in human and non-human primates caused by either of the two Marburgviruses : Marburg virus (MARV) and Ravn virus (RAVV). Its clinical symptoms are very similar to those of Ebola virus disease (EVD). Egyptian fruit bats are believed to be the normal carrier in nature and Marburg virus RNA has been isolated from them. The most detailed study on the frequency, onset, and duration of MVD clinical signs and symptoms was performed during the 1998–2000 mixed MARV/RAVV disease outbreak. A skin rash , red or purple spots (e.g. petechiae or purpura ), bruises , and hematomas (especially around needle injection sites) are typical hemorrhagic manifestations. However, contrary to popular belief, hemorrhage does not lead to hypovolemia and is not the cause of death (total blood loss is minimal except during labor ). Instead, death occurs due to multiple organ dysfunction syndrome (MODS) due to fluid redistribution, hypotension , disseminated intravascular coagulation , and focal tissue necroses . Clinical phases of Marburg hemorrhagic fever's presentation are described below. Note that phases overlap due to variability between cases.MVD is caused by two viruses; Marburg virus (MARV) and Ravn virus (RAVV) , family Filoviridae. : 458 Marburgviruses are endemic in arid woodlands of equatorial Africa . Most marburgvirus infections were repeatedly associated with people visiting natural caves or working in mines . In 2009, the successful isolation of infectious MARV and RAVV was reported from healthy Egyptian fruit bat caught in caves. This isolation strongly suggests that Old World fruit bats are involved in the natural maintenance of marburgviruses and that visiting bat-infested caves is a risk factor for acquiring marburgvirus infections. Further studies are necessary to establish whether Egyptian rousettes are the actual hosts of MARV and RAVV or whether they get infected via contact with another animal and therefore serve only as intermediate hosts. Another risk factor is contact with nonhuman primates, although only one outbreak of MVD (in 1967) was due to contact with infected monkeys. Contrary to Ebola virus disease (EVD) , which has been associated with heavy rains after long periods of dry weather, triggering factors for spillover of marburgviruses into the human population have not yet been described.MVD is clinically indistinguishable from Ebola virus disease (EVD) , and it can also easily be confused with many other diseases prevalent in Equatorial Africa , such as other viral hemorrhagic fevers , falciparum malaria , typhoid fever , shigellosis , rickettsial diseases such as typhus , cholera , gram-negative sepsis , borreliosis such as relapsing fever or EHEC enteritis . Other infectious diseases that ought to be included in the differential diagnosis include leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , hemorrhagic smallpox , measles , and fulminant viral hepatitis . Non-infectious diseases that can be confused with MVD are acute promyelocytic leukemia , hemolytic uremic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary hemorrhagic telangiectasia , Kawasaki disease , and even warfarin intoxication. The most important indicator that may lead to the suspicion of MVD at clinical examination is the medical history of the patient, in particular the travel and occupational history (which countries and caves were visited?) and the patient's exposure to wildlife (exposure to bats or bat excrements?). MVD can be confirmed by isolation of marburgviruses from or by detection of marburgvirus antigen or genomic or subgenomic RNAs in patient blood or serum samples during the acute phase of MVD. Marburgvirus isolation is usually performed by inoculation of grivet kidney epithelial Vero E6 or MA-104 cell cultures or by inoculation of human adrenal carcinoma SW-13 cells, all of which react to infection with characteristic cytopathic effects . Filovirions can easily be visualized and identified in cell culture by electron microscopy due to their unique filamentous shapes, but electron microscopy cannot differentiate the various filoviruses alone despite some overall length differences. Immunofluorescence assays are used to confirm marburgvirus presence in cell cultures. During an outbreak, virus isolation and electron microscopy are most often not feasible options. The most common diagnostic methods are therefore RT-PCR in conjunction with antigen-capture ELISA , which can be performed in field or mobile hospitals and laboratories. Indirect immunofluorescence assays (IFAs) are not used for diagnosis of MVD in the field anymore. [ citation needed ] Marburg virus disease (MVD) is the official name listed in the World Health Organization 's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg , where MARV was first discovered. Marburg virus disease (MVD) is the official name listed in the World Health Organization 's International Statistical Classification of Diseases and Related Health Problems 10 (ICD-10) for the human disease caused by any of the two marburgviruses Marburg virus (MARV) and Ravn virus (RAVV). In the scientific literature, Marburg hemorrhagic fever (MHF) is often used as an unofficial alternative name for the same disease. Both disease names are derived from the German city Marburg , where MARV was first discovered. The details of the initial transmission of MVD to humans remain incompletely understood. Transmission most likely occurs from Egyptian fruit bats or another natural host, such as non-human primates or through the consumption of bushmeat , but the specific routes and body fluids involved are unknown. Human-to-human transmission of MVD occurs through direct contact with infected bodily fluids such as blood. Transmission events are relatively rare – there have been only 11 recorded outbreaks of MARV between 1975 and 2011, with one event involving both MARV and RAVV. There are currently no Food and Drug Administration -approved vaccines for the prevention of MVD. Many candidate vaccines have been developed and tested in various animal models. Of those, the most promising ones are DNA vaccines or based on Venezuelan equine encephalitis virus replicons , vesicular stomatitis Indiana virus (VSIV) or filovirus-like particles (VLPs) as all of these candidates could protect nonhuman primates from marburgvirus-induced disease. DNA vaccines have entered clinical trials. Marburgviruses are highly infectious , but not very contagious . They do not get transmitted by aerosol during natural MVD outbreaks. Due to the absence of an approved vaccine, prevention of MVD therefore relies predominantly on quarantine of confirmed or high probability cases, proper personal protective equipment , and sterilization and disinfection . [ citation needed ] The natural maintenance hosts of marburgviruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in Marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source. [ citation needed ] Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids , and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers . Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment , laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.The natural maintenance hosts of marburgviruses remain to be identified unequivocally. However, the isolation of both MARV and RAVV from bats and the association of several MVD outbreaks with bat-infested mines or caves strongly suggests that bats are involved in Marburg virus transmission to humans. Avoidance of contact with bats and abstaining from visits to caves is highly recommended, but may not be possible for those working in mines or people dependent on bats as a food source. [ citation needed ]Since marburgviruses are not spread via aerosol, the most straightforward prevention method during MVD outbreaks is to avoid direct (skin-to-skin) contact with patients, their excretions and body fluids , and any possibly contaminated materials and utensils. Patients should be isolated, but still are safe to be visited by family members. Medical staff should be trained in and apply strict barrier nursing techniques (disposable face mask, gloves, goggles, and a gown at all times). Traditional burial rituals, especially those requiring embalming of bodies, should be discouraged or modified, ideally with the help of local traditional healers . Marburgviruses are World Health Organization Risk Group 4 Pathogens, requiring Biosafety Level 4-equivalent containment , laboratory researchers have to be properly trained in BSL-4 practices and wear proper personal protective equipment.There is currently no effective marburgvirus-specific therapy for MVD. Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration , administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation , administration of procoagulants late in infection to control hemorrhaging , maintaining oxygen levels, pain management , and administration of antibiotics or antifungals to treat secondary infections. Although supportive care can improve survival chances, marburg virus disease is fatal in the majority of cases. As of 2023 [ update ] the case fatality rate was assessed to be 61.9%. The WHO identifies marburg virus disease as having pandemic potential. Below is a table of outbreaks concerning MVD from 1967 to 2023: MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main , and in Belgrade , Yugoslavia . The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops ) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines . The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine , Emil von Behring . The company, which at the time was owned by Hoechst , was originally set up to develop sera against tetanus and diphtheria . Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment . Secondary cases involved two physicians , a nurse , a post-mortem attendant, and the wife of a veterinarian . All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe ). He died in a hospital in Johannesburg , South Africa . His girlfriend and an attending nurse were subsequently infected with MVD, but survived. A case of MARV infection occurred in 1980 in Kenya . A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma ) at the base of Mount Elgon (which contains Kitum Cave ), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston 's book The Hot Zone (the French man is referred to under the pseudonym "Charles Monet", whereas the physician is identified under his real name, Shem Musoke). In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu , Kenya . He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa , where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston 's book The Hot Zone (the boy is referred to under the pseudonym "Peter Cardinal"). In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs . The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR (today Russia ). Very little information is publicly available about this MVD case because Ustinov's experiments were classified. A popular science account of this case can be found in Ken Alibek 's book Biohazard . Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR , when a scientist contracted MARV by unknown means. A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa , Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine. In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola , which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity . Contact tracing was complicated by the fact that the country's roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines . Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died. In 2007, four miners became infected with marburgviruses in Kamwenge District , Uganda . The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection. On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda , had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands . The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin . At the time, serologic testing was negative for viral hemorrhagic fever . She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA . In October 2017 an outbreak of Marburg virus disease was detected in Kween District , Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala . It is reported that several hundred people may have been exposed to infection. In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. This was the first case of the Marburg hemorrhagic fever confirmed to happen in West Africa. The case of Marburg also has been identified in Guéckédou . During the outbreak, a total of one confirmed case, who died ( CFR =100%), and 173 contacts were identified, including 14 high-risk contacts based on exposure. Among them, 172 were followed for a period of 21 days, of which none developed symptoms. One high-risk contact was lost to follow up. Sequencing of an isolate from the Guinean patient showed that this outbreak was caused by the Angola-like Marburg virus. A colony of Egyptian rousettus bats ( reservoir host of Marburg virus ) was found in close proximity (4.5 km) to the village, where the Marburg virus disease outbreak emerged in 2021. Two sampled fruit bats from this colony were PCR-positive on the Marburg virus. In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three. A disease outbreak was first reported in Equatorial Guinea on 7 February 2023, and on 13 February 2023, it was identified as being Marburg virus disease. It was the first time the disease was detected in the country. Neighbouring Cameroon detected two suspected cases of Marburg virus disease on 13 February 2023, but they were later ruled out. On 25 February, a suspected case of Marburg was reported in the Spanish city of Valencia , however this case was subsequently discounted. As of 4 April 2023, there were 14 confirmed cases and 28 suspected cases, including ten confirmed deaths from the disease in Equatorial Guinea. On 8 June 2023, the World Health Organization declared the outbreak over. In total, 17 laboratory-confirmed cases and 12 deaths were recorded. All the 23 probable cases reportedly died. Four patients recovered from the virus and have been enrolled in a survivors programme to receive psychosocial and other post-recovery support. A Marburg virus disease outbreak in Tanzania was first reported on 21 March 2023 by the Ministry of Health of Tanzania. This was the first time that Tanzania had reported an outbreak of the disease. On 2 June 2023, Tanzania declared the outbreak over. There were 9 total infections, resulting in 6 total deaths. The WHO identifies marburg virus disease as having pandemic potential. Below is a table of outbreaks concerning MVD from 1967 to 2023:MVD was first documented in 1967, when 31 people became ill in the German towns of Marburg and Frankfurt am Main , and in Belgrade , Yugoslavia . The outbreak involved 25 primary MARV infections and seven deaths, and six nonlethal secondary cases. The outbreak was traced to infected grivets (species Chlorocebus aethiops ) imported from an undisclosed location in Uganda and used in developing poliomyelitis vaccines . The monkeys were received by Behringwerke, a Marburg company founded by the first winner of the Nobel Prize in Medicine , Emil von Behring . The company, which at the time was owned by Hoechst , was originally set up to develop sera against tetanus and diphtheria . Primary infections occurred in Behringwerke laboratory staff while working with grivet tissues or tissue cultures without adequate personal protective equipment . Secondary cases involved two physicians , a nurse , a post-mortem attendant, and the wife of a veterinarian . All secondary cases had direct contact, usually involving blood, with a primary case. Both physicians became infected through accidental skin pricks when drawing blood from patients. In 1975, an Australian tourist became infected with MARV in Rhodesia (today Zimbabwe ). He died in a hospital in Johannesburg , South Africa . His girlfriend and an attending nurse were subsequently infected with MVD, but survived. A case of MARV infection occurred in 1980 in Kenya . A French man, who worked as an electrical engineer in a sugar factory in Nzoia (close to Bungoma ) at the base of Mount Elgon (which contains Kitum Cave ), became infected by unknown means and died on 15 January shortly after admission to Nairobi Hospital. The attending physician contracted MVD, but survived. A popular science account of these cases can be found in Richard Preston 's book The Hot Zone (the French man is referred to under the pseudonym "Charles Monet", whereas the physician is identified under his real name, Shem Musoke). In 1987, a single lethal case of RAVV infection occurred in a 15-year-old Danish boy, who spent his vacation in Kisumu , Kenya . He had visited Kitum Cave on Mount Elgon prior to travelling to Mombasa , where he developed clinical signs of infection. The boy died after transfer to Nairobi Hospital. A popular science account of this case can be found in Richard Preston 's book The Hot Zone (the boy is referred to under the pseudonym "Peter Cardinal"). In 1988, researcher Nikolai Ustinov infected himself lethally with MARV after accidentally pricking himself with a syringe used for inoculation of guinea pigs . The accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR (today Russia ). Very little information is publicly available about this MVD case because Ustinov's experiments were classified. A popular science account of this case can be found in Ken Alibek 's book Biohazard . Another laboratory accident occurred at the Scientific-Production Association "Vektor" (today the State Research Center of Virology and Biotechnology "Vektor" ) in Koltsovo , USSR , when a scientist contracted MARV by unknown means. A major MVD outbreak occurred among illegal gold miners around Goroumbwa mine in Durba and Watsa , Democratic Republic of Congo from 1998 to 2000, when co-circulating MARV and RAVV caused 154 cases of MVD and 128 deaths. The outbreak ended with the flooding of the mine. In early 2005, the World Health Organization (WHO) began investigating an outbreak of viral hemorrhagic fever in Angola , which was centered in the northeastern Uíge Province but also affected many other provinces. The Angolan government had to ask for international assistance, pointing out that there were only approximately 1,200 doctors in the entire country, with some provinces having as few as two. Health care workers also complained about a shortage of personal protective equipment such as gloves, gowns, and masks. Médecins Sans Frontières (MSF) reported that when their team arrived at the provincial hospital at the center of the outbreak, they found it operating without water and electricity . Contact tracing was complicated by the fact that the country's roads and other infrastructure were devastated after nearly three decades of civil war and the countryside remained littered with land mines . Americo Boa Vida Hospital in the Angolan capital Luanda set up a special isolation ward to treat infected people from the countryside. Unfortunately, because MVD often results in death, some people came to view hospitals and medical workers with suspicion and treated helpers with hostility. For instance, a specially-equipped isolation ward at the provincial hospital in Uíge was reported to be empty during much of the epidemic, even though the facility was at the center of the outbreak. WHO was forced to implement what it described as a "harm reduction strategy", which entailed distributing disinfectants to affected families who refused hospital care. Of the 252 people who contracted MVD during outbreak, 227 died. In 2007, four miners became infected with marburgviruses in Kamwenge District , Uganda . The first case, a 29-year-old man, became symptomatic on July 4, 2007, was admitted to a hospital on July 7, and died on July 13. Contact tracing revealed that the man had had prolonged close contact with two colleagues (a 22-year-old man and a 23-year-old man), who experienced clinical signs of infection before his disease onset. Both men had been admitted to hospitals in June and survived their infections, which were proven to be due to MARV. A fourth, 25-year-old man, developed MVD clinical signs in September and was shown to be infected with RAVV. He also survived the infection. On July 10, 2008, the Netherlands National Institute for Public Health and the Environment reported that a 41-year-old Dutch woman, who had visited Python Cave in Maramagambo Forest during her holiday in Uganda , had MVD due to MARV infection, and had been admitted to a hospital in the Netherlands . The woman died under treatment in the Leiden University Medical Centre in Leiden on July 11. The Ugandan Ministry of Health closed the cave after this case. On January 9 of that year an infectious diseases physician notified the Colorado Department of Public Health and the Environment that a 44-year-old American woman who had returned from Uganda had been hospitalized with a fever of unknown origin . At the time, serologic testing was negative for viral hemorrhagic fever . She was discharged on January 19, 2008. After the death of the Dutch patient and the discovery that the American woman had visited Python Cave, further testing confirmed the patient demonstrated MARV antibodies and RNA . In October 2017 an outbreak of Marburg virus disease was detected in Kween District , Eastern Uganda. All three initial cases (belonging to one family – two brothers and one sister) had died by 3 November. The fourth case – a health care worker – developed symptoms on 4 November and was admitted to a hospital. The first confirmed case traveled to Kenya before the death. A close contact of the second confirmed case traveled to Kampala . It is reported that several hundred people may have been exposed to infection. In August 2021, two months after the re-emergent Ebola epidemic in the Guéckédou prefecture was declared over, a case of the Marburg disease was confirmed by health authorities through laboratory analysis. Other potential case of the disease in a contact awaits official results. This was the first case of the Marburg hemorrhagic fever confirmed to happen in West Africa. The case of Marburg also has been identified in Guéckédou . During the outbreak, a total of one confirmed case, who died ( CFR =100%), and 173 contacts were identified, including 14 high-risk contacts based on exposure. Among them, 172 were followed for a period of 21 days, of which none developed symptoms. One high-risk contact was lost to follow up. Sequencing of an isolate from the Guinean patient showed that this outbreak was caused by the Angola-like Marburg virus. A colony of Egyptian rousettus bats ( reservoir host of Marburg virus ) was found in close proximity (4.5 km) to the village, where the Marburg virus disease outbreak emerged in 2021. Two sampled fruit bats from this colony were PCR-positive on the Marburg virus. In July 2022, preliminary analysis of samples taken from two patients – both deceased – in Ghana indicated the cases were positive for Marburg. However, per standard procedure, the samples were sent to the Pasteur Institute of Dakar for confirmation. On 17 July 2022 the two cases were confirmed by Ghana, which caused the country to declare a Marburg virus disease outbreak. An additional case was identified, bringing the total to three. A disease outbreak was first reported in Equatorial Guinea on 7 February 2023, and on 13 February 2023, it was identified as being Marburg virus disease. It was the first time the disease was detected in the country. Neighbouring Cameroon detected two suspected cases of Marburg virus disease on 13 February 2023, but they were later ruled out. On 25 February, a suspected case of Marburg was reported in the Spanish city of Valencia , however this case was subsequently discounted. As of 4 April 2023, there were 14 confirmed cases and 28 suspected cases, including ten confirmed deaths from the disease in Equatorial Guinea. On 8 June 2023, the World Health Organization declared the outbreak over. In total, 17 laboratory-confirmed cases and 12 deaths were recorded. All the 23 probable cases reportedly died. Four patients recovered from the virus and have been enrolled in a survivors programme to receive psychosocial and other post-recovery support. A Marburg virus disease outbreak in Tanzania was first reported on 21 March 2023 by the Ministry of Health of Tanzania. This was the first time that Tanzania had reported an outbreak of the disease. On 2 June 2023, Tanzania declared the outbreak over. There were 9 total infections, resulting in 6 total deaths. Experimentally, recombinant vesicular stomatitis Indiana virus (VSIV) expressing the glycoprotein of MARV has been used successfully in nonhuman primate models as post-exposure prophylaxis. A vaccine candidate has been effective in nonhuman primates. Experimental therapeutic regimens relying on antisense technology have shown promise, with phosphorodiamidate morpholino oligomers (PMOs) targeting the MARV genome New therapies from Sarepta and Tekmira have also been successfully used in humans as well as primates.

Wiki

Rift Valley fever

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

Phlebovirus

See text Phlebovirus is one of twenty genera of the family Phenuiviridae in the order Bunyavirales . The genus contains 66 species. It derives its name from Phlebotominae , the vectors of member species Naples phlebovirus , which is said to be ultimately from the Greek phlebos , meaning "vein". The proper word for "vein" in ancient Greek is however phleps (φλέψ). Phleboviruses are viruses with a negative-sense RNA genome consisting of three segments. The small segment (S) codes for the viral N protein and a non structural protein, NSs via an ambisense coding strategy. The medium-sized segment (M) codes for a precursor of the viral glycoproteins and non-structural components. The product of the largest segment (L) is the viral RNA-dependent RNA polymerase. The Phlebovirus replicates in a 7 step process. First, the cellular attachment is driven through the glycoprotein interactions with host cells. Examples of this are Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Non-Integrin (DC-SIGN), heparan sulfate (HS), or Non-Muscle Myosin Heavy Chain (NMMHC-IIA). Second, in the late endosome, the low pH causes fusion activity in the membrane of the Gc protein. Uukuniemi virus (UUKV) penetration is promoted by the expression of vesicle-associated membrane protein 3 (VAMP3). Additionally, the fusion of Rift Valley fever virus (RVFV) in late endosomes is inhibited by the interferon-induced transmembrane proteins 2 and 3 (IFITIM2 and IFITIM3). Third, the viral and endosomal membranes are fused to allow for the release of the viral ribonucleoprotein complexes into the cytoplasm (Also the site of viral transcription and replication). Fourth, the precursor protein, Gn/Gc, is translated at the rough endoplasmic reticulum (ER). This precursor protein is cleaved by signal peptidase. Synthesis of the viral nucleoprotein and viral polymerase in the cytoplasm combines with the newly formed genomic RNA (gRNA) ribonucleic protein complexes (RNP). Fifth, two ER chaperones, binding immunoglobulin protein (BiP) and calnexin, are required to ensure proper folding of GN/Gc. Gn/Gc are similarly catalyzed by protein-disulfide-isomerase through the formation of disulfide bonds. At the same time, calreticulin prevents any misfolded Gn/Gc from being exported to the Golgi. Sixth, The correctly folded Gn/Gc heterodimers are transported to the Golgi apparatus. The cytoplasmic tails of Gn in the budding process associate with RNPs during this time. Seventh, once the budding of the new virus particles is completed, vesicles that contain the virus are transported to the plasma membrane to be released by exocytosis. A study of the family Bunyaviridae showed that bunyavirus particles are pleomorphic. This known fact cased some surprise when studies showed that UUKKV and RVFV particles are spherically shaped and highly ordered. The configuration of Gn and Gc proteins in the viral envelope imposes the order of the particle. The viral envelope forms an icosahedral lattice with a triangulation number of 12. Also included in the lattice composition are 110 hexametric and 12 pentameric capsomeres. For RVFV in particular, 720 Gn/Gc heterodimers are included in the capsomeres. In these cases, Gn forms the spikes of the capsomere while Gc is closer to the lipid membrane, thus placing it underneath. The pH surrounding the capsomere ultimately determines its shape. This is largely due to protonation triggering conformational changes in Gc, commonly included with membrane fusion. An assembly model for the RVFV envelope has been proposed which consists of Gc dimers positioned horizontally with respect to the viral membrane. This is known because the RVFV Gc ectodomain is crystallized as a dimer. This is opposed to the virion interior of bunyaviruses which has no matrix protein, and thus, has no defining organization. This means that on the virion surface, the Gc and Gn proteins must be present in a highly ordered placement. To begin entry, phlebovirus particles bind to various components of the plasma membrane. These components interact with the viral glycoproteins of phlebovirus and regulate entry efficiency. While these components are not crucial to the actual entry of the virus itself, receptors are components of the plasma membrane that bind to the glycoproteins and are critical for entry. In Phleboviruses, it was determined that glycan-protein interactions play a crucial role in phlebovirus entry. Heparan Sulfate (HS) is another crucial component aspect in Phlebovirus attachment. It is a glycosaminoglycan (GAG), which is an unbranched polysaccharide made of disaccharide repeats, that results in the creation of a proteoglycan. Cell lines with defined glycosylation defects were analyzed and showed that HS is necessary for the entry of RVFV. This was confirmed by the removal of HS using an enzyme. HS is charge-dependent in their interactions with virus particles, and studies showed that there are basic amino acid clusters on the P78 protein that interact with negative sulfate clusters on HS. In comparison, there were no identified HS binding sites on Gn and Gc. The P78 protein is plentiful in RVFV-infected cells in insects, while infected cells in mammals produce significantly less P78 proteins. The P78 protein is much more efficiently produced in RVFV in mosquito cells as it is required for viral spread in mosquitos. Overall, the cell line is heavily dependent on HS in RVFV entry. A computational study provided evidence that phlebovirus Gc proteins might be class II membrane fusion proteins. Final proof for this theory was given by the elucidation of the ectodomain's structure of RVFV Gc in its pre-fusion status. Gc has three domains with characteristics that resembled other class II proteins. An internal fusion loop was discovered, which is a critical aspect of all class II proteins. The location of a histidine in Gc resembled a pH sensing feature, which matches class II characteristics. Although there were many similarities within the structure of the RVFV Gc and class II proteins, the interface between domains I and II in RVFV Gc is more rigid and bigger than other class II proteins. Additionally, RVFV Gc has more disulfide bridges centralized in different locations than the other compared proteins. However, its overall structure and functionality is most closely resembling a class II membrane fusion protein compared to any other class. The pH sensing feature in the Gc protein is of note. The membrane fusion activity of the phlebovirus Gc proteins is very dependent on pH, as a low pH triggers the transport of virions into endolysosomes. Elevating intravesicular pH inhibits phlebovirus entry. However, it is still unclear whether Gc proteins must bind to a receptor before being triggered by pH or not. After the viral and endosomal membranes have been fused together, the L,M, and S genomic segments (associated with viral polymerase) are released into the cytoplasm. This initiates the transcription to genomic RNA into mRNA. Viral proteins begin undergoing translation before the transcription of mRNA has finished. The Gn and Gc phlebovirus proteins are encoded on the M-segment and undergo synthesis. The precursor Gn/Gc protein cannot be detected in a cell already infected with phlebovirus. It only is visible after the expression of the M-segment. If microsomal membranes are present, the precursor is cleaved, indicating cleaving by a host factor during the synthesis of the viral protein. The signal peptidase complex in the ER membrane is responsible for the cleaving of the precursor. This precursor is then translocated into the ER lumen, in which two hydrophobic domains are inserted with a third, cleaved hydrophobic domain in between. A study of the family Bunyaviridae showed that bunyavirus particles are pleomorphic. This known fact cased some surprise when studies showed that UUKKV and RVFV particles are spherically shaped and highly ordered. The configuration of Gn and Gc proteins in the viral envelope imposes the order of the particle. The viral envelope forms an icosahedral lattice with a triangulation number of 12. Also included in the lattice composition are 110 hexametric and 12 pentameric capsomeres. For RVFV in particular, 720 Gn/Gc heterodimers are included in the capsomeres. In these cases, Gn forms the spikes of the capsomere while Gc is closer to the lipid membrane, thus placing it underneath. The pH surrounding the capsomere ultimately determines its shape. This is largely due to protonation triggering conformational changes in Gc, commonly included with membrane fusion. An assembly model for the RVFV envelope has been proposed which consists of Gc dimers positioned horizontally with respect to the viral membrane. This is known because the RVFV Gc ectodomain is crystallized as a dimer. This is opposed to the virion interior of bunyaviruses which has no matrix protein, and thus, has no defining organization. This means that on the virion surface, the Gc and Gn proteins must be present in a highly ordered placement. To begin entry, phlebovirus particles bind to various components of the plasma membrane. These components interact with the viral glycoproteins of phlebovirus and regulate entry efficiency. While these components are not crucial to the actual entry of the virus itself, receptors are components of the plasma membrane that bind to the glycoproteins and are critical for entry. In Phleboviruses, it was determined that glycan-protein interactions play a crucial role in phlebovirus entry. Heparan Sulfate (HS) is another crucial component aspect in Phlebovirus attachment. It is a glycosaminoglycan (GAG), which is an unbranched polysaccharide made of disaccharide repeats, that results in the creation of a proteoglycan. Cell lines with defined glycosylation defects were analyzed and showed that HS is necessary for the entry of RVFV. This was confirmed by the removal of HS using an enzyme. HS is charge-dependent in their interactions with virus particles, and studies showed that there are basic amino acid clusters on the P78 protein that interact with negative sulfate clusters on HS. In comparison, there were no identified HS binding sites on Gn and Gc. The P78 protein is plentiful in RVFV-infected cells in insects, while infected cells in mammals produce significantly less P78 proteins. The P78 protein is much more efficiently produced in RVFV in mosquito cells as it is required for viral spread in mosquitos. Overall, the cell line is heavily dependent on HS in RVFV entry. A computational study provided evidence that phlebovirus Gc proteins might be class II membrane fusion proteins. Final proof for this theory was given by the elucidation of the ectodomain's structure of RVFV Gc in its pre-fusion status. Gc has three domains with characteristics that resembled other class II proteins. An internal fusion loop was discovered, which is a critical aspect of all class II proteins. The location of a histidine in Gc resembled a pH sensing feature, which matches class II characteristics. Although there were many similarities within the structure of the RVFV Gc and class II proteins, the interface between domains I and II in RVFV Gc is more rigid and bigger than other class II proteins. Additionally, RVFV Gc has more disulfide bridges centralized in different locations than the other compared proteins. However, its overall structure and functionality is most closely resembling a class II membrane fusion protein compared to any other class. The pH sensing feature in the Gc protein is of note. The membrane fusion activity of the phlebovirus Gc proteins is very dependent on pH, as a low pH triggers the transport of virions into endolysosomes. Elevating intravesicular pH inhibits phlebovirus entry. However, it is still unclear whether Gc proteins must bind to a receptor before being triggered by pH or not. After the viral and endosomal membranes have been fused together, the L,M, and S genomic segments (associated with viral polymerase) are released into the cytoplasm. This initiates the transcription to genomic RNA into mRNA. Viral proteins begin undergoing translation before the transcription of mRNA has finished. The Gn and Gc phlebovirus proteins are encoded on the M-segment and undergo synthesis. The precursor Gn/Gc protein cannot be detected in a cell already infected with phlebovirus. It only is visible after the expression of the M-segment. If microsomal membranes are present, the precursor is cleaved, indicating cleaving by a host factor during the synthesis of the viral protein. The signal peptidase complex in the ER membrane is responsible for the cleaving of the precursor. This precursor is then translocated into the ER lumen, in which two hydrophobic domains are inserted with a third, cleaved hydrophobic domain in between. Phleboviruses are arboviruses taxonomically split into tick- and dipteran-borne viruses. Phlebotomus sandflies are the primary sources for dipteran-borne phleboviruses, with Rift Valley fever virus being the exception (RVFV is associated with mosquitos and has a greater variety in its vector range). Maintenance of the viruses is mainly completed through the vector species by means of vertical (transovarial) transmission. Concerns over the potential introduction of RVFV into susceptible areas has grown due to the increasing spread of vector species. The potential ramifications of this spread could cause massive economic loss through the harming of livestock. Two new members of phlebovirus as causative agents of traumatic human disease have been identified. In rural China, SFTSV, which is transmitted by ticks, was identified as the result of increased cases of a febrile illness combined with thrombocytopenia, leukenocytopenia, multiple organ dysfunction, and a high case-fatality rate. After this discovery, SFTSV was reported in Japan and Korea as well. North America had a similar case, which was found to be a result of the Heartland virus, which is transmitted by ticks. These two discoveries changed the perception of the effect of tick-borne phleboviruses with regards to public health. These discoveries caused the re-classification of the Bhanja virus (BHAV) into the tick-borne phlebovirus group. Novel associations of phlebovirus diseases have been reported in the Mediterranean area. Examples include the sandfly fever Turkey virus, Adria virus, Granada virus, Adana virus, and Medjerda virus, among others. The Toscana virus has a high rate of vertical transmission, as demonstrated in sandflies through experimental infection. This suggests that there is an amplified role for vertebrate hosts despite the maintenance in nature coming mainly from sandflies. A sandfly is a name for members of any species or genus of flying, blood-sucking dipteran in sandy areas. For example, "sandfly" in the United States refers to horse flies or members of the family Ceratopogonidae. In other parts of the world, "sandfly" refers to members of the subfamily Phlebotominae within Psychodidae. Two of the three main genera were found in the Old World, Phlebotomus and Sergentomyia, and contain the prominent species that transmit the viral pathogens. The third genera was found in the New World and is called Lutzomyia. Other examples are biting midges, or Austrosimulium, a black fly found in New Zealand. The result of many of these viruses are some sort of fever. Pappataci fevers, or Phlebotomus fevers, are mild 3-day fevers that are similar to influenza and have a rapid onset. They are most common in endemic areas during the summer months, particularly August, which is when sandflies are active. Some more extreme cases are the Toscana virus, which is associated with meningitis in humans, and the Rift Valley fever virus which has caused wide-spread epidemics in livestock in Africa. The following twelve viruses have been linked to disease in humans: Alenquer phlebovirus , Bhanja virus , Candiru phlebovirus , Chagres virus , Sandfly fever Naples phlebovirus , Punta Toro phlebovirus , Rift Valley fever virus , Sicilian phlebovirus , Toscana phlebovirus , Uukuniemi virus , Heartland bandavirus (the first tick-borne phlebovirus known to cause disease in the Western Hemisphere, discovered in 2009), and the Sandfly Turkey virus (discovered in China in 2011). They cause symptoms ranging from short self-limiting fevers, such as pappataci fever , to encephalitis and fatal viral hemorrhagic fever . [ citation needed ]Phlebovirus is derived from Phlebotominae, which is the taxon of vectors of member species sandfly fever Naples phlebovirus. The name comes from the Greek root phlebos, which means "vein". Serological cross reactivity previously defined species in the genus. A change in classification rules was prompted due to the difficulty in detecting new phlebovirus in serological assays. As a result, viral species are now defined by 95% or greater identity in the amino acid sequences of their respective RNA-dependent RNA plymerase (RdRp). Currently, the genus consists of 67 species. Some of the viruses have other hematophagous arthropods as their main vectors. Examples of this include mosquitos for the Rift Valley fever virus, and the Mukawa virus, which has been isolated from ticks, but remains in Phlebovirus despite the common shift of tick-borne viruses from Phlebovirus to Uukuvirus. In addition to ticks and mosquitos, some Phleboviruses have been isolated from vertebrates like rodents in America and opossums or sloths in Africa. This wide variety of sources shows the possible presence of diversified epidemiological cycles. The following species are recognized: As of 2015, within the phlebovirus there are four genetic groups of tick-borne phleboviruses: the SFTS group, the Bhanja group, the Uukuniemi group, and the Kaisodi group.

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Recombinase polymerase amplification

Recombinase polymerase amplification (RPA) is a single tube, isothermal alternative to the polymerase chain reaction (PCR). By adding a reverse transcriptase enzyme to an RPA reaction it can detect RNA as well as DNA , without the need for a separate step to produce cDNA ,. Because it is isothermal , RPA can use much simpler equipment than PCR, which requires a thermal cycler . Operating best at temperatures of 37–42 °C and still working, albeit more slowly, at room temperature means RPA reactions can in theory be run quickly simply by holding a tube. This makes RPA an excellent candidate for developing low-cost, rapid, point-of-care molecular tests. An international quality assessment of molecular detection of Rift Valley fever virus performed as well as the best RT-PCR tests, detecting less concentrated samples missed by some PCR tests and an RT-LAMP test. RPA was developed and launched by TwistDx Ltd. (formerly known as ASM Scientific Ltd), a biotechnology company based in Cambridge, UK.The RPA process employs three core enzymes – a recombinase , a single-stranded DNA-binding protein (SSB) and strand-displacing polymerase . Recombinases are capable of pairing oligonucleotide primers with homologous sequence in duplex DNA. SSB bind to displaced strands of DNA and prevent the primers from being displaced. Finally, the strand displacing polymerase begins DNA synthesis where the primer has bound to the target DNA. By using two opposing primers, much like PCR, if the target sequence is indeed present, an exponential DNA amplification reaction is initiated. No other sample manipulation such as thermal or chemical melting is required to initiate amplification. At optimal temperatures (37–42 °C), the reaction progresses rapidly and results in specific DNA amplification from just a few target copies to detectable levels, typically within 10 minutes, for rapid detection of viral genomic DNA or RNA, pathogenic bacterial genomic DNA, as well as short length aptamer DNA. The three core RPA enzymes can be supplemented by further enzymes to provide extra functionality. Addition of exonuclease III allows the use of an exo probe for real-time, fluorescence detection akin to real-time PCR. Addition of endonuclease IV means that a nfo probe can be used for lateral flow strip detection of successful amplification. If a reverse transcriptase that works at 37–42 °C is added then RNA can be reverse transcribed and the cDNA produced amplified all in one step. Currently only the TwistAmp exo version of RPA is available with the reverse transcriptase included, although users can simply supplement other TwistAmp reactions with a reverse transcriptase to produce the same effect. As with PCR, all forms of RPA reactions can be multiplexed by the addition of further primer/probe pairs, allowing the detection of multiple analytes or an internal control in the same tube.RPA is one of several isothermal nucleic acid amplification techniques to be developed as a molecular diagnostic technique, frequently with the objective of simplifying the laboratory instrumentation required relative to PCR . A partial list of other isothermal amplification techniques include LAMP , NASBA , helicase-dependent amplification (HDA), and nicking enzyme amplification reaction (NEAR). The techniques differ in the specifics of primer design and reaction mechanism, and in some cases (like RPA) make use of cocktails of two or more enzymes. Like RPA, many of these techniques offer rapid amplification times with the potential for simplified instrumentation, and reported resistance to substances in unpurified samples that are known to inhibit PCR. With respect to amplification time, modern thermocyclers with rapid temperature ramps can reduce PCR amplification times to less than 30 minutes, particularly for short amplicons using dual-temperature cycling rather than the conventional three-temperature protocols. In addition, the demands of sample prep (including lysis and extraction of DNA or RNA, if necessary) should be considered as part of the overall time and complexity inherent to the technique. These requirements vary according to the technique as well as to the specific target and sample type. Compared to PCR, the guidelines for primer and probe design for RPA are less established, and may take a certain degree of trial and error, although recent results indicate that standard PCR primers can work as well. The general principle of a discrete amplicon bounded by a forward and reverse primer with an (optional) internal fluorogenic probe is similar to PCR. PCR primers may be used directly in RPA, but their short length means that recombination rates are low and RPA will not be especially sensitive or fast. Typically 30–38 base primers are needed for efficient recombinase filament formation and RPA performance. This is in contrast to some other techniques such as LAMP which use a larger number of primers subject to additional design constraints. Although the original 2006 report of RPA describes a functional set of reaction components, the current (proprietary) formulation of the TwistAmp kit is "substantially different" and is available only from the TwistDx supplier. This is in comparison to reaction mixtures for PCR which are available from many suppliers, or LAMP or NASBA for which the composition of the reaction mixture is freely published, allowing researchers to create their own customized "kits" from inexpensive ingredients. Published scientific literature generally lacks detailed comparison of the performance of isothermal amplification techniques such as RPA, HDA, and LAMP relative to each other, often rather comparing a single isothermal technique to a "gold standard" PCR assay. This makes it difficult to judge the merits of these techniques independently from the claims of the manufacturers, inventors, or proponents. Furthermore, performance characteristics of any amplification technique are difficult to decouple from primer design: a "good" primer set for one target for RPA may give faster amplification or more sensitive detection than a "poor" LAMP primer set for the same target, but the converse may be true for different primer sets for a different target. An exception is a recent study comparing RT-qPCR, RT-LAMP, and RPA for detection of Schmallenberg virus and bovine viral diarrhea virus, which effectively makes the point that each amplification technique has strengths and weaknesses, which may vary by the target, and that the properties of the available amplification techniques need to be evaluated in combination with the requirements for each application. As with PCR and any other amplification technique, there is obviously a publication bias, with poorly performing primer sets rarely deemed worthy of reporting.

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Tick-borne encephalitis

Tick-borne encephalitis ( TBE ) is a viral infectious disease involving the central nervous system . The disease most often manifests as meningitis , encephalitis or meningoencephalitis . Myelitis and spinal paralysis also occurs. In about one third of cases sequelae , predominantly cognitive dysfunction, persist for a year or more. The number of reported cases has been increasing in most countries. TBE is posing a concerning health challenge to Europe, as the number of reported human cases of TBE in all endemic regions of Europe have increased by almost 400% within the last three decades. The tick-borne encephalitis virus is known to infect a range of hosts including ruminants , birds , rodents , carnivores, horses , and humans. The disease can also be spread from animals to humans , with ruminants and dogs providing the principal source of infection for humans. The disease is most often biphasic . After an incubation period of approximately one week (range: 4–28 days) from exposure (tick bite) non-specific symptoms occurs. These symptoms are fever, malaise, headache, nausea, vomiting and myalgias that persist for about 5 days. Then, after approximately one week without symptoms, some of the infected develop neurological symptoms, i.e. meningitis, encephalitis or meningoencephalitis. Myelitis also occurs with or without encephalitis. Sequelae persist for a year or more in approximately one third of people who develop neurological disease. Most common long-term symptoms are headache, concentration difficulties, memory impairment and other symptoms of cognitive dysfunction. Mortality depends on the subtype of the virus. For the European subtype mortality rates are 0.5% to 2% for people who develop neurological disease. In dogs, the disease also manifests as a neurological disorder with signs varying from tremors to seizures and death. In ruminants, neurological disease is also present, and animals may refuse to eat, appear lethargic, and also develop respiratory signs. TBE is caused by tick-borne encephalitis virus , a member of the genus Flavivirus in the family Flaviviridae . It was first isolated in 1937. Three virus sub-types also exist: The former Soviet Union conducted research on tick-borne diseases, including the TBE viruses. It is transmitted by the bite of several species of infected woodland ticks , including Ixodes scapularis , I. ricinus and I. persulcatus , or (rarely) through the non-pasteurized milk of infected cows. Infection acquired through goat milk consumed as raw milk or fresh cheese (Frischkäse) has been documented in 2016 and 2017 in the German state of Baden-Württemberg . None of the infected had neurological disease. It is transmitted by the bite of several species of infected woodland ticks , including Ixodes scapularis , I. ricinus and I. persulcatus , or (rarely) through the non-pasteurized milk of infected cows. Infection acquired through goat milk consumed as raw milk or fresh cheese (Frischkäse) has been documented in 2016 and 2017 in the German state of Baden-Württemberg . None of the infected had neurological disease. Detection of specific IgM and IgG antibodies in patients' sera combined with typical clinical signs, is the principal method for diagnosis. In more complicated situations, e.g. after vaccination, testing for presence of antibodies in cerebrospinal fluid may be necessary. It has been stated that lumbar puncture always should be performed when diagnosing TBE and that pleocytosis in cerebrospinal fluid should be added to the diagnostic criteria. PCR ( polymerase chain reaction ) method is rarely used, since TBE virus RNA is most often not present in patient sera or cerebrospinal fluid at the time of neurological symptoms. Prevention includes non-specific (tick-bite prevention) and specific prophylaxis in the form of a vaccination . Tick checks, while useful for preventing some other tick-borne diseases such as Lyme borreliosis , would not be expected to be effective in the prevention of tick-borne encephalitis as the virus is transmitted within minutes of attachment by the tick. Tick-borne encephalitis vaccines are very effective and available in many disease endemic areas and in travel clinics. Trade names are Encepur N and FSME-Immun CC . There is no specific antiviral treatment for TBE. Symptomatic brain damage requires hospitalization and supportive care based on syndrome severity. Anti-inflammatory drugs , such as corticosteroids , may be considered under specific circumstances for symptomatic relief. Tracheal intubation and respiratory support may be necessary.As of 2011, the disease was most common in Central and Eastern Europe, and Northern Asia. About ten to twelve thousand cases are documented a year but the rates vary widely from one region to another. Most of the variation has been the result of variation in host population, particularly that of deer. In Austria, an extensive vaccination program since the 1970s reduced the incidence in 2013 by roughly 85%. In Germany, during the 2010s, there have been a minimum of 95 (2012) and a maximum of 584 cases (2018) of TBE (or FSME as it is known in German). More than half of the reported cases from 2019 had meningitis , encephalitis or myelitis . The risk of infection was noted to be increasing with age, especially in people older than 40 years and it was greater in men than women. Most cases were acquired in Bavaria (46%) and Baden-Württemberg (37%), much less in Saxony, Hesse, Lower Saxony and other states. Altogether 164 Landkreise are designated TBE-risk areas, including all of Baden-Württemberg except for the city of Heilbronn. In Sweden, most cases of TBE occur in a band running from Stockholm to the west, especially around lakes and the nearby region of the Baltic sea. It reflects the greater population involved in outdoor activities in these areas. Overall, for Europe, the estimated risk is roughly 1 case per 10,000 human-months of woodland activity. Although in some regions of Russia and Slovenia, the prevalence of cases can be as high as 70 cases per 100,000 people per year. Travelers to endemic regions do not often become cases, with only 8 cases reported among U.S. travelers returning from Eurasia between 2000 and 2017, a rate so low that as of 2020 the U.S. Centers for Disease Control and Prevention recommended vaccination only for those who will be extensively exposed in high risk areas.

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Phenuiviridae

Phenuiviridae is a family of negative-strand RNA viruses in the order Bunyavirales . Ruminants , camels , humans, and mosquitoes serve as natural hosts. Member genus Phlebovirus is the only genus of the family that has viruses that cause disease in humans (e.g. Rift Valley fever virus) except Dabie bandavirus . Members of Phenuiviridae are enveloped viruses with helical capsid morphology. Envelope glycoproteins of these viruses are distributed with icosahedral symmetry (T=12). Phenuiviridae is a negative-sense single-stranded RNA virus family. Its genome is segmented into three pieces: L segment (encoding RNA-dependent RNA polymerase), M segment, and S segment. Some members of the family have ambisense gene encoding on the S segment ( nucleocapsid proteins ). The M segment includes envelope glycoproteins encoded in a polyprotein that is cleaved by host proteases . Multiple different proteins can be encoded on the M segment due to leaky scanning by the ribosome . RNA transcripts are capped through cap snatching , but not polyadenylated . Translation is terminated by a hairpin sequence at the end of each RNA transcript. Members of Phenuiviridae are enveloped viruses with helical capsid morphology. Envelope glycoproteins of these viruses are distributed with icosahedral symmetry (T=12). Phenuiviridae is a negative-sense single-stranded RNA virus family. Its genome is segmented into three pieces: L segment (encoding RNA-dependent RNA polymerase), M segment, and S segment. Some members of the family have ambisense gene encoding on the S segment ( nucleocapsid proteins ). The M segment includes envelope glycoproteins encoded in a polyprotein that is cleaved by host proteases . Multiple different proteins can be encoded on the M segment due to leaky scanning by the ribosome . RNA transcripts are capped through cap snatching , but not polyadenylated . Translation is terminated by a hairpin sequence at the end of each RNA transcript. The following genera are recognized:

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Biological agent

Biological weapons are pathogens used as weapons. In addition to these living or replicating pathogens , toxins and biotoxins are also included among the bio-agents. More than 1,200 different kinds of potentially weaponizable bio-agents have been described and studied to date. Some biological agents have the ability to adversely affect human health in a variety of ways, ranging from relatively mild allergic reactions to serious medical conditions, including serious injury, as well as serious or permanent disability or even death . Many of these organisms are ubiquitous in the natural environment where they are found in water, soil, plants, or animals. Bio-agents may be amenable to "weaponization" to render them easier to deploy or disseminate. Genetic modification may enhance their incapacitating or lethal properties, or render them impervious to conventional treatments or preventives. Since many bio-agents reproduce rapidly and require minimal resources for propagation, they are also a potential danger in a wide variety of occupational settings. The 1972 Biological Weapons Convention (BWC) is an international treaty banning the development, use or stockpiling of biological weapons; as of March 2021, there were 183 States Parties to the BWC. Bio-agents are, however, widely studied for both defensive and medical research purposes under various biosafety levels and within biocontainment facilities throughout the world.The former US biological warfare program (1943–1969) categorized its weaponized anti-personnel bio-agents as either "lethal agents" ( Bacillus anthracis , Francisella tularensis , Botulinum toxin ) or "incapacitating agents" ( Brucella suis , Coxiella burnetii , Venezuelan equine encephalitis virus , staphylococcal enterotoxin B ). Since 1997, United States law has declared a list of bio-agents designated by the U.S. Department of Health and Human Services or the U.S. Department of Agriculture that have the "potential to pose a severe threat to public health and safety" to be officially defined as " select agents " and possession or transportation of them are tightly controlled as such. Select agents are divided into "HHS select agents and toxins", "USDA select agents and toxins" and "Overlap select agents and toxins". The U.S. Centers for Disease Control and Prevention (CDC) breaks biological agents into three categories: Category A, Category B, and Category C . Category A agents pose the greatest threat to the U.S. criteria for being a Category "A" agent include high rates of morbidity and mortality; ease of dissemination and communicability; ability to cause a public panic; and special action required by public health officials to respond. Category A agents include anthrax , botulism , plague , smallpox , and viral hemorrhagic fevers.The former US biological warfare program (1943–1969) categorized its weaponized anti-personnel bio-agents as either "lethal agents" ( Bacillus anthracis , Francisella tularensis , Botulinum toxin ) or "incapacitating agents" ( Brucella suis , Coxiella burnetii , Venezuelan equine encephalitis virus , staphylococcal enterotoxin B ). Since 1997, United States law has declared a list of bio-agents designated by the U.S. Department of Health and Human Services or the U.S. Department of Agriculture that have the "potential to pose a severe threat to public health and safety" to be officially defined as " select agents " and possession or transportation of them are tightly controlled as such. Select agents are divided into "HHS select agents and toxins", "USDA select agents and toxins" and "Overlap select agents and toxins".The U.S. Centers for Disease Control and Prevention (CDC) breaks biological agents into three categories: Category A, Category B, and Category C . Category A agents pose the greatest threat to the U.S. criteria for being a Category "A" agent include high rates of morbidity and mortality; ease of dissemination and communicability; ability to cause a public panic; and special action required by public health officials to respond. Category A agents include anthrax , botulism , plague , smallpox , and viral hemorrhagic fevers.Simulants are organisms or substances which mimic physical or biological properties of real biological agents, without being pathogenic. They are used to study the efficiency of various dissemination techniques or the risks caused by the use of biological agents in bioterrorism . To simulate dispersal, attachment or the penetration depth in human or animal lungs, simulants must have particle sizes, specific weight and surface properties, similar to the simulated biological agent. The typical size of simulants (1–5 µm) enables it to enter buildings with closed windows and doors and penetrate deep into the lungs. This bears a significant health risk, even if the biological agent is normally not pathogenic.Simulants are organisms or substances which mimic physical or biological properties of real biological agents, without being pathogenic. They are used to study the efficiency of various dissemination techniques or the risks caused by the use of biological agents in bioterrorism . To simulate dispersal, attachment or the penetration depth in human or animal lungs, simulants must have particle sizes, specific weight and surface properties, similar to the simulated biological agent. The typical size of simulants (1–5 µm) enables it to enter buildings with closed windows and doors and penetrate deep into the lungs. This bears a significant health risk, even if the biological agent is normally not pathogenic.While the history of biological weapons use goes back more than six centuries to the siege of Caffa in 1346, international restrictions on biological weapons began only with the 1925 Geneva Protocol , which prohibits the use but not the possession or development of chemical and biological weapons in international armed conflicts. Upon ratification of the Geneva Protocol, several countries made reservations regarding its applicability and use in retaliation. Due to these reservations, it was in practice a " no-first-use " agreement only. The 1972 Biological Weapons Convention (BWC) supplements the Geneva Protocol by prohibiting the development, production, acquisition, transfer, stockpiling and use of biological weapons. Having entered into force on 26 March 1975, the BWC was the first multilateral disarmament treaty to ban the production of an entire category of weapons of mass destruction. As of March 2021, 183 states have become party to the treaty . The BWC is considered to have established a strong global norm against biological weapons, which is reflected in the treaty's preamble, stating that the use of biological weapons would be "repugnant to the conscience of mankind". However, the BWC's effectiveness has been limited due to insufficient institutional support and the absence of any formal verification regime to monitor compliance. In 1985, the Australia Group was established, a multilateral export control regime of 43 countries aiming to prevent the proliferation of chemical and biological weapons. In 2004, the United Nations Security Council passed Resolution 1540 , which obligates all UN Member States to develop and enforce appropriate legal and regulatory measures against the proliferation of chemical , biological, radiological , and nuclear weapons and their means of delivery, in particular, to prevent the spread of weapons of mass destruction to non-state actors .

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C. J. Peters

Clarence James Peters, Jr (born September 23, 1940, Midland, Texas ) is a physician , field virologist and former U.S. Army colonel . He is noted for his efforts in trying to stem epidemics of exotic infectious diseases such as the Ebola virus , Hanta virus and Rift Valley fever (RVF). He is an eminent authority on the virology, pathogenesis and epidemiology of hemorrhagic fever viruses .Peters grew up in Odessa, Texas . At Rice University , he initially majored in chemical engineering , but switched to chemistry his junior year after taking courses with Thomas Brackett . He obtained his medical degree at Johns Hopkins School of Medicine and served his residency in internal medicine at the University of Texas Southwestern Medical School . He developed an interest in tropical medicine and virology while serving five years as a research associate at the National Institute of Allergy and Infectious Disease intramural laboratory in Panama . Upon returning Stateside, he completed his fellowship in immunology at the Scripps Clinic and Research Foundation . He entered active duty in the U.S. Army and from 1977 through 1992 held several positions at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick , Maryland , where he worked on biodefense and hazardous virus research. His positions there ranged from research scientist and Medical Division chief to Disease Assessment Division chief. He led the team that controlled a 1989 Ebola introduction into a monkey facility in Reston, Virginia (a story recounted in Richard Preston 's best-selling 1994 book The Hot Zone ). From 1992 to 2000 Peters was head of the Special Pathogens Branch at the Centers for Disease Control where he investigated hazardous emerging viruses. These included the agent causing the new disease hantavirus pulmonary syndrome in the southwestern US, which he discovered and named. He also led efforts in Africa (Ebola, Marburg , Lassa , Rift Valley fever ), Asia ( Nipah virus in Malaysia ), and South America ( Bolivian hemorrhagic fever , hantavirus pulmonary syndrome, Venezuelan equine encephalitis ) to control outbreaks. Since 2000, Peters has been the John Sealy Distinguished University Professor of Tropical and Emerging Virology at the University of Texas Medical Branch (UTMB) at Galveston, where he has an active research program in SARS , Rift Valley fever , and other human pathogens. He is a professor in the department of pathology and in the department of microbiology and immunology. He is a member of the World Health Organization Collaborating Center for Tropical Diseases. He is also director for biodefense at the UTMB Center for Biodefense and Emerging Infectious Diseases. Peters has published more than 300 papers on research and control of viral diseases including more than 70 publications on Rift Valley fever virus and more than 60 publications on arenaviruses . He has served on numerous committees dealing with disease problems worldwide and has been called back as a consultant to CDC and USAMRIID on influenza, vaccines, and other issues after his departure. He consulted with Taiwan on SARS control.Most of Peters' current work in the laboratory deals with Bunyaviridae (including the phylogeny of phleboviruses such as Rift Valley fever (RVF), Arenaviridae (Lassa fever, South American hemorrhagic fevers) and SARS CoV. He runs an active program of human and animal vaccine development for RVF using reverse genetics . He and his colleague Ilya Frolov are developing alphavirus replicon vectored RVF vaccines for use in livestock and ultimately in humans. His arenavirus research concentrates on the effects of infection on cellular function, particularly those molecular interactions related to vascular permeability. SARS-CoV work includes antiviral drug development, model characterization, and interferon interactions. The Galveston National Laboratory , a Biosafety Level 4 laboratory, opened in 2008 at the University of Texas Medical Branch to allow scientists there to work safely with any pathologic agent. Peters expects to transition some projects to higher hazard viral hemorrhagic fevers and to develop projects on other viruses such as tick-borne flaviviruses , highly virulent avian influenza strains, and Nipah virus, a new, highly virulent paramyxovirus .

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Mosquito control

Mosquito control manages the population of mosquitoes to reduce their damage to human health, economies, and enjoyment. Mosquito control is a vital public-health practice throughout the world and especially in the tropics because mosquitoes spread many diseases, such as malaria and the Zika virus . Mosquito-control operations are targeted to multiple problems: Disease organisms transmitted by mosquitoes include West Nile virus , Saint Louis encephalitis virus , Eastern equine encephalomyelitis virus , Everglades virus , Highlands J virus , La Crosse Encephalitis virus in the United States; dengue fever , yellow fever , Ilheus virus, malaria , Zika virus and filariasis in the American tropics ; Rift Valley fever , Wuchereria bancrofti , Japanese encephalitis , chikungunya and filariasis in Africa and Asia; and Murray Valley encephalitis in Australia. Vertical transmission from adult mosquitos to larvae is possible. Depending on the situation, source reduction, biocontrol, larviciding (killing of larvae ), or adulticiding (killing of adults) may be used to manage mosquito populations. These techniques are accomplished using habitat modification, pesticide , biological-control agents, and trapping. The advantage of non-toxic methods of control is they can be used in Conservation Areas . Integrated pest management (IPM) is the use of the most environmentally appropriate method or combination of methods to control pest populations. Typical mosquito-control programs using IPM first conduct surveys, in order to determine the species composition , relative abundance and seasonal distribution of adult and larval mosquitoes, and only then is a control strategy defined.Adult mosquito populations may be monitored by landing rate counts, mechanical traps or by, lidar technology For landing rate counts, an inspector visits a set number of sites every day, counting the number of adult female mosquitoes that land on a part of the body, such as an arm or both legs, within a given time interval. Mechanical traps use a fan to blow adult mosquitoes into a collection bag that is taken back to the laboratory for analysis of catch. The mechanical traps use visual cues (light, black/white contrasts) or chemical attractants that are normally given off by mosquito hosts (e.g., carbon dioxide , ammonia , lactic acid , octenol ) to attract adult female mosquitoes. These cues are often used in combination. Entomology lidar detection has the possibility of showing the difference between male and female mosquitoes. Monitoring larval mosquito populations involves collecting larvae from standing water with a dipper or a turkey baster . The habitat, approximate total number of larvae and pupae , and species are noted for each collection. An alternative method works by providing artificial breeding spots ( ovitraps ) and collecting and counting the developing larvae at fixed intervals. Monitoring these mosquito populations is crucial to see what species are present, if mosquito numbers are rising or falling, and detecting any diseases they carry. Mosquito Alert is a cooperative citizen science project, currently run as a non-profit and coordinated by four public research centers in Spain. The aim of the project is to study, monitor, and fight the spread of invasive mosquitos. The project provided the first detection of the Asian bush mosquito Aedes japonicus in Spain in 2018, providing the first report of a population of mosquitos that were located 1,300 km from their previously nearest known location in Europe. Mechanical control is the management and control using physical means. Since many mosquitoes breed in standing water , source reduction can be as simple as emptying water from containers around the home. This is something that homeowners can accomplish. Mosquito breeding grounds can be eliminated at home by removing unused plastic pools , old tires , or buckets ; by clearing clogged gutters and repairing leaks around faucets ; by regularly (at most every 4 days) changing water in bird baths ; and by filling or draining puddles, swampy areas, and tree stumps. Eliminating such mosquito breeding areas can be an extremely effective and permanent way to reduce mosquito populations without resorting to insecticides. However, this may not be possible in parts of the developing world where water cannot be readily replaced due to irregular water supply. Many individuals also believe mosquito control is the government's responsibility, so if these methods are not done regularly by homeowners then the effectiveness is reduced. Open water marsh management (OWMM) involves the use of shallow ditches, to create a network of water flow within marshes and to connect the marsh to a pond or canal. The network of ditches drains the mosquito habitat and lets in fish which will feed on mosquito larvae. This reduces the need for other control methods such as pesticides . Simply giving the predators access to the mosquito larvae can result in long-term mosquito control. Open-water marsh management is used on both the eastern and western coasts of the United States. [ citation needed ] Rotational impoundment management (RIM) involves the use of large pumps and culverts with gates to control the water level within an impounded marsh. RIM allows mosquito control to occur while still permitting the marsh to function in a state as close to its natural condition as possible. Water is pumped into the marsh in the late spring and summer to prevent the female mosquito from laying her eggs on the soil. The marsh is allowed to drain in the fall, winter, and early spring. Gates in the culverts are used to permit fish, crustaceans, and other marsh organisms to enter and exit the marsh. RIM allows the mosquito-control goals to be met while at the same time reducing the need for pesticide use within the marsh. Rotational impoundment management is used to a great extent on the east coast of Florida. A 2019 study also explored the idea of using unmanned aerial vehicles as a valid strategy to identify and prioritize water bodies where disease vectors such as Ny . darlingi are most likely to breed. An oil drip can or oil drip barrel was a common and nontoxic anti-mosquito measure. The thin layer of oil on top of the water prevents mosquito breeding in two ways: mosquito larvae in the water cannot penetrate the oil film with their breathing tube, and so drown and die; also adult mosquitoes do not lay eggs on the oiled water. A traditional approach to controlling mosquito populations is the use of ovitraps or lethal ovitraps , which provide artificial breeding spots for mosquitoes to lay their eggs. While ovitraps only trap eggs, lethal ovitraps usually contain a chemical inside the trap that is used to kill the adult mosquito and/or the larvae in the trap. Studies have shown that with enough of these lethal ovitraps, Aedes mosquito populations can be controlled. A recent approach is the automatic lethal ovitrap, which works like a traditional ovitrap but automates all steps needed to provide the breeding spots and to destroy the developing larvae. In 2016 researchers from Laurentian University released a design for a low cost trap called an Ovillanta which consists of attractant-laced water in a section of discarded rubber tire. At regular intervals the water is run through a filter to remove any deposited eggs and larva. The water, which then contains an 'oviposition' pheromone deposited during egg-laying, is reused to attract more mosquitoes. Two studies have shown that this type of trap can attract about seven times as many mosquito eggs as a conventional ovitrap. Some newer mosquito traps or known mosquito attractants emit a plume of carbon dioxide together with other mosquito attractants such as sugary scents, lactic acid , octenol , warmth, water vapor and sounds. By mimicking a mammal's scent and outputs, the trap draws female mosquitoes toward it, where they are typically sucked into a net or holder by an electric fan where they are collected. According to the American Mosquito Control Association, the trap will kill some mosquitoes, but their effectiveness in any particular case will depend on a number of factors such as the size and species of the mosquito population and the type and location of the breeding habitat. They are useful in specimen collection studies to determine the types of mosquitoes prevalent in an area but are typically far too inefficient to be useful in reducing mosquito populations. This is a process of achieving sustainable mosquito control in an eco friendly manner by providing artificial breeding grounds with an ovitrap or an ovillanta utilizing common household utensils and destroying larvae by non-hazardous natural means such as throwing them in dry places or feeding them to larvae eating fishes like Gambusia affinis , or suffocating them by spreading a thin plastic sheet over the entire water surface to block atmospheric air. Shifting the water with larvae to another vessel and pouring a few drops of kerosene oil or insecticide/larvicide in it is another option for killing wrigglers, but not preferred due to its environmental impact . Most of the ornamental fishes eat mosquito larvae. [ citation needed ]Since many mosquitoes breed in standing water , source reduction can be as simple as emptying water from containers around the home. This is something that homeowners can accomplish. Mosquito breeding grounds can be eliminated at home by removing unused plastic pools , old tires , or buckets ; by clearing clogged gutters and repairing leaks around faucets ; by regularly (at most every 4 days) changing water in bird baths ; and by filling or draining puddles, swampy areas, and tree stumps. Eliminating such mosquito breeding areas can be an extremely effective and permanent way to reduce mosquito populations without resorting to insecticides. However, this may not be possible in parts of the developing world where water cannot be readily replaced due to irregular water supply. Many individuals also believe mosquito control is the government's responsibility, so if these methods are not done regularly by homeowners then the effectiveness is reduced. Open water marsh management (OWMM) involves the use of shallow ditches, to create a network of water flow within marshes and to connect the marsh to a pond or canal. The network of ditches drains the mosquito habitat and lets in fish which will feed on mosquito larvae. This reduces the need for other control methods such as pesticides . Simply giving the predators access to the mosquito larvae can result in long-term mosquito control. Open-water marsh management is used on both the eastern and western coasts of the United States. [ citation needed ] Rotational impoundment management (RIM) involves the use of large pumps and culverts with gates to control the water level within an impounded marsh. RIM allows mosquito control to occur while still permitting the marsh to function in a state as close to its natural condition as possible. Water is pumped into the marsh in the late spring and summer to prevent the female mosquito from laying her eggs on the soil. The marsh is allowed to drain in the fall, winter, and early spring. Gates in the culverts are used to permit fish, crustaceans, and other marsh organisms to enter and exit the marsh. RIM allows the mosquito-control goals to be met while at the same time reducing the need for pesticide use within the marsh. Rotational impoundment management is used to a great extent on the east coast of Florida. A 2019 study also explored the idea of using unmanned aerial vehicles as a valid strategy to identify and prioritize water bodies where disease vectors such as Ny . darlingi are most likely to breed. An oil drip can or oil drip barrel was a common and nontoxic anti-mosquito measure. The thin layer of oil on top of the water prevents mosquito breeding in two ways: mosquito larvae in the water cannot penetrate the oil film with their breathing tube, and so drown and die; also adult mosquitoes do not lay eggs on the oiled water. A traditional approach to controlling mosquito populations is the use of ovitraps or lethal ovitraps , which provide artificial breeding spots for mosquitoes to lay their eggs. While ovitraps only trap eggs, lethal ovitraps usually contain a chemical inside the trap that is used to kill the adult mosquito and/or the larvae in the trap. Studies have shown that with enough of these lethal ovitraps, Aedes mosquito populations can be controlled. A recent approach is the automatic lethal ovitrap, which works like a traditional ovitrap but automates all steps needed to provide the breeding spots and to destroy the developing larvae. In 2016 researchers from Laurentian University released a design for a low cost trap called an Ovillanta which consists of attractant-laced water in a section of discarded rubber tire. At regular intervals the water is run through a filter to remove any deposited eggs and larva. The water, which then contains an 'oviposition' pheromone deposited during egg-laying, is reused to attract more mosquitoes. Two studies have shown that this type of trap can attract about seven times as many mosquito eggs as a conventional ovitrap. Some newer mosquito traps or known mosquito attractants emit a plume of carbon dioxide together with other mosquito attractants such as sugary scents, lactic acid , octenol , warmth, water vapor and sounds. By mimicking a mammal's scent and outputs, the trap draws female mosquitoes toward it, where they are typically sucked into a net or holder by an electric fan where they are collected. According to the American Mosquito Control Association, the trap will kill some mosquitoes, but their effectiveness in any particular case will depend on a number of factors such as the size and species of the mosquito population and the type and location of the breeding habitat. They are useful in specimen collection studies to determine the types of mosquitoes prevalent in an area but are typically far too inefficient to be useful in reducing mosquito populations.This is a process of achieving sustainable mosquito control in an eco friendly manner by providing artificial breeding grounds with an ovitrap or an ovillanta utilizing common household utensils and destroying larvae by non-hazardous natural means such as throwing them in dry places or feeding them to larvae eating fishes like Gambusia affinis , or suffocating them by spreading a thin plastic sheet over the entire water surface to block atmospheric air. Shifting the water with larvae to another vessel and pouring a few drops of kerosene oil or insecticide/larvicide in it is another option for killing wrigglers, but not preferred due to its environmental impact . Most of the ornamental fishes eat mosquito larvae. [ citation needed ]Chemical control is the management and control using chemical means. Control of larvae can be accomplished through use of contact poisons, growth regulators, surface films, stomach poisons (including bacterial agents), and biological agents such as fungi, nematodes, copepods, and fish. A chemical commonly used in the United States is methoprene , considered slightly toxic to larger animals, which mimics and interferes with natural growth hormones in mosquito larvae, preventing development. Methoprene is frequently distributed in time-release briquette form in breeding areas. Another chemical is Temefos or temephos , a sand granular insecticide is used to treat water infected with disease carrying insects. It is believed by some researchers that the larvae of Anopheles gambiae (important vectors of malaria) can survive for several days on moist mud, and that treatments should therefore include mud and soil several meters from puddles. Control of adult mosquitoes is the most familiar aspect of mosquito control to most of the public. It is accomplished by ground-based applications or via aerial application of residual chemical insecticides such as Duet . Generally modern mosquito-control programs in developed countries use low-volume applications of insecticides, although some programs may still use thermal fogging. Beside fogging there are some other insect repellents for indoors and outdoors. An example of a synthetic insect repellent is DEET . A naturally occurring repellent is citronella . Indoor Residual Spraying ( IRS ) is another method of adulticide. Walls of properties are sprayed with an insecticide, the mosquitoes die when they land on the surface covered in insecticide. To control adult mosquitoes in India, van mounted fogging machines and hand fogging machines are used. DDT was formerly used throughout the world for large area mosquito control, but it is now banned in most developed countries. Controversially, DDT remains in common use in many developing countries (14 countries were reported to be using it in 2009 ), which claim that the public-health cost of switching to other control methods would exceed the harm caused by using DDT. It is sometimes approved for use only in specific, limited circumstances where it is most effective, such as application to walls. [ citation needed ] The role of DDT in combating mosquitoes has been the subject of considerable controversy. Although DDT has been proven to affect biodiversity and cause eggshell thinning in birds such as the bald eagle, some say that DDT is the most effective weapon in combating mosquitoes, and hence malaria. While some of this disagreement is based on differences in the extent to which disease control is valued as opposed to the value of biodiversity, [ citation needed ] there is also genuine disagreement amongst experts about the costs and benefits of using DDT. [ dubious – discuss ] Notwithstanding, DDT-resistant mosquitoes have started to increase in numbers, especially in tropics due to mutations, reducing the effectiveness of this chemical; these mutations can rapidly spread over vast areas if pesticides are applied indiscriminately (Chevillon et al. 1999). In areas where DDT resistance is encountered, malathion , propoxur or lindane is used.Control of larvae can be accomplished through use of contact poisons, growth regulators, surface films, stomach poisons (including bacterial agents), and biological agents such as fungi, nematodes, copepods, and fish. A chemical commonly used in the United States is methoprene , considered slightly toxic to larger animals, which mimics and interferes with natural growth hormones in mosquito larvae, preventing development. Methoprene is frequently distributed in time-release briquette form in breeding areas. Another chemical is Temefos or temephos , a sand granular insecticide is used to treat water infected with disease carrying insects. It is believed by some researchers that the larvae of Anopheles gambiae (important vectors of malaria) can survive for several days on moist mud, and that treatments should therefore include mud and soil several meters from puddles. Control of adult mosquitoes is the most familiar aspect of mosquito control to most of the public. It is accomplished by ground-based applications or via aerial application of residual chemical insecticides such as Duet . Generally modern mosquito-control programs in developed countries use low-volume applications of insecticides, although some programs may still use thermal fogging. Beside fogging there are some other insect repellents for indoors and outdoors. An example of a synthetic insect repellent is DEET . A naturally occurring repellent is citronella . Indoor Residual Spraying ( IRS ) is another method of adulticide. Walls of properties are sprayed with an insecticide, the mosquitoes die when they land on the surface covered in insecticide. To control adult mosquitoes in India, van mounted fogging machines and hand fogging machines are used. DDT was formerly used throughout the world for large area mosquito control, but it is now banned in most developed countries. Controversially, DDT remains in common use in many developing countries (14 countries were reported to be using it in 2009 ), which claim that the public-health cost of switching to other control methods would exceed the harm caused by using DDT. It is sometimes approved for use only in specific, limited circumstances where it is most effective, such as application to walls. [ citation needed ] The role of DDT in combating mosquitoes has been the subject of considerable controversy. Although DDT has been proven to affect biodiversity and cause eggshell thinning in birds such as the bald eagle, some say that DDT is the most effective weapon in combating mosquitoes, and hence malaria. While some of this disagreement is based on differences in the extent to which disease control is valued as opposed to the value of biodiversity, [ citation needed ] there is also genuine disagreement amongst experts about the costs and benefits of using DDT. [ dubious – discuss ] Notwithstanding, DDT-resistant mosquitoes have started to increase in numbers, especially in tropics due to mutations, reducing the effectiveness of this chemical; these mutations can rapidly spread over vast areas if pesticides are applied indiscriminately (Chevillon et al. 1999). In areas where DDT resistance is encountered, malathion , propoxur or lindane is used.Biological control is the management and control using biological means. Biological pest control , or "biocontrol", is the use of the natural enemies of pests like mosquitoes to manage the pest's populations. There are several types of biocontrol, including the direct introduction of parasites, pathogens, and predators to target mosquitoes. Effective biocontrol agents include predatory fish that feed on mosquito larvae such as mosquitofish ( Gambusia affinis ) and some cyprinids (carps and minnows) and killifish . Tilapia also consume mosquito larvae. Direct introduction of tilapia and mosquitofish into ecosystems around the world have had disastrous consequences. However, utilizing a controlled system via aquaponics provides the mosquito control without the adverse effects to the ecosystem. Other predators include dragonfly (fly) naiads , which consume mosquito larvae in the breeding waters, adult dragonflies , which eat adult mosquitoes, and some species of lizard and gecko . Biocontrol agents that have had lesser degrees of success include the predator mosquito Toxorhynchites and predator crustaceans — Mesocyclops copepods , nematodes and fungi . Predators such as birds, bats, lizards, and frogs have been used, but their effectiveness is only anecdotal. Instead of chemical insecticides, some researchers are studying biocides. Like all animals, mosquitoes are subject to disease. Invertebrate pathologists study these diseases in the hope that some of them can be utilized for mosquito management. Microbial pathogens of mosquitoes include viruses, bacteria, fungi, protozoa, nematodes and microsporidia. [ page needed ] Most notably, scientists in Burkina Faso were studying the Metarhizium fungal species. This fungus in a high concentration can slowly kill mosquitoes. To increase the lethality of the fungus, a gene from a spider was inserted into the fungus causing it to produce a neurotoxin . But it is only activated when in mosquito hemolymph. Research was done to show the fungi would not affect other insects or humans. Two other species of fungi that can kill adult mosquitoes are Metarhizium anisopliae and Beauveria bassiana . Dead spores of the soil bacterium Bacillus thuringiensis , especially Bt israelensis (BTI) interfere with dipteran larval digestive systems. It can be dispersed by hand or dropped by helicopter in large areas. BTI loses effectiveness after the larvae turn into pupae, because they stop eating. [ citation needed ] BTI was reported to be widely applied in West Africa with limited adverse effects, and may pose lesser risk than chemical pesticides. In the Wolbachia method, both male and female mosquitos that carry the Wolbachia bacterium are released into natural populations. Wolbachia boosts the natural immune response of the mosquito so that it does not easily get infected and become a host vector for mosquito-borne diseases. Therefore it is unable to easily transmit those viruses to people. This is known as replacement strategy as it aims to replace the natural population with Wolbachia -carrying ones. Since 2011, the World Mosquito Program has conducted several trials and projects, in 14 countries across Asia, Latin America and Oceania. This approach also uses Wolbachia but involves the release of only male mosquitos that carry the Wolbachia bacterium. When these male mosquitos mate with wild female mosquitos, her eggs do not hatch due to lack of biocompatibility. Wolbachia is not endemic to wild mosquito populations although it is endemic in 50% of all insect species. This is known as suppression strategy as it aims to suppress the natural reproduction cycle. Wolbachia-Aedes suppression has been piloted in various countries such as Myanmar (1967), French Polynesia (2009, 2012), USA (2014-2016, 2018), Thailand (2016), Australia (2017), Singapore (since 2016) and Puerto Rico (2020). Maui and Kuai, Hawaii - A series of IIT projects were planned to protect endangered bird species from avian malaria . The projects involve the release of large numbers of male mosquitos infected with a strain of Wolbachia that is incompatible with the strain carried by resident females. These mosquitos would not be irradiated or subject to genetic modification. Introducing large numbers of sterile males is another approach to reducing mosquito numbers. This is called Sterile Insect Technique (SIT). Radiation is used to disrupt DNA in the mosquitoes and randomly create mutations. Males with mutations that disrupt their fertility are selected and released in mass into the wild population. These sterile males mate with wild type females and no offspring is produced, reducing the population size. Guangzhou, China - A combination of SIT with IIT, were used in a mosquito control program in Guangzhou, China. The pilot trial was carried out with the support of the IAEA in cooperation with the Food and Agriculture Organization of the United Nations (FAO). The pilot demonstrated the successful near-elimination of field populations of the world's most invasive mosquito species, Aedes albopictus (Asian tiger mosquito). The two-year trial (2016–2017) covered a 32.5-hectare area on two relatively isolated islands in the Pearl River in Guangzhou. It involved the release of about 200 million irradiated mass-reared adult male mosquitoes exposed to Wolbachia bacteria. Biological pest control , or "biocontrol", is the use of the natural enemies of pests like mosquitoes to manage the pest's populations. There are several types of biocontrol, including the direct introduction of parasites, pathogens, and predators to target mosquitoes. Effective biocontrol agents include predatory fish that feed on mosquito larvae such as mosquitofish ( Gambusia affinis ) and some cyprinids (carps and minnows) and killifish . Tilapia also consume mosquito larvae. Direct introduction of tilapia and mosquitofish into ecosystems around the world have had disastrous consequences. However, utilizing a controlled system via aquaponics provides the mosquito control without the adverse effects to the ecosystem. Other predators include dragonfly (fly) naiads , which consume mosquito larvae in the breeding waters, adult dragonflies , which eat adult mosquitoes, and some species of lizard and gecko . Biocontrol agents that have had lesser degrees of success include the predator mosquito Toxorhynchites and predator crustaceans — Mesocyclops copepods , nematodes and fungi . Predators such as birds, bats, lizards, and frogs have been used, but their effectiveness is only anecdotal.Instead of chemical insecticides, some researchers are studying biocides. Like all animals, mosquitoes are subject to disease. Invertebrate pathologists study these diseases in the hope that some of them can be utilized for mosquito management. Microbial pathogens of mosquitoes include viruses, bacteria, fungi, protozoa, nematodes and microsporidia. [ page needed ] Most notably, scientists in Burkina Faso were studying the Metarhizium fungal species. This fungus in a high concentration can slowly kill mosquitoes. To increase the lethality of the fungus, a gene from a spider was inserted into the fungus causing it to produce a neurotoxin . But it is only activated when in mosquito hemolymph. Research was done to show the fungi would not affect other insects or humans. Two other species of fungi that can kill adult mosquitoes are Metarhizium anisopliae and Beauveria bassiana . Dead spores of the soil bacterium Bacillus thuringiensis , especially Bt israelensis (BTI) interfere with dipteran larval digestive systems. It can be dispersed by hand or dropped by helicopter in large areas. BTI loses effectiveness after the larvae turn into pupae, because they stop eating. [ citation needed ] BTI was reported to be widely applied in West Africa with limited adverse effects, and may pose lesser risk than chemical pesticides. In the Wolbachia method, both male and female mosquitos that carry the Wolbachia bacterium are released into natural populations. Wolbachia boosts the natural immune response of the mosquito so that it does not easily get infected and become a host vector for mosquito-borne diseases. Therefore it is unable to easily transmit those viruses to people. This is known as replacement strategy as it aims to replace the natural population with Wolbachia -carrying ones. Since 2011, the World Mosquito Program has conducted several trials and projects, in 14 countries across Asia, Latin America and Oceania.This approach also uses Wolbachia but involves the release of only male mosquitos that carry the Wolbachia bacterium. When these male mosquitos mate with wild female mosquitos, her eggs do not hatch due to lack of biocompatibility. Wolbachia is not endemic to wild mosquito populations although it is endemic in 50% of all insect species. This is known as suppression strategy as it aims to suppress the natural reproduction cycle. Wolbachia-Aedes suppression has been piloted in various countries such as Myanmar (1967), French Polynesia (2009, 2012), USA (2014-2016, 2018), Thailand (2016), Australia (2017), Singapore (since 2016) and Puerto Rico (2020). Maui and Kuai, Hawaii - A series of IIT projects were planned to protect endangered bird species from avian malaria . The projects involve the release of large numbers of male mosquitos infected with a strain of Wolbachia that is incompatible with the strain carried by resident females. These mosquitos would not be irradiated or subject to genetic modification. Maui and Kuai, Hawaii - A series of IIT projects were planned to protect endangered bird species from avian malaria . The projects involve the release of large numbers of male mosquitos infected with a strain of Wolbachia that is incompatible with the strain carried by resident females. These mosquitos would not be irradiated or subject to genetic modification. Introducing large numbers of sterile males is another approach to reducing mosquito numbers. This is called Sterile Insect Technique (SIT). Radiation is used to disrupt DNA in the mosquitoes and randomly create mutations. Males with mutations that disrupt their fertility are selected and released in mass into the wild population. These sterile males mate with wild type females and no offspring is produced, reducing the population size. Guangzhou, China - A combination of SIT with IIT, were used in a mosquito control program in Guangzhou, China. The pilot trial was carried out with the support of the IAEA in cooperation with the Food and Agriculture Organization of the United Nations (FAO). The pilot demonstrated the successful near-elimination of field populations of the world's most invasive mosquito species, Aedes albopictus (Asian tiger mosquito). The two-year trial (2016–2017) covered a 32.5-hectare area on two relatively isolated islands in the Pearl River in Guangzhou. It involved the release of about 200 million irradiated mass-reared adult male mosquitoes exposed to Wolbachia bacteria. Guangzhou, China - A combination of SIT with IIT, were used in a mosquito control program in Guangzhou, China. The pilot trial was carried out with the support of the IAEA in cooperation with the Food and Agriculture Organization of the United Nations (FAO). The pilot demonstrated the successful near-elimination of field populations of the world's most invasive mosquito species, Aedes albopictus (Asian tiger mosquito). The two-year trial (2016–2017) covered a 32.5-hectare area on two relatively isolated islands in the Pearl River in Guangzhou. It involved the release of about 200 million irradiated mass-reared adult male mosquitoes exposed to Wolbachia bacteria. These techniques share the characteristic of introducing lethal genes and reducing the size of the mosquito population over time. Another control approach under investigation for Aedes aegypti uses a strain that is genetically modified to require the antibiotic tetracycline to develop beyond the larval stage. Modified males develop normally in a nursery while they are supplied with this chemical and can be released into the wild. However, their subsequent offspring will lack tetracycline in the wild and never mature. Field trials were conducted in the Cayman Islands, Malaysia and Brazil to control the mosquitoes that cause dengue fever. In April 2014, Brazil's National Technical Commission for Biosecurity approved the commercial release of the modified mosquito. The FDA is the lead agency for regulating genetically-engineered mosquitoes in the United States. In 2014 and 2018 research was reported into other genetic methods including cytoplasmic incompatibility, chromosomal translocations, sex distortion and gene replacement. Although several years away from the field trial stage, if successful these other methods have the potential to be cheaper and to eradicate the Aedes aegypti mosquito more efficiently. A pioneering experimental demonstration of the gene drive method eradicated small populations of Anopheles gambiae . In 2020, Oxitec 's non-biting Friendly Aedes aegypti mosquito was approved for release by the US EPA and Florida state authorities. Malaysia - In several experiments, researchers released batches of male adult Aedes mosquitos with genetic modifications to study the effects of dispersal and reproduction in natural populations. Mosquito traps were ultilized for the purpose of these studies. The process allowed for the opportunity to determine which mosquitoes were affected, and provided a group to be re-released with genetic modifications resulting in the OX513A variant to reduce reproduction. Adult mosquitoes are attracted inside the traps where they died of dehydration. Research is being conducted that indicates that dismantling a protein associated with eggshell organization, factor EOF1 (factor 1), which may be unique to mosquitoes, may be a means to hamper their reproduction effectively in the wild without creating a resistant population or affecting other animals. Another control approach under investigation for Aedes aegypti uses a strain that is genetically modified to require the antibiotic tetracycline to develop beyond the larval stage. Modified males develop normally in a nursery while they are supplied with this chemical and can be released into the wild. However, their subsequent offspring will lack tetracycline in the wild and never mature. Field trials were conducted in the Cayman Islands, Malaysia and Brazil to control the mosquitoes that cause dengue fever. In April 2014, Brazil's National Technical Commission for Biosecurity approved the commercial release of the modified mosquito. The FDA is the lead agency for regulating genetically-engineered mosquitoes in the United States. In 2014 and 2018 research was reported into other genetic methods including cytoplasmic incompatibility, chromosomal translocations, sex distortion and gene replacement. Although several years away from the field trial stage, if successful these other methods have the potential to be cheaper and to eradicate the Aedes aegypti mosquito more efficiently. A pioneering experimental demonstration of the gene drive method eradicated small populations of Anopheles gambiae . In 2020, Oxitec 's non-biting Friendly Aedes aegypti mosquito was approved for release by the US EPA and Florida state authorities. Malaysia - In several experiments, researchers released batches of male adult Aedes mosquitos with genetic modifications to study the effects of dispersal and reproduction in natural populations. Mosquito traps were ultilized for the purpose of these studies. The process allowed for the opportunity to determine which mosquitoes were affected, and provided a group to be re-released with genetic modifications resulting in the OX513A variant to reduce reproduction. Adult mosquitoes are attracted inside the traps where they died of dehydration.Malaysia - In several experiments, researchers released batches of male adult Aedes mosquitos with genetic modifications to study the effects of dispersal and reproduction in natural populations. Mosquito traps were ultilized for the purpose of these studies. The process allowed for the opportunity to determine which mosquitoes were affected, and provided a group to be re-released with genetic modifications resulting in the OX513A variant to reduce reproduction. Adult mosquitoes are attracted inside the traps where they died of dehydration.Research is being conducted that indicates that dismantling a protein associated with eggshell organization, factor EOF1 (factor 1), which may be unique to mosquitoes, may be a means to hamper their reproduction effectively in the wild without creating a resistant population or affecting other animals. In Singapore , under the Control of Vectors and Pesticides Act there a legal duty on occupiers to prevent Aedes mosquitos from breeding in their homes. If breeding mosquitos are found by inspectors, occupiers are subject to a fine of 5,000 Singapore dollars or imprisonment for a term not exceeding 3 months or both. Some biologists have proposed the deliberate extinction of certain mosquito species. Biologist Olivia Judson has advocated " specicide " of thirty mosquito species by introducing a genetic element which can insert itself into another crucial gene, to create recessive " knockout genes ". She says that the Anopheles mosquitoes (which spread malaria ) and Aedes mosquitoes (which spread dengue fever , yellow fever , elephantiasis , zika , and other diseases) represent only 30 out of some 3,500 mosquito species; eradicating these would save at least one million human lives per year, at a cost of reducing the genetic diversity of the family Culicidae by 1%. She further argues that since species become extinct "all the time" the disappearance of a few more will not destroy the ecosystem : "We're not left with a wasteland every time a species vanishes. Removing one species sometimes causes shifts in the populations of other species — but different need not mean worse." In addition, anti-malarial and mosquito control programs offer little realistic hope to the 300 million people in developing nations who will be infected with acute illnesses each year. Although trials are ongoing, she writes that if they fail: "We should consider the ultimate swatting." Biologist E. O. Wilson has advocated the extinction of several species of mosquito, including malaria vector Anopheles gambiae . Wilson stated, "I'm talking about a very small number of species that have co-evolved with us and are preying on humans, so it would certainly be acceptable to remove them. I believe it's just common sense." Insect ecologist Steven Juliano has argued that "it's difficult to see what the downside would be to removal, except for collateral damage". Entomologist Joe Conlon stated that "If we eradicated them tomorrow, the ecosystems where they are active will hiccup and then get on with life. Something better or worse would take over." However, David Quammen has pointed out that mosquitoes protect forests from human exploitation and may act as competitors for other insects. In terms of malaria control, if populations of mosquitoes were temporarily reduced to zero in a region, then this would exterminate malaria, and the mosquito population could then be allowed to rebound.

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Rift Valley fever

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Yellow fever

Yellow fever is a viral disease of typically short duration . In most cases, symptoms include fever , chills , loss of appetite , nausea , muscle pains—particularly in the back—and headaches . Symptoms typically improve within five days. In about 15% of people, within a day of improving the fever comes back, abdominal pain occurs, and liver damage begins causing yellow skin . If this occurs, the risk of bleeding and kidney problems is increased. The disease is caused by the yellow fever virus and is spread by the bite of an infected mosquito . It infects humans, other primates , and several types of mosquitoes. In cities, it is spread primarily by Aedes aegypti , a type of mosquito found throughout the tropics and subtropics . The virus is an RNA virus of the genus Flavivirus . The disease may be difficult to tell apart from other illnesses, especially in the early stages. To confirm a suspected case, blood-sample testing with a polymerase chain reaction is required. A safe and effective vaccine against yellow fever exists, and some countries require vaccinations for travelers. Other efforts to prevent infection include reducing the population of the transmitting mosquitoes. In areas where yellow fever is common, early diagnosis of cases and immunization of large parts of the population are important to prevent outbreaks . Once a person is infected, management is symptomatic; no specific measures are effective against the virus. Death occurs in up to half of those who get severe disease. In 2013, yellow fever was estimated to have caused 130,000 severe infections and 78,000 deaths in Africa. Approximately 90 percent of an estimated 200,000 cases of yellow fever per year occur in Africa. Nearly a billion people live in an area of the world where the disease is common. It is common in tropical areas of the continents of South America and Africa, but not in Asia. Since the 1980s, the number of cases of yellow fever has been increasing. This is believed to be due to fewer people being immune, more people living in cities, people moving frequently, and changing climate increasing the habitat for mosquitoes. The disease originated in Africa and spread to the Americas starting in the 17th century with the European trafficking of enslaved Africans from sub-Saharan Africa. Since the 17th century, several major outbreaks of the disease have occurred in the Americas, Africa, and Europe. In the 18th and 19th centuries, yellow fever was considered one of the most dangerous infectious diseases ; numerous epidemics swept through major cities of the US and in other parts of the world. In 1927, yellow fever virus became the first human virus to be isolated. Yellow fever begins after an incubation period of three to six days. Most cases cause only mild infection with fever, headache, chills, back pain, fatigue, loss of appetite, muscle pain, nausea, and vomiting. In these cases, the infection lasts only three to six days. But in 15% of cases, people enter a second, toxic phase of the disease characterized by recurring fever, this time accompanied by jaundice due to liver damage , as well as abdominal pain . Bleeding in the mouth, nose, eyes, and the gastrointestinal tract cause vomit containing blood , hence one of the names in Spanish for yellow fever, vómito negro ("black vomit"). There may also be kidney failure, hiccups, and delirium. Among those who develop jaundice, the fatality rate is 20 to 50%, while the overall fatality rate is about 3 to 7.5%. Severe cases may have a mortality rate greater than 50%. Surviving the infection provides lifelong immunity , and normally results in no permanent organ damage. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time. {| class="infobox biota" style="text-align: left; width: 200px; font-size: 100%" |- ! Yellow fever virus |- | |- | Flavivirus structure and genome |- |- |- |- ! Virus classification |- |(unranked): | Virus |- | Realm : | Riboviria |- |Kingdom: | Orthornavirae |- |Phylum: | Kitrinoviricota |- |Class: | Flasuviricetes |- |Order: | Amarillovirales |- |Family: | Flaviviridae |- |Genus: | Flavivirus |- | Species: | |- |- |- |- |- |- |- |- |- |- |- |- |- |- |- |} Yellow fever is caused by Yellow fever virus (YFV), an enveloped RNA virus 40–50 nm in width, the type species and namesake of the family Flaviviridae . It was the first illness shown to be transmissible by filtered human serum and transmitted by mosquitoes, by American doctor Walter Reed around 1900. The positive- sense , single-stranded RNA is around 10,862 nucleotides long and has a single open reading frame encoding a polyprotein . Host proteases cut this polyprotein into three structural (C, prM, E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding genes in the genome . Minimal YFV 3 ′ UTR region is required for stalling of the host 5 ′ -3 ′ exonuclease XRN1. The UTR contains PKS3 pseudoknot structure, which serves as a molecular signal to stall the exonuclease and is the only viral requirement for subgenomic flavivirus RNA (sfRNA) production. The sfRNAs are a result of incomplete degradation of the viral genome by the exonuclease and are important for viral pathogenicity. Yellow fever belongs to the group of hemorrhagic fevers . The viruses infect, amongst others, monocytes , macrophages , Schwann cells , and dendritic cells . They attach to the cell surfaces via specific receptors and are taken up by an endosomal vesicle . Inside the endosome , the decreased pH induces the fusion of the endosomal membrane with the virus envelope . The capsid enters the cytosol , decays, and releases the genome. Receptor binding, as well as membrane fusion, are catalyzed by the protein E, which changes its conformation at low pH, causing a rearrangement of the 90 homo dimers to 60 homo trimers . After entering the host cell, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the so-called vesicle packets. At first, an immature form of the virus particle is produced inside the ER, whose M-protein is not yet cleaved to its mature form, so is denoted as precursor M (prM) and forms a complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin , which cleaves prM to M. This releases E from the complex, which can now take its place in the mature, infectious virion . Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti , but other mostly Aedes mosquitoes such as the tiger mosquito ( Aedes albopictus ) can also serve as a vector for this virus. Like other arboviruses , which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate. Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands . When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti , that is, the transmission from a female mosquito to its eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease. Three epidemiologically different infectious cycles occur in which the virus is transmitted from mosquitoes to humans or other primates. In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever , dengue fever , and chikungunya . The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America. Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent. People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors. In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa. Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs. After transmission from a mosquito, the viruses replicate in the lymph nodes and infect dendritic cells in particular. From there, they reach the liver and infect hepatocytes (probably indirectly via Kupffer cells ), which leads to eosinophilic degradation of these cells and to the release of cytokines . Apoptotic masses known as Councilman bodies appear in the cytoplasm of hepatocytes. Fatality may occur when cytokine storm , shock , and multiple organ failure follow. Yellow fever is most frequently a clinical diagnosis , based on symptomatology and travel history. Mild cases of the disease can only be confirmed virologically. Since mild cases of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea, and vomiting 6–10 days after leaving the affected area) is treated seriously. If yellow fever is suspected, the virus cannot be confirmed until 6–10 days following the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction , where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma ; this can take 1–4 weeks. Serologically, an enzyme-linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG titer (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a four-fold increase in IgG titer is considered sufficient indication for yellow fever. As these tests can cross-react with other flaviviruses, such as dengue virus , these indirect methods cannot conclusively prove yellow fever infection. Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens . Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable post mortem to confirm the cause of death. In a differential diagnosis , infections with yellow fever must be distinguished from other feverish illnesses such as malaria . Other viral hemorrhagic fevers , such as Ebola virus , Lassa virus , Marburg virus , and Junin virus , must be excluded as the cause. Personal prevention of yellow fever includes vaccination and avoidance of mosquito bites in areas where yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes and measures to control mosquitoes. Programmes for distribution of mosquito nets for use in homes produce reductions in cases of both malaria and yellow fever. Use of EPA-registered insect repellent is recommended when outdoors. Exposure for even a short time is enough for a potential mosquito bite. Long-sleeved clothing, long pants, and socks are useful for prevention. The application of larvicides to water-storage containers can help eliminate potential mosquito breeding sites. EPA-registered insecticide spray decreases the transmission of yellow fever. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler . The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection. In rare cases (less than one in 200,000 to 300,000), the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5% of cases. The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes. Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply. Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016. Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose. In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated. Control of the yellow fever mosquito A. aegypti is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. A. aegypti breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries. Two main strategies are employed to reduce A. aegypti populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods , which reduce the number of larvae. For many years, copepods of the genus Mesocyclops have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses. The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce Aedes populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the Anopheles mosquito that carries malaria. As with other Flavivirus infections, no cure is known for yellow fever. Hospitalization is advisable and intensive care may be necessary because of rapid deterioration in some cases. Certain acute treatment methods lack efficacy: passive immunization after the emergence of symptoms is probably without effect; ribavirin and other antiviral drugs , as well as treatment with interferons , are ineffective in yellow fever patients. Symptomatic treatment includes rehydration and pain relief with drugs such as paracetamol (acetaminophen). However, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are often avoided because of an increased risk of gastrointestinal bleeding due to their anticoagulant effects. Yellow fever is common in tropical and subtropical areas of South America and Africa. Worldwide, about 600 million people live in endemic areas. The WHO estimates 200,000 cases of yellow fever worldwide each year. About 15% of people infected with yellow fever progress to a severe form of the illness, and up to half of those will die, as there is no cure for yellow fever. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history. Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector A. aegypti . Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years. In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvatic or jungle epizootic . Real-time phylogenetic investigations at the epicentre of the outbreak revealed that the outbreak was caused by the introduction of a virus lineage from the Amazon region into the southeast region around July 2016, spreading rapidly across several neotropical monkey species, including brown howler monkeys, which serve as a sentinel species for yellow fever. No cases had been transmitted between humans by the A. aegypti mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvatic outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.) A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil , Colombia , Venezuela , and Trinidad and Tobago , while genotype II accounted for all cases in Peru . Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval [HPD]: 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10 −4 substitutions/site/year, similar to that of other RNA viruses. The main vector ( A. aegypti ) also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever had never occurred there until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include: But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza . This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity . The virus, as well as the vector A. aegypti, were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus Haemagogus , which is indigenous to the Americas, have been known to carry the disease. The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados . An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula , where the indigenous Mayan people called the illness xekik ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife . The first mention of the disease by the name "yellow fever" occurred in 1744. However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs. In Colonial times and during the Napoleonic Wars , the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack" . Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated. Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore , and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson , a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington . The southern city of New Orleans was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in Cartagena, Chile , in 1741; Cuba in 1762 and 1900; Santo Domingo in 1803; and Memphis, Tennessee , in 1878. In the early 19th century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the United States Navy as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS Macedonian left Boston and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana , had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of Savannah, Georgia , died from yellow fever. In 1858, St. Matthew's German Evangelical Lutheran Church in Charleston, South Carolina , had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 1855. The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth . In 1873, Shreveport, Louisiana , lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe. Gibraltar lost many lives to outbreaks in 1804, 1814, and 1828. Barcelona suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between France and Spain in the Pyrenees Mountains , to establish a cordon sanitaire in order to prevent the epidemic from spreading from Spain into France. Ezekiel Stone Wiggins , known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in Jacksonville, Florida , in 1888, was astrological. The planets were in the same line as the sun and earth and this produced, besides Cyclones, Earthquakes, etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants were probably protected from the fever by their newly discovered canals , which were perhaps made to absorb carbon and prevent the disease. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease. Carlos Finlay , a Cuban-Spanish doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, U.S. Army doctors began research experiments with a team led by Walter Reed , and composed of doctors James Carroll , Aristides Agramonte , and Jesse William Lazear . They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician William Gorgas applied these insights and eradicated yellow fever from Havana . He also campaigned against yellow fever during the construction of the Panama Canal . A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz , then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in favelas . During 1920–1923, the Rockefeller Foundation 's International Health Board undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the yellow fever virus in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the Nobel Prize in Physiology or Medicine . That vaccine, 17D, is still in use, although newer vaccines, based on vero cells , are in development (as of 2018). Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in Santa Cruz de la Sierra , Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in Paraguay in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely. In the hamster model of yellow fever, early administration of the antiviral ribavirin is an effective treatment of many pathological features of the disease. Ribavirin treatment during the first five days after virus infection improved survival rates, reduced tissue damage in the liver and spleen , prevented hepatocellular steatosis , and normalised levels of alanine aminotransferase, a liver damage marker. The mechanism of action of ribavirin in reducing liver pathology in yellow fever virus infection may be similar to its activity in treatment of hepatitis C , a related virus. Because ribavirin had failed to improve survival in a virulent rhesus model of yellow fever infection, it had been previously discounted as a possible therapy. Infection was reduced in mosquitoes with the wMel strain of Wolbachia . Yellow fever has been researched by several countries as a potential biological weapon .

Wiki

Rift Valley fever

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

Operation Whitecoat

Operation Whitecoat was a biodefense medical research program carried out by the United States Army at Fort Detrick , Maryland between 1954 and 1973. The program pursued medical research using volunteer enlisted personnel who were eventually nicknamed "Whitecoats". These volunteers, all conscientious objectors , including many members of the Seventh-day Adventist Church , were informed of the purpose and goals of each project before providing consent to participate in any project. The stated purpose of the research was to defend troops and civilians against biological weapons . Although the program was discontinued in 1973, human use research for biodefense purposes is still conducted at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick and at other government and civilian research institutes. However, these post-Whitecoat studies are often human use challenge studies, in which a person is inoculated with a known pathogen to determine how effective an investigational treatment will be.Over the course of the 19-year program, more than 2,300 U.S. Army soldiers, many of whom were trained medics, contributed to the Whitecoat experiments by allowing themselves to be infected with bacteria (tularemia, Black Plague, Q fever, etc. ) that were considered likely choices for a biological attack. While some volunteered immediately after basic training, for conscientious objectors at Ft. Sam Houston , TX (before they began their medic training), the near certainty of being assigned as a combat medic in Vietnam helped some medics choose instead to remain in the United States with the Whitecoat program. The goal of the program was to determine dose response for these agents. The volunteers were then treated with antibiotics to cure the infections. Some volunteers, under experimental protocol, were also given investigational vaccines for Q fever and tularemia, as well as for yellow fever , Rift Valley fever , hepatitis A , Yersinia pestis (plague), and Venezuelan equine encephalitis and other diseases. Some soldiers were given two weeks of leave in exchange for being used as a test subject. These experiments took place at Fort Detrick which is a U.S. Army research installation in Frederick, Maryland . The volunteers were allowed to consult with outside sources, such as family and clergy members, before deciding to participate. The participants were required to sign consent forms after discussing the risks and treatments with a medical officer. Of the soldiers who were approached about participating, 20% declined. Many of the vaccines that protect against biowarfare agents were first tested on humans in Operation Whitecoat. According to USAMRIID , the Whitecoat operation contributed to vaccines approved by the U.S. Food and Drug Administration (FDA) for yellow fever and hepatitis, and investigational drugs for Q fever, Venezuelan equine encephalitis, Rift Valley fever, and tularemia. USAMRIID also states that Operation Whitecoat helped develop biological safety equipment, including hooded safety cabinets, decontamination procedures, fermentors, incubators, centrifuges, and particle sizers. Operation Whitecoat came to an end in 1973 when the draft for the U.S. military ended and thus no more conscientious objectors were to be conscripted.Many of the vaccines that protect against biowarfare agents were first tested on humans in Operation Whitecoat. According to USAMRIID , the Whitecoat operation contributed to vaccines approved by the U.S. Food and Drug Administration (FDA) for yellow fever and hepatitis, and investigational drugs for Q fever, Venezuelan equine encephalitis, Rift Valley fever, and tularemia. USAMRIID also states that Operation Whitecoat helped develop biological safety equipment, including hooded safety cabinets, decontamination procedures, fermentors, incubators, centrifuges, and particle sizers. Operation Whitecoat came to an end in 1973 when the draft for the U.S. military ended and thus no more conscientious objectors were to be conscripted.The United States Government Accountability Office issued a report on September 28, 1994, which stated that between 1940 and 1974, the United States Department of Defense and other national security agencies studied hundreds of thousands of human subjects in tests and experiments involving hazardous substances. A quotation from the study: Many experiments that tested various biological agents on human subjects, referred to as Operation Whitecoat, were carried out at Fort Detrick , Maryland , in the 1950s. The human subjects originally consisted of volunteer enlisted men. However, after the enlisted men staged a sitdown strike to obtain more information about the dangers of the biological tests, Seventh-day Adventists who were conscientious objectors were recruited for the studies. No Whitecoats died during the test period. The Army has addresses for only 1000 of the 2300 people known to have volunteered. Only about 500 (23%) of the Whitecoats have been surveyed, and the military chose not to fund blood tests. A handful of respondents claim to have lingering health effects, and at least one subject claims to have serious health problems as a result of the experiments. In 2005, an assessment of health status among the Project Whitecoat research volunteers was published. It reflected the self-reported, current health status among 358 "exposed" individuals and 164 unexposed "control" subjects and found no conclusive evidence that receipt of investigational agents was related to any adverse health outcomes. No differences in current overall health, current exercise levels, self-reported symptoms, and self-reported medical conditions were seen between the study groups. However, possible associations were seen between exposure to antibiotics or other biological agents and self-reported asthma , as well as between receipt of tularemia vaccine(s) and self-reported asthma and increased frequency/severity of headaches. The size of the study population was judged to be insufficient to assert with confidence that the statistical associations with asthma and headaches were real. The United States Government Accountability Office issued a report on September 28, 1994, which stated that between 1940 and 1974, the United States Department of Defense and other national security agencies studied hundreds of thousands of human subjects in tests and experiments involving hazardous substances. A quotation from the study: Many experiments that tested various biological agents on human subjects, referred to as Operation Whitecoat, were carried out at Fort Detrick , Maryland , in the 1950s. The human subjects originally consisted of volunteer enlisted men. However, after the enlisted men staged a sitdown strike to obtain more information about the dangers of the biological tests, Seventh-day Adventists who were conscientious objectors were recruited for the studies. No Whitecoats died during the test period. The Army has addresses for only 1000 of the 2300 people known to have volunteered. Only about 500 (23%) of the Whitecoats have been surveyed, and the military chose not to fund blood tests. A handful of respondents claim to have lingering health effects, and at least one subject claims to have serious health problems as a result of the experiments. In 2005, an assessment of health status among the Project Whitecoat research volunteers was published. It reflected the self-reported, current health status among 358 "exposed" individuals and 164 unexposed "control" subjects and found no conclusive evidence that receipt of investigational agents was related to any adverse health outcomes. No differences in current overall health, current exercise levels, self-reported symptoms, and self-reported medical conditions were seen between the study groups. However, possible associations were seen between exposure to antibiotics or other biological agents and self-reported asthma , as well as between receipt of tularemia vaccine(s) and self-reported asthma and increased frequency/severity of headaches. The size of the study population was judged to be insufficient to assert with confidence that the statistical associations with asthma and headaches were real. The Seventh-day Adventist Church's relationship to government military activity has been supportive but noncombative. In 1936, the Adventist Church established the Medical Cadet Corps Training Program. This allowed Adventists to remain noncombatant but positive toward the war effort. Sabbath observance remained a concern for the drafted members of the church. Adventist Conscientious Objector perspective differed from the National Interreligious Service Board for Conscientious Objectors , (NISBCO). In 1967, Adventists withdrew from NISBCO because that organization opposed conscription. According to Bull and Lockhart, Operation Whitecoat, and the earlier established Medical Corps, enabled Adventists to participate in the armed services without violating their Sabbath principles. The Seventh-day Adventist Church's relationship to government military activity has been supportive but noncombative. In 1936, the Adventist Church established the Medical Cadet Corps Training Program. This allowed Adventists to remain noncombatant but positive toward the war effort. Sabbath observance remained a concern for the drafted members of the church. Adventist Conscientious Objector perspective differed from the National Interreligious Service Board for Conscientious Objectors , (NISBCO). In 1967, Adventists withdrew from NISBCO because that organization opposed conscription. According to Bull and Lockhart, Operation Whitecoat, and the earlier established Medical Corps, enabled Adventists to participate in the armed services without violating their Sabbath principles.

Wiki

Rift Valley fever

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

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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Rift Valley fever

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Chikungunya

Chikungunya is an infection caused by the Chikungunya virus ( CHIKV ). The disease was first identified in 1952 in Tanzania and named based on the Kimakonde words for "to become contorted". Symptoms include fever and joint pain . These typically occur two to twelve days after exposure. Other symptoms may include headache , muscle pain , joint swelling , and a rash . Symptoms usually improve within a week; however, occasionally the joint pain may last for months or years. The risk of death is around 1 in 1,000. The very young, old, and those with other health problems are at risk of more severe disease. The virus is spread between people by two types of mosquitos : Aedes albopictus and Aedes aegypti . They mainly bite during the day. The virus may circulate within a number of animals including birds and rodents . Diagnosis is by either testing the blood for viral RNA or antibodies to the virus. The symptoms can be mistaken for those of dengue fever and Zika fever . It is believed most people become immune after a single infection. The best means of prevention are overall mosquito control and the avoidance of bites in areas where the disease is common. This may be partly achieved by decreasing mosquitos' access to water and by the use of insect repellent and mosquito nets . In November 2023 the USFDA approved an adults-only vaccine ( Ixchiq ) for prevention of the disease. Once infected and symptomatic, recommendations to patients should include rest, fluids, and medications to help with fever and joint pain. In 2014, more than a million suspected cases occurred globally. While the disease is endemic in Africa and Asia, outbreaks have been reported in Europe and the Americas since the 2000s; in 2014, an outbreak was reported in Florida in the continental United States , but as of 2016 there were no further locally-acquired cases. Around 85% of people infected with Chikungunya virus experience symptoms, typically beginning with a sudden high fever above 39 °C (102 °F) . The fever is soon followed by severe muscle and joint pain . Pain usually affects multiple joints in the arms and legs, and is symmetric – i.e. if one elbow is affected, the other is as well. People with Chikungunya also frequently experience headache , back pain, nausea , and fatigue . Around half of those affected develop a rash , with reddening and sometimes small bumps on the palms, foot soles, torso, and face. For some, the rash remains constrained to a small part of the body; for others, the rash can be extensive, covering more than 90% of the skin. Some people experience gastrointestinal issues, with abdominal pain and vomiting. Others experience eye problems, namely sensitivity to light , conjunctivitis , and pain behind the eye. This first set of symptoms – called the "acute phase" of Chikungunya – lasts around a week, after which most symptoms resolve on their own. Many people continue to have symptoms after the "acute phase" resolves, termed the "post-acute phase" for symptoms lasting three weeks to three months, and the "chronic stage" for symptoms lasting longer than three months. In both cases, the lasting symptoms tend to be joint pains: arthritis , tenosynovitis , and/or bursitis . If the affected person had pre-existing joint issues, these tend to worsen. Overuse of a joint can result in painful swelling, stiffness, nerve damage, and neuropathic pain . Typically the joint pain improves with time; however, the chronic stage can last anywhere from a few months to several years. Joint pain is reported in 87–98% of cases, and nearly always occurs in more than one joint, though joint swelling is uncommon. Typically the affected joints are located in both arms and legs. Joints are more likely to be affected if they have previously been damaged by disorders such as arthritis . Pain most commonly occurs in peripheral joints, such as the wrists, ankles, and joints of the hands and feet as well as some of the larger joints, typically the shoulders, elbows and knees. Pain may also occur in the muscles or ligaments . In more than half of cases, normal activity is limited by significant fatigue and pain. Infrequently, inflammation of the eyes may occur in the form of iridocyclitis , or uveitis , and retinal lesions may occur. Temporary damage to the liver may occur. People with Chikungunya occasionally develop neurologic disorders, most frequently swelling or degeneration of the brain, inflammation or degeneration of the myelin sheaths around neurons, Guillain–Barré syndrome , acute disseminated encephalomyelitis , hypotonia (in newborns), and issues with visual processing. In particularly rare cases, people may develop behavioral changes, seizures, irritation of the cerebellum or meninges , oculomotor nerve palsy , or paralysis of the eye muscles . Newborns are susceptible to particularly severe effects of Chikungunya infection. Signs of infection typically begin with fever, rash, and swelling in the extremities. Around half of newborns have a mild case of the disease that resolves on its own; the other half have severe disease with inflammation of the brain and seizures . In severe cases, affected newborns may also have issues with bleeding and bloodflow, and problems with heart function. In addition to newborns, the elderly, and those with diabetes , heart disease , liver and kidney diseases, and human immunodeficiency virus infection tend to have more severe cases of Chikungunya. Around 1 to 5 in 1,000 people with symptomatic Chikungunya die of the disease. Chikungunya virus (CHIKV), is a member of the genus Alphavirus , and family Togaviridae . It was first isolated in 1953 in Tanzania and is an RNA virus with a positive-sense single-stranded genome of about 11.6kb. It is a member of the Semliki Forest virus complex and is closely related to Ross River virus , O'nyong'nyong virus , and Semliki Forest virus . Because it is transmitted by arthropods , namely mosquitoes, it can also be referred to as an arbovirus ( ar thropod- bo rne virus). In the United States, it is classified as a category B priority pathogen , and work requires biosafety level III precautions. Chikungunya is generally transmitted from mosquitoes to humans. Less common modes of transmission include vertical transmission , which is transmission from mother to child during pregnancy or at birth. Transmission via infected blood products and through organ donation is also theoretically possible during times of outbreak, though no cases have yet been documented. The incubation period ranges from one to twelve days, and is most typically three to seven. Chikungunya is related to mosquitoes , their environments, and human behavior. The adaptation of mosquitoes to the changing climate of North Africa around 5,000 years ago made them seek out environments where humans stored water. Human habitation and the mosquitoes' environments were then very closely connected. During periods of epidemics humans are the reservoir of the virus. Because high amounts of virus are present in the blood in the beginning of acute infection, the virus can be spread from a viremic human to a mosquito, and back to a human. During other times, monkeys, birds and other vertebrates have served as reservoirs. Three genotypes of this virus have been described, each with a distinct genotype and antigenic character: West African, East/Central/South African, and Asian genotypes. The Asian lineage originated in 1952 and has subsequently split into two lineages – India (Indian Ocean Lineage) and South East Asian clades. This virus was first reported in the Americas in 2014. Phylogenetic investigations have shown that there are two strains in Brazil – the Asian and East/Central/South African types – and that the Asian strain arrived in the Caribbean (most likely from Oceania) in about March 2013. The rate of molecular evolution was estimated to have a mean rate of 5 × 10 −4 substitutions per site per year (95% higher probability density 2.9–7.9 × 10 −4 ). Chikungunya is spread through bites from Aedes mosquitoes, and the species A. aegypti was identified as the most common vector, though the virus has recently been associated with many other species, including A. albopictus . Research by the Pasteur Institute in Paris has suggested Chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by the Asian tiger mosquito ( A. albopictus ). Other species potentially able to transmit Chikungunya virus include Ae. furcifer-taylori , Ae. africanus , and Ae. luteocephalus . Chikungunya virus (CHIKV), is a member of the genus Alphavirus , and family Togaviridae . It was first isolated in 1953 in Tanzania and is an RNA virus with a positive-sense single-stranded genome of about 11.6kb. It is a member of the Semliki Forest virus complex and is closely related to Ross River virus , O'nyong'nyong virus , and Semliki Forest virus . Because it is transmitted by arthropods , namely mosquitoes, it can also be referred to as an arbovirus ( ar thropod- bo rne virus). In the United States, it is classified as a category B priority pathogen , and work requires biosafety level III precautions. Chikungunya is generally transmitted from mosquitoes to humans. Less common modes of transmission include vertical transmission , which is transmission from mother to child during pregnancy or at birth. Transmission via infected blood products and through organ donation is also theoretically possible during times of outbreak, though no cases have yet been documented. The incubation period ranges from one to twelve days, and is most typically three to seven. Chikungunya is related to mosquitoes , their environments, and human behavior. The adaptation of mosquitoes to the changing climate of North Africa around 5,000 years ago made them seek out environments where humans stored water. Human habitation and the mosquitoes' environments were then very closely connected. During periods of epidemics humans are the reservoir of the virus. Because high amounts of virus are present in the blood in the beginning of acute infection, the virus can be spread from a viremic human to a mosquito, and back to a human. During other times, monkeys, birds and other vertebrates have served as reservoirs. Three genotypes of this virus have been described, each with a distinct genotype and antigenic character: West African, East/Central/South African, and Asian genotypes. The Asian lineage originated in 1952 and has subsequently split into two lineages – India (Indian Ocean Lineage) and South East Asian clades. This virus was first reported in the Americas in 2014. Phylogenetic investigations have shown that there are two strains in Brazil – the Asian and East/Central/South African types – and that the Asian strain arrived in the Caribbean (most likely from Oceania) in about March 2013. The rate of molecular evolution was estimated to have a mean rate of 5 × 10 −4 substitutions per site per year (95% higher probability density 2.9–7.9 × 10 −4 ). Chikungunya is spread through bites from Aedes mosquitoes, and the species A. aegypti was identified as the most common vector, though the virus has recently been associated with many other species, including A. albopictus . Research by the Pasteur Institute in Paris has suggested Chikungunya virus strains in the 2005-2006 Reunion Island outbreak incurred a mutation that facilitated transmission by the Asian tiger mosquito ( A. albopictus ). Other species potentially able to transmit Chikungunya virus include Ae. furcifer-taylori , Ae. africanus , and Ae. luteocephalus . Chikungunya virus is passed to humans when a bite from an infected mosquito breaks the skin and introduces the virus into the body. The pathogenesis of chikungunya infection in humans is still poorly understood, despite recent outbreaks. It appears that in vitro , Chikungunya virus is able to replicate in human epithelial and endothelial cells , primary fibroblasts , and monocyte-derived macrophages . Viral replication is highly cytopathic , but susceptible to type-I and -II interferon . In vivo , in studies using living cells, chikungunya virus appears to replicate in fibroblasts, skeletal muscle progenitor cells, and myofibers. The type-1 interferon response seems to play an important role in the host's response to chikungunya infection. Upon infection with chikungunya, the host's fibroblasts produce type-1 alpha and beta interferon ( IFN-α and IFN-β ). In mouse studies, deficiencies in INF-1 in mice exposed to the virus cause increased morbidity and mortality. The chikungunya-specific upstream components of the type-1 interferon pathway involved in the host's response to chikungunya infection are still unknown. Nonetheless, mouse studies suggest that IPS-1 is an important factor, and that IRF3 and IRF7 are important in an age-dependent manner. Mouse studies also suggest that chikungunya evades host defenses and counters the type-I interferon response by producing NS2, a nonstructural protein that degrades RBP1 and turns off the host cell's ability to transcribe DNA. NS2 interferes with the JAK-STAT signaling pathway and prevents STAT from becoming phosphorylated . In the acute phase of chikungunya, the virus is typically present in the areas where symptoms present, specifically skeletal muscles, and joints . In the chronic phase, it is suggested that viral persistence (the inability of the body to entirely rid itself of the virus), lack of clearance of the antigen , or both, contribute to joint pain. The inflammation response during both the acute and chronic phase of the disease results in part from interactions between the virus and monocytes and macrophages. Chikungunya virus disease in humans is associated with elevated serum levels of specific cytokines and chemokines . High levels of specific cytokines have been linked to more severe acute disease: interleukin-6 (IL-6), IL-1β , RANTES , monocyte chemoattractant protein 1 (MCP-1), monokine induced by gamma interferon (MIG), and interferon gamma-induced protein 10 (IP-10). Cytokines may also contribute to chronic Chikungunya virus disease, as persistent joint pain has been associated with elevated levels of IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF). In those with chronic symptoms, a mild elevation of C-reactive protein (CRP) has been observed, suggesting ongoing chronic inflammation. However, there is little evidence linking chronic Chikungunya virus disease and the development of autoimmunity . [ citation needed ] The virus consists of four nonstructural proteins and three structural proteins. The structural proteins are the capsid and two envelope glycoproteins: E1 and E2, which form heterodimeric spikes on the viron surface. E2 binds to cellular receptors in order to enter the host cell through receptor-mediated endocytosis . E1 contains a fusion peptide which, when exposed to the acidity of the endosome in eukaryotic cells , dissociates from E2 and initiates membrane fusion that allows the release of nucleocapsids into the host cytoplasm, promoting infection. The mature virion contains 240 heterodimeric spikes of E2/E1, which after release, bud on the surface of the infected cell, where they are released by exocytosis to infect other cells. The virus consists of four nonstructural proteins and three structural proteins. The structural proteins are the capsid and two envelope glycoproteins: E1 and E2, which form heterodimeric spikes on the viron surface. E2 binds to cellular receptors in order to enter the host cell through receptor-mediated endocytosis . E1 contains a fusion peptide which, when exposed to the acidity of the endosome in eukaryotic cells , dissociates from E2 and initiates membrane fusion that allows the release of nucleocapsids into the host cytoplasm, promoting infection. The mature virion contains 240 heterodimeric spikes of E2/E1, which after release, bud on the surface of the infected cell, where they are released by exocytosis to infect other cells. Chikungunya is diagnosed on the basis of clinical, epidemiological, and laboratory criteria. Clinically, acute onset of high fever and severe joint pain would lead to suspicion of chikungunya. Epidemiological criteria consist of whether the individual has traveled to or spent time in an area in which chikungunya is present within the last twelve days (i.e.) the potential incubation period). Laboratory criteria include a decreased lymphocyte count consistent with viremia . However a definitive laboratory diagnosis can be accomplished through viral isolation, RT-PCR, or serological diagnosis. The differential diagnosis may include other mosquito-borne diseases , such as dengue or malaria , or other infections such as influenza . Chronic recurrent polyarthralgia occurs in at least 20% of chikungunya patients one year after infection, whereas such symptoms are uncommon in dengue. Virus isolation provides the most definitive diagnosis, but takes one to two weeks for completion and must be carried out in biosafety level III laboratories . The technique involves exposing specific cell lines to samples from whole blood and identifying Chikungunya virus -specific responses. RT-PCR using nested primer pairs is used to amplify several chikungunya-specific genes from whole blood, generating thousands to millions of copies of the genes in order to identify them. RT-PCR can also be used to quantify the viral load in the blood. Using RT-PCR, diagnostic results can be available in one to two days. Serological diagnosis requires a larger amount of blood than the other methods, and uses an ELISA assay to measure chikungunya-specific IgM levels in the blood serum. One advantage offered by serological diagnosis is that serum IgM is detectable from 5 days to months after the onset of symptoms, but drawbacks are that results may require two to three days, and false positives can occur with infection due to other related viruses, such as o'nyong'nyong virus and Semliki Forest virus . Presently, there is no specific way to test for chronic signs and symptoms associated with Chikungunya fever although nonspecific laboratory findings such as C reactive protein and elevated cytokines can correlate with disease activity. Because no approved vaccine exists, the most effective means of prevention are protection against contact with the disease-carrying mosquitoes and controlling mosquito populations by limiting their habitat . Mosquito control focuses on eliminating the standing water where mosquitos lay eggs and develop as larva; if elimination of the standing water is not possible, insecticides or biological control agents can be added. Methods of protection against contact with mosquitos include using insect repellents with substances such as DEET , icaridin , PMD ( p-menthane-3,8-diol , a substance derived from the lemon eucalyptus tree), or ethyl butylacetylaminopropionate (IR3535). However, increasing insecticide resistance presents a challenge to chemical control methods. [ citation needed ] Wearing bite-proof long sleeves and trousers also offers protection, and garments can be treated with pyrethroids , a class of insecticides that often has repellent properties. Vaporized pyrethroids (for example in mosquito coils) are also insect repellents. As infected mosquitoes often feed and rest inside homes, securing screens on windows and doors will help to keep mosquitoes out of the house. In the case of the day-active A. aegypti and A. albopictus , however, this will have only a limited effect, since many contacts between the mosquitoes and humans occur outdoors. [ citation needed ] A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus . The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. A Chikungunya vaccine is a vaccine intended to provide acquired immunity against the chikungunya virus . The most commonly reported side effects include headache, fatigue, muscle pain, joint pain, fever, nausea and tenderness at the injection site. Currently, no specific treatment for chikungunya is available. Supportive care is recommended, and symptomatic treatment of fever and joint swelling includes the use of nonsteroidal anti-inflammatory drugs such as naproxen , non-aspirin analgesics such as paracetamol (acetaminophen) and fluids. Aspirin is not recommended due to the increased risk of bleeding. Despite anti-inflammatory effects, corticosteroids are not recommended during the acute phase of disease, as they may cause immunosuppression and worsen infection. Passive immunotherapy has potential benefit in treatment of chikungunya. Studies in animals using passive immunotherapy have been effective, and clinical studies using passive immunotherapy in those particularly vulnerable to severe infection are currently in progress. Passive immunotherapy involves administration of anti-CHIKV hyperimmune human intravenous antibodies (immunoglobulins) to those exposed to a high risk of chikungunya infection. No antiviral treatment for Chikungunya virus is currently available, though testing has shown several medications to be effective in vitro . In those who have more than two weeks of arthritis, ribavirin may be useful. The effect of chloroquine is not clear. It does not appear to help acute disease, but tentative evidence indicates it might help those with chronic arthritis. Steroids do not appear to be an effective treatment. NSAIDs and simple analgesics can be used to provide partial symptom relief in most cases. Methotrexate , a drug used in the treatment of rheumatoid arthritis , has been shown to have benefit in treating inflammatory polyarthritis resulting from chikungunya, though the drug mechanism for improving viral arthritis is unclear. In those who have more than two weeks of arthritis, ribavirin may be useful. The effect of chloroquine is not clear. It does not appear to help acute disease, but tentative evidence indicates it might help those with chronic arthritis. Steroids do not appear to be an effective treatment. NSAIDs and simple analgesics can be used to provide partial symptom relief in most cases. Methotrexate , a drug used in the treatment of rheumatoid arthritis , has been shown to have benefit in treating inflammatory polyarthritis resulting from chikungunya, though the drug mechanism for improving viral arthritis is unclear. The mortality rate of chikungunya is slightly less than 1 in 1000. Those over the age of 65, neonates, and those with underlying chronic medical problems are most likely to have severe complications. Neonates are vulnerable as it is possible to vertically transmit chikungunya from mother to infant during delivery, which results in high rates of morbidity, as infants lack fully developed immune systems . The likelihood of prolonged symptoms or chronic joint pain is increased with increased age and prior rheumatological disease. Historically, chikungunya has been present mostly in the developing world . The disease causes an estimated 3 million infections each year. Epidemics in the Indian Ocean, Pacific Islands, and in the Americas, continue to change the distribution of the disease. In Africa, chikungunya is spread by a sylvatic cycle in which the virus largely cycles between other non-human primates , small mammals, and mosquitos between human outbreaks. During outbreaks, due to the high concentration of virus in the blood of those in the acute phase of infection, the virus can circulate from humans to mosquitoes and back to humans. The transmission of the pathogen between humans and mosquitoes that exist in urban environments was established on multiple occasions from strains occurring on the eastern half of Africa in non-human primate hosts. This emergence and spread beyond Africa may have started as early as the 18th century. Currently, available data does not indicate whether the introduction of chikungunya into Asia occurred in the 19th century or more recently, but this epidemic Asian strain causes outbreaks in India and continues to circulate in Southeast Asia. In Africa, outbreaks were typically tied to heavy rainfall causing increased mosquito population. In recent outbreaks in urban centers, the virus has spread by circulating between humans and mosquitoes. Global rates of chikungunya infection are variable, depending on outbreaks. When chikungunya was first identified in 1952, it had a low-level circulation in West Africa, with infection rates linked to rainfall. Beginning in the 1960s, periodic outbreaks were documented in Asia and Africa. However, since 2005, following several decades of relative inactivity, chikungunya has re-emerged and caused large outbreaks in Africa, Asia, and the Americas. In India, for instance, chikungunya re-appeared following 32 years of absence of viral activity. Outbreaks have occurred in Europe, the Caribbean, and South America, areas in which chikungunya was not previously transmitted. Local transmission has also occurred in the United States and Australia, countries in which the virus was previously unknown. In 2005, an outbreak on the island of Réunion was the largest then documented, with an estimated 266,000 cases on an island with a population of approximately 770,000. In a 2006 outbreak, India reported 1.25 million suspected cases. Chikungunya was introduced to the Americas in 2013, first detected on the French island of Saint Martin , and for the next two years in the Americas, 1,118,763 suspected cases and 24,682 confirmed cases were reported by the PAHO . An analysis of the genetic code of Chikungunya virus suggests that the increased severity of the 2005–present outbreak may be due to a change in the genetic sequence which altered the E1 segment of the virus' viral coat protein, a variant called E1-A226V. This mutation potentially allows the virus to multiply more easily in mosquito cells. The change allows the virus to use the Asian tiger mosquito (an invasive species ) as a vector in addition to the more strictly tropical main vector, Aedes aegypti . Enhanced transmission of Chikungunya virus by A. albopictus could mean an increased risk for outbreaks in other areas where the Asian tiger mosquito is present. A albopictus is an invasive species which has spread through Europe, the Americas, the Caribbean, Africa and the Middle East. [ citation needed ] After the detection of zika virus in Brazil in April 2015, the first ever in the Western Hemisphere, it is now thought some chikungunya and dengue cases could in fact be zika virus cases or coinfections .The disease was first described by Marion Robinson and W.H.R. Lumsden in a pair of 1955 papers, following an outbreak in 1952 on the Makonde Plateau , along the border between Mozambique and Tanganyika (the mainland part of modern-day Tanzania ). Since then outbreaks have occurred occasionally in Africa, South Asia, and Southeast Asia; recent outbreaks have spread the disease over a wider range. [ citation needed ] The first recorded outbreak may have been in 1779. This is in agreement with the molecular genetics evidence that suggests it evolved around the year 1700. According to the original paper by Lumsden, the term 'chikungunya' is derived from the Makonde root verb kungunyala , meaning to dry up or become contorted. In concurrent research, Robinson [ citation needed ] glossed the Makonde term more specifically as "that which bends up". It is understood to refer to the contorted posture of people affected with the severe joint pain and arthritic symptoms associated with this disease. Subsequent authors apparently overlooked the references to the Makonde language and assumed the term to have been derived from Swahili , the lingua franca of the region. The erroneous attribution to Swahili has been repeated in numerous print sources. Erroneous spellings of the name of the disease are also in common use. [ citation needed ]Chikungunya is one of more than a dozen agents researched as a potential biological weapon . This disease is part of the group of neglected tropical diseases .

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Rift Valley fever

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Batai orthobunyavirus

Batai virus Batai orthobunyavirus (BATV) is a RNA virus belonging to order Bunyavirales , genus Orthobunyavirus .Batai virus (BATV) is an enveloped, single-stranded, negative sense RNA genome. It is a member of the genus Orthobunyavirus and belongs to the order Bunyavirales ; it was first isolated from Culex mosquitoes in Malaysia in 1955. Evidence from serological surveillance and virus isolation shows that this virus is widely distributed around the world. Similar to other orthobunyaviruses it contributes to both human and animal disease. In humans it has been noted in causing severe fever, and in bovines has been associated with premature birth, birth defects, and increased abortion rates. It is transmitted through mosquito bites, ticks, and biting midges, and occurs from cold to tropical regions of Africa, Asia, and Europe. The structure of Batai virus (BATV) consists of an enveloped nucleocapsid that is composed of three RNA segments: small (S), medium (M), and large (L). The S segment encodes the nucleocapsid (N) and the non-structural (NSs) proteins. The M segment encodes the virion surface glycoproteins (Gn, Gc) and non-structural proteins (NSm). The L segment encodes for the replicase/ transcriptase L protein. The nonstructural proteins NSm participate in virus assembly and NSs plays a key role in counteracting the host immune response by blocking alpha/beta interferon induction The full-length genome of NM/12 consists of a 947 base pair nucleotide S segment, a 4405 base pair nucleotide M segment, and a 6870 base pair nucleotide L segment. It also contains one open reading frame that encode three proteins of 151, 943, or 1395 amino acids. Viral enveloped nucleocapsids utilize membrane glycoproteins on their surface to mediate entry into host cells. Averaging of glycoprotein spikes of membrane viruses, such as HIV-1, has been a particularly successful approach for studying their structure. An understanding of the structure is integral for revealing both the molecular basis of virus–host interactions and guiding antiviral and vaccine design development. A software named Jsubtomo enables visualization of the structure of viral glycoprotein spikes to a resolution in the range of 20-40 à and allows for study of the study of higher order spike-to-spike interactions on the virion membrane. Extensive research has yet to be performed on the detailed crystalline structure of Batai virus, but research on the closely related Bunyamwera virus has shown a distinct functionality of each of the two nucleocapsid side chains. An N-terminal arm and a C-terminal tail were found to interact with neighboring NP protomers to form a tetrameric ring-shaped organization. Each protomer bound a 10-nucleotide RNA molecule, which was acquired from the expression host, in the positively charged crevice between the N and C lobes. Cryo-electron microscopy has also determined that whilst Bunyamwera virions are pleomorphic in shape, they display a locally ordered lattice of glycoprotein spikes. Each spike protrudes 18 nanometers from the viral membrane and becomes disordered upon introduction to an acidic environment. Although the exact icosahedral symmetry of a Batai virus viron is yet to be determined, studies using Cryo-electron tomography on related viruses of the Bunyaviridae family have shown that there exists an icosahedral lattice with clear T=12 quasisymmetry. Consequently, this triangulation number would correlate with a viral nuclear capsid exhibiting 720 faces. This study was performed on the Rift Valley Fever Virus (RVFV), which is an arthropod borne disease that is endemic to regions of Africa and Asia, namely the Rift Valley in Kenya from which its name is derived. Batai virus is a member of the genus Orthobunyavirus and a member of the family Bunyaviridae . Batai virus is part of a diverse group of arthropod-borne viruses. Classified via the Baltimore scheme , Batai virus is a negative-sense, single-stranded RNA virus. The orthobunyavirus genome has a characteristic segmented genome, with small, medium, and large (S, M, and L) segments which generally encode the nucleocapsid, envelope protein and the polymerase protein, respectively. The size of the S segment is 943 nucleotides, the size of the M segment is 4440 nucleotides, and the size of the L segment is 6870 nucleotides. In the S segment there are two open reading frames (ORFs), the nucleocapsid and non-structurals which were overlapping. The M segment has a polyprotein precursor in the open reading frame. The L segment encodes for an RNA-dependent RNA polymerase. Batai virus is geographically spread throughout Asia and Europe. It has been shown that batai viruses from Japan, Malaysia and India share homologies in the genomic sequence more so than when virus strains from Europe and Asia are compared to each other. Reassortment of the genome can have some serious effects. It has been observed that reassortment between the M segment and the S and L segments with another strain of Batai virus ( BUNV ) can cause an increase in the virulence of Batai virus. Reassortment of the genome within the genus Orthobunyavirus are not uncommon and can lead to an increase in virulence. It is well known that the geographical distribution of Batai virus (BATV) includes the regions of Europe, Asia and Africa. The most common vertebrate affected by BATV are domestic pigs, horses, ruminants and wild birds, which have been known to be the primary mammalian hosts. The transmission cycle of BATV occurs in agricultural ecosystems via Anopheles , Culex and Ochlerotatus species mosquitoes in a typical vertebrate–mosquito cycle. While limited research has been conducted on the viral cycle of the Batai virus, comparable studies with the close relative Bunyamwera virus has shown that viral infection begins in the salivary glands of mosquitos. At the onset of replication the virus particles coalesce into vacuole membranes lining the cytoplasm of the infected cells. Entry into the cell is facilitated by the viral enveloped nucleocapsid, which contains glycoproteins G1 and G2. Encoded by the M RNA segment they are involved in attachment to the host cell through unidentified receptors on the surface and elicit neutralizing antibodies. Transcription of BATV is said to be similar to that of influenza in that mRNA synthesis is primed by cap-containing oligonucleotides that are generated by a certain viral- endonuclease , functioning to cleave the host cell mRNA. These resulting primers are then incorporated into the viral mRNA. BATV will also encode for two non-structural proteins, NSm on the M segment and NSs on the S segment. During the process it is believed that NSm actively participates in assembly of the virus. These newly assembled viral particles will mature over a period of time inside of the hosts cell in the membranes of the Golgi apparatus before being released. However, while able to replicate in both vertebrate and invertebrate species, in mosquito cells no cell death is observed and persistent infection is established. Whereas in mammalian cells infection is typically categorized as lytic and eventually leads to cell death. This stems from the viruses ability to form clear lytic plaques in cells of vertebrate species but not in those derived from insects. It has been demonstrated in previous studies that in mammalian cells, the NSs protein will induce a shut-off of host protein synthesis which will lead to the death of the host cell. It has also been shown to counteract the host cell antiviral response. This would establish it as the main virulence factor as it acts during the transcriptional phase by inhibiting RNA polymerase II –mediated transcription. Meanwhile, the mosquito cells neither host cell transcription nor translation are inhibited by this fact. It would seem the difference in the behavior of the NSs protein could be one of the factors responsible for the different outcomes of infection attributed to the Batai virus in mammalian and mosquito cells. Some have theorized that a release method that does not rupture the cell membrane could explain why viral replication does not kill mosquito cells and persistence is maintained. Similar NSs proteins of the Rift Valley fever phlebovirus have quite a distinct size and amino acid sequence, but they play a similar role in mammalian cells in overcoming the innate immune responses that are a consequence of the global shut-down of the cells transcription mechanisms. Similar NSs proteins of the Rift Valley fever phlebovirus have quite a distinct size and amino acid sequence, but they play a similar role in mammalian cells in overcoming the innate immune responses that are a consequence of the global shut-down of the cells transcription mechanisms. Batai virus (BATV) is a member of the family Bunyaviridae. Associated viruses include Crimean-Congo hemorrhagic fever , Bunyamwera orthobunyavirus , and severe fever with thrombocytopenia syndrome. Crimean-Congo hemorrhagic fever is one of the viruses that is associated with Batai virus, as it is in the same family Bunyaviridae. This occurs in the same areas throughout the world including Africa, Asia, Europe. It mainly infects farmworkers in these regions of the world, and is a tick-borne illness. Infection results in high fever, chills, severe headache, dizziness, back, and abdominal pains. Other symptoms that have been noted include nausea, vomiting, diarrhea, and cardiovascular and neuropsychiatric changes. If severe symptoms may include hemorrhages in the skin, causing lesions or bruising. It has a 30% fatality rate. A closely associated disease is the Bunyamwera virus , which is of the same family and genus as the Batai virus (BATV); it is known to cause Bunyamwera fever. This particular virus is spread by mosquitos biting infected mice and then biting humans. Batai virus (BATV) is also associated with severe fever with thrombocytopenia syndrome (SFTS). This was a recently discovered in China in 2011 and is transmitted either directly to humans through ticks, or to house pets as an intermediate host and then on to humans. Symptoms are characterized by fever, vomiting, diarrhea, thrombocytopenia and leukopenia . SFTS virus has a 6-30% fatality rate.

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Rift Valley fever

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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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Orthohantavirus

Hantavirus Orthohantavirus is a genus of single-stranded, enveloped, negative-sense RNA viruses in the family Hantaviridae within the order Bunyavirales . Members of this genus may be called orthohantaviruses or simply hantaviruses . Orthohantaviruses typically cause chronic asymptomatic infection in rodents . Humans may become infected with hantaviruses through contact with rodent urine, saliva, or feces. Some strains cause potentially fatal diseases in humans, such as hantavirus hemorrhagic fever with renal syndrome (HFRS), or hantavirus pulmonary syndrome (HPS), also known as hantavirus cardiopulmonary syndrome (HCPS), while others have not been associated with known human disease (e.g. Prospect Hill virus ). HPS (HCPS) is a "rare respiratory illness associated with the inhalation of aerosolized rodent excreta (urine and feces) contaminated by hantavirus particles". Human infections of hantaviruses have almost entirely been linked to human contact with rodent excrement; however, in 2005 and 2019, human-to-human transmission of the Andes virus was reported in South America. Orthohantaviruses are named for the Greek word ortho - meaning "straight" or "true" and for the Hantan River in South Korea , where the first member species ( Hantaan virus ) was identified and isolated in 1976 by Ho Wang Lee . Hantavirus infections in humans are associated with two diseases: hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), caused by Old World and New World hantaviruses, respectively. A common feature of the two diseases is increased vascular permeability, which causes hypotension , thrombocytopenia , and leukocytosis . The pulmonary illness is the more fatal of the two, whereas the hemorrhagic fever is much more common. Treatment for both is primarily supportive as there is no specific treatment for hantavirus infections. While many hantaviruses cause either of the two diseases, some are not known to cause illness, such as the Prospect Hill orthohantavirus . Hemorrhagic fever with renal syndrome (HFRS) is caused chiefly by hantaviruses in Asia and Europe. Clinical presentation varies from subclinical to fatal, depending on the virus. After an incubation period of 2–4 weeks, the typical illness starts with non-specific symptoms such as high fever, chills, headache, backache, abdominal pains, nausea, and vomiting. After the initial period, bleeding under the skin begins, often paired with low blood pressure, followed by further internal bleeding throughout the body. Renal dysfunction leading to further health issues begins thereafter, which may cause death. A more mild form of HFRS that occurs in Europe is called "nephropathia epidemica" (NE). Trench nephritis during World War I is now thought to have been HFRS. [ citation needed ] Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is usually caused by hantaviruses in the Americas. Its incubation period ranges from 16 to 24 days. Illness initially shows similar symptoms as HFRS. After a few days of non-specific symptoms, sudden onset of progressive, or productive, coughing, shortness of breath, and elevated heart rate occur due to fluid buildup in the lungs . These symptoms are accompanied by impairment of lymphoid organs . Death from cardiovascular shock may occur rapidly after the appearance of severe symptoms. While HCPS is typically associated with New World hantaviruses, the Puumala orthohantavirus in Europe has also caused the syndrome on rare occasions. Hantaviruses are transmitted by contact with the bodily fluids of rodents, particularly from saliva from bites and especially from inhalation of viral particles from urine and feces in aerosols . The manner of transmission is the same for both diseases caused by hantaviruses. Among the HCPS-causing hantaviruses is the Andes orthohantavirus , which is the only hantavirus confirmed to be capable of spreading from person to person, though this is rare. Hemorrhagic fever with renal syndrome (HFRS) is caused chiefly by hantaviruses in Asia and Europe. Clinical presentation varies from subclinical to fatal, depending on the virus. After an incubation period of 2–4 weeks, the typical illness starts with non-specific symptoms such as high fever, chills, headache, backache, abdominal pains, nausea, and vomiting. After the initial period, bleeding under the skin begins, often paired with low blood pressure, followed by further internal bleeding throughout the body. Renal dysfunction leading to further health issues begins thereafter, which may cause death. A more mild form of HFRS that occurs in Europe is called "nephropathia epidemica" (NE). Trench nephritis during World War I is now thought to have been HFRS. [ citation needed ]Hantavirus pulmonary syndrome (HPS), also called hantavirus cardiopulmonary syndrome (HCPS), is usually caused by hantaviruses in the Americas. Its incubation period ranges from 16 to 24 days. Illness initially shows similar symptoms as HFRS. After a few days of non-specific symptoms, sudden onset of progressive, or productive, coughing, shortness of breath, and elevated heart rate occur due to fluid buildup in the lungs . These symptoms are accompanied by impairment of lymphoid organs . Death from cardiovascular shock may occur rapidly after the appearance of severe symptoms. While HCPS is typically associated with New World hantaviruses, the Puumala orthohantavirus in Europe has also caused the syndrome on rare occasions. Hantaviruses are transmitted by contact with the bodily fluids of rodents, particularly from saliva from bites and especially from inhalation of viral particles from urine and feces in aerosols . The manner of transmission is the same for both diseases caused by hantaviruses. Among the HCPS-causing hantaviruses is the Andes orthohantavirus , which is the only hantavirus confirmed to be capable of spreading from person to person, though this is rare. Hantavirus virions are about 80–120 nm in diameter. The lipid bilayer of the viral envelope is about 5 nm thick and is embedded with viral surface proteins to which sugar residues are attached. These glycoproteins, known as Gn and Gc, are encoded by the M segment of the viral genome. They tend to associate ( heterodimerize ) with each other and have both an interior tail and an exterior domain that extends to about 6 nm beyond the envelope surface. [ citation needed ] Inside the envelope are the nucleocapsids. These are composed of many copies of the nucleocapsid protein N, which interact with the three segments of the viral genome to form helical structures. The virally encoded RNA polymerase is also found in the interior. By mass, the virion is greater than 50% protein, 20–30% lipid, and 2–7% carbohydrate. The density of the virions is 1.18 g/cm 3 . These features are common to all members of the family Hantaviridae . [ citation needed ] The genome of hantaviruses is negative-sense, single-stranded RNA . Their genomes are composed of three segments: the small (S), medium (M), and large (L) segments. The S segment, 1–3 kilobases (kb) in length, encodes for the nucleocapsid (N) protein. The M segment, 3.2–4.9 kb in length, encodes a glycoprotein precursor polyprotein that is co-translationally cleaved into the envelope glycoproteins Gn and Gc, alternatively called G1 and G2. The L segment, 6.8–12 kb in length, encodes the L protein which functions primarily as the viral RNA-dependent RNA polymerase used for transcription and replication. Within virions , the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5′ and 3′ terminal sequences of genomic segments. [ citation needed ] As with other Bunyavirales , each of the three segments has a consensus 3′-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 5′-terminal sequence and is distinct from those of the other four genera in the family. These sequences appear to form panhandle structure which seem likely to play a role in replication and encapsidation facilitated by binding with the viral nucleocapsid (N) protein. The large segment is 6530–6550 nucleotides (nt) in length, the medium is 3613–3707 nt in length and the small is 1696–2083 nt in length. [ citation needed ] No nonstructural proteins are known, unlike the other genera in this family. At the 5′ and 3′ of each segment are short noncoding sequences: the noncoding segment in all sequences at the 5′ end is 37–51 nt. The 3′ noncoding regions differ: L segment 38–43 nt; M segment 168–229 nt; and S segment 370–730 nt. The 3′ end of the S segment is conserved between the genera suggesting a functional role. [ citation needed ] Viral entry into host cells initiates by binding to surface cell receptors. Integrins are considered to be the main receptors for hantaviruses in vitro , but complement decay-accelerating factor (DAF) and globular heads of complement C1q receptor (gC1qR) have mediated attachment in cultured cells too. Entry may proceed through a number of possible routes, including clathrin -dependent endocytosis , clathrin-independent receptor-mediated endocytosis, and micro pinocytosis . Viral particles are then transported to late endosomes . Gc-mediated membrane fusion with the endosomal membrane , triggered by low pH , releases the nucleocapsid into the cytoplasm . After the release of the nucleocapsids into cytoplasm, the complexes are targeted to the endoplasmic reticulum–Golgi intermediate compartments (ERGIC) through microtubular -associated movement resulting in the formation of viral factories at ERGIC. [ citation needed ] These factories then facilitate transcription and subsequent translation of the viral proteins. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this cap snatching , the mRNAs of hantaviruses are capped and contain nontemplated 5′-terminal extensions. The G1 (or Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex , where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae . Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis . [ citation needed ] The pathogenesis of hantavirus infections is unclear as there is a lack of animal models to describe it (rats and mice do not seem to acquire severe disease). While the primary site of viral replication in the body is not known, in HFRS the main effect is in the blood vessels while in HPS most symptoms are associated with the lungs. In HFRS, there are increased vascular permeability and decreased blood pressure due to endothelial dysfunction and the most dramatic damage is seen in the kidneys, whereas in HPS, the lungs, spleen, and gall bladder are most affected. Early symptoms of HPS tend to present similarly to the flu (muscle aches, fever and fatigue) and usually appear around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) include difficulty breathing, shortness of breath and coughing. Findings of significant congruence between phylogenies of hantaviruses and phylogenies of their rodent reservoirs have led to the theory that rodents, although infected by the virus, are not harmed by it because of long-standing hantavirus–rodent host coevolution , although findings in 2008 led to new hypotheses regarding hantavirus evolution. Various hantaviruses have been found to infect multiple rodent species, and cases of cross-species transmission ( host switching ) have been recorded. Additionally, rates of substitution based on nucleotide sequence data reveal that hantavirus clades and rodent subfamilies may not have diverged at the same time. Furthermore, as of 2007 hantaviruses have been found in multiple species of non-rodent shrews and moles. Taking into account the inconsistencies in the theory of coevolution, it was proposed in 2009 that the patterns seen in hantaviruses in relation to their reservoirs could be attributed to preferential host switching directed by geographical proximity and adaptation to specific host types. Another proposal from 2010 is that geographical clustering of hantavirus sequences may have been caused by an isolation-by-distance mechanism. Upon comparison of the hantaviruses found in hosts of orders Rodentia and Eulipotyphla , it was proposed in 2011 that the hantavirus evolutionary history is a mix of both host switching and codivergence and that ancestral shrews or moles, rather than rodents, may have been the early original hosts of ancient hantaviruses. A Bayesian analysis in 2014 suggested a common origin for these viruses ~2000 years ago. The association with particular rodent families appears to have been more recent. The viruses carried by the subfamilies Arvicolinae and Murinae originated in Asia 500–700 years ago. These subsequently spread to Africa , Europe , North America and Siberia possibly carried by their hosts. The species infecting the subfamily Neotominae evolved 500–600 years ago in Central America and then spread toward North America. The species infecting Sigmodontinae evolved in Brazil 400 years ago. Their ancestors may have been a Neotominae-associated virus from northern South America. The evolution of shrew -borne hantaviruses appears to have involved natural occurrences of homologous recombination events and the reassortment of genome segments. The evolution of Tula orthohantavirus carried by the European common vole also appears to have involved homologous recombination events. Hantavirus virions are about 80–120 nm in diameter. The lipid bilayer of the viral envelope is about 5 nm thick and is embedded with viral surface proteins to which sugar residues are attached. These glycoproteins, known as Gn and Gc, are encoded by the M segment of the viral genome. They tend to associate ( heterodimerize ) with each other and have both an interior tail and an exterior domain that extends to about 6 nm beyond the envelope surface. [ citation needed ] Inside the envelope are the nucleocapsids. These are composed of many copies of the nucleocapsid protein N, which interact with the three segments of the viral genome to form helical structures. The virally encoded RNA polymerase is also found in the interior. By mass, the virion is greater than 50% protein, 20–30% lipid, and 2–7% carbohydrate. The density of the virions is 1.18 g/cm 3 . These features are common to all members of the family Hantaviridae . [ citation needed ]The genome of hantaviruses is negative-sense, single-stranded RNA . Their genomes are composed of three segments: the small (S), medium (M), and large (L) segments. The S segment, 1–3 kilobases (kb) in length, encodes for the nucleocapsid (N) protein. The M segment, 3.2–4.9 kb in length, encodes a glycoprotein precursor polyprotein that is co-translationally cleaved into the envelope glycoproteins Gn and Gc, alternatively called G1 and G2. The L segment, 6.8–12 kb in length, encodes the L protein which functions primarily as the viral RNA-dependent RNA polymerase used for transcription and replication. Within virions , the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, the RNA component of which circularizes due to sequence complementarity between the 5′ and 3′ terminal sequences of genomic segments. [ citation needed ] As with other Bunyavirales , each of the three segments has a consensus 3′-terminal nucleotide sequence (AUCAUCAUC), which is complementary to the 5′-terminal sequence and is distinct from those of the other four genera in the family. These sequences appear to form panhandle structure which seem likely to play a role in replication and encapsidation facilitated by binding with the viral nucleocapsid (N) protein. The large segment is 6530–6550 nucleotides (nt) in length, the medium is 3613–3707 nt in length and the small is 1696–2083 nt in length. [ citation needed ] No nonstructural proteins are known, unlike the other genera in this family. At the 5′ and 3′ of each segment are short noncoding sequences: the noncoding segment in all sequences at the 5′ end is 37–51 nt. The 3′ noncoding regions differ: L segment 38–43 nt; M segment 168–229 nt; and S segment 370–730 nt. The 3′ end of the S segment is conserved between the genera suggesting a functional role. [ citation needed ]Viral entry into host cells initiates by binding to surface cell receptors. Integrins are considered to be the main receptors for hantaviruses in vitro , but complement decay-accelerating factor (DAF) and globular heads of complement C1q receptor (gC1qR) have mediated attachment in cultured cells too. Entry may proceed through a number of possible routes, including clathrin -dependent endocytosis , clathrin-independent receptor-mediated endocytosis, and micro pinocytosis . Viral particles are then transported to late endosomes . Gc-mediated membrane fusion with the endosomal membrane , triggered by low pH , releases the nucleocapsid into the cytoplasm . After the release of the nucleocapsids into cytoplasm, the complexes are targeted to the endoplasmic reticulum–Golgi intermediate compartments (ERGIC) through microtubular -associated movement resulting in the formation of viral factories at ERGIC. [ citation needed ] These factories then facilitate transcription and subsequent translation of the viral proteins. Transcription of viral genes must be initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this cap snatching , the mRNAs of hantaviruses are capped and contain nontemplated 5′-terminal extensions. The G1 (or Gn) and G2 (Gc) glycoproteins form hetero-oligomers and are then transported from the endoplasmic reticulum to the Golgi complex , where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirus virions are believed to assemble by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae . Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis . [ citation needed ]The pathogenesis of hantavirus infections is unclear as there is a lack of animal models to describe it (rats and mice do not seem to acquire severe disease). While the primary site of viral replication in the body is not known, in HFRS the main effect is in the blood vessels while in HPS most symptoms are associated with the lungs. In HFRS, there are increased vascular permeability and decreased blood pressure due to endothelial dysfunction and the most dramatic damage is seen in the kidneys, whereas in HPS, the lungs, spleen, and gall bladder are most affected. Early symptoms of HPS tend to present similarly to the flu (muscle aches, fever and fatigue) and usually appear around 2 to 3 weeks after exposure. Later stages of the disease (about 4 to 10 days after symptoms start) include difficulty breathing, shortness of breath and coughing. Findings of significant congruence between phylogenies of hantaviruses and phylogenies of their rodent reservoirs have led to the theory that rodents, although infected by the virus, are not harmed by it because of long-standing hantavirus–rodent host coevolution , although findings in 2008 led to new hypotheses regarding hantavirus evolution. Various hantaviruses have been found to infect multiple rodent species, and cases of cross-species transmission ( host switching ) have been recorded. Additionally, rates of substitution based on nucleotide sequence data reveal that hantavirus clades and rodent subfamilies may not have diverged at the same time. Furthermore, as of 2007 hantaviruses have been found in multiple species of non-rodent shrews and moles. Taking into account the inconsistencies in the theory of coevolution, it was proposed in 2009 that the patterns seen in hantaviruses in relation to their reservoirs could be attributed to preferential host switching directed by geographical proximity and adaptation to specific host types. Another proposal from 2010 is that geographical clustering of hantavirus sequences may have been caused by an isolation-by-distance mechanism. Upon comparison of the hantaviruses found in hosts of orders Rodentia and Eulipotyphla , it was proposed in 2011 that the hantavirus evolutionary history is a mix of both host switching and codivergence and that ancestral shrews or moles, rather than rodents, may have been the early original hosts of ancient hantaviruses. A Bayesian analysis in 2014 suggested a common origin for these viruses ~2000 years ago. The association with particular rodent families appears to have been more recent. The viruses carried by the subfamilies Arvicolinae and Murinae originated in Asia 500–700 years ago. These subsequently spread to Africa , Europe , North America and Siberia possibly carried by their hosts. The species infecting the subfamily Neotominae evolved 500–600 years ago in Central America and then spread toward North America. The species infecting Sigmodontinae evolved in Brazil 400 years ago. Their ancestors may have been a Neotominae-associated virus from northern South America. The evolution of shrew -borne hantaviruses appears to have involved natural occurrences of homologous recombination events and the reassortment of genome segments. The evolution of Tula orthohantavirus carried by the European common vole also appears to have involved homologous recombination events. Orthohantaviruses belong to the family Hantaviridae and members of both the genus and the family are called hantaviruses. The genus also belongs to the subfamily Mammantavirinae , the mammalian hantaviruses, with three other genera. Orthohantaviruses specifically are mammalian hantaviruses that are transmitted among rodents. The genus contains these 38 species: Hantaviruses that were formerly classified as species in this genus and which were not reassigned as member viruses of any existing species include: Isla Vista hantavirus , also called Isla Vista virus Muleshoe hantavirus , also called Muleshoe virus Rio Segundo hantavirus , also called Rio Segundo virusAccording to the U.S. CDC, the best prevention against contracting hantavirus is to eliminate or minimize contact with rodents in the home, workplace, or campsite. As the virus can be transmitted by rodent saliva, excretions, and bites, control of rats and mice in areas frequented by humans is key for disease prevention. General prevention can be accomplished by disposing of rodent nests, sealing any cracks and holes in homes where mice or rats could enter, setting traps, or laying down poisons or using natural predators such as cats in the home. The duration that hantaviruses remain infectious in the environment varies based on factors such as the rodent's diet, temperature, humidity, and whether indoors or outdoors. The viruses have been demonstrated to remain active for 2–3 days at normal room temperature, while ultraviolet rays in direct sunlight kill them within a few hours. Rodent droppings or urine of indeterminate age, though, should always be treated as infectious. As of 2021 [ update ] , no vaccines against hantaviruses have been approved by the U.S. FDA, but whole virus inactivated bivalent vaccines against Hantaan virus and Seoul virus are available in China and South Korea. In both countries, the use of the vaccine, combined with other preventive measures, has significantly reduced the incidence of hantavirus infections. Apart from these vaccines, four types of vaccines have been researched: DNA vaccines targeting the M genome segment and the S genome segment, subunit vaccines that use recombinant Gn, Gc, and N proteins of the virus, virus vector vaccines that have recombinant hantavirus proteins inserted in them, and virus-like particle vaccines that contain viral proteins, but lack genetic material. Of these, only DNA vaccines have entered into clinical trials. As of 2021 [ update ] , no vaccines against hantaviruses have been approved by the U.S. FDA, but whole virus inactivated bivalent vaccines against Hantaan virus and Seoul virus are available in China and South Korea. In both countries, the use of the vaccine, combined with other preventive measures, has significantly reduced the incidence of hantavirus infections. Apart from these vaccines, four types of vaccines have been researched: DNA vaccines targeting the M genome segment and the S genome segment, subunit vaccines that use recombinant Gn, Gc, and N proteins of the virus, virus vector vaccines that have recombinant hantavirus proteins inserted in them, and virus-like particle vaccines that contain viral proteins, but lack genetic material. Of these, only DNA vaccines have entered into clinical trials. Ribavirin may be a drug for HPS and HFRS, but its effectiveness remains unknown; still, spontaneous recovery is possible with supportive treatment. People with suspected hantavirus infection may be admitted to a hospital, and given oxygen and mechanical ventilation support to help them breathe during the acute pulmonary stage with severe respiratory distress. Immunotherapy, administration of human neutralizing antibodies during acute phases of hantavirus, has been studied only in mice, hamsters, and rats. No controlled clinical trials have been reported. Hantavirus infections have been reported from all continents except Australia. Regions especially affected by HFRS include China , the Korean Peninsula , Russia (Hantaan, Puumala, and Seoul viruses), and Northern and Western Europe ( Puumala and Dobrava virus). Regions with the highest incidences of hantavirus pulmonary syndrome include Argentina , Chile , Brazil , the United States , Canada , and Panama . [ citation needed ] In 2010, a novel hantavirus, Sangassou virus , was isolated in Africa, which causes HFRS. In China, Hong Kong, the Korean Peninsula, and Russia, HFRS is caused by Hantaan, Puumala, and Seoul viruses. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. As of 2005 [ update ] , no human infections have been reported in Australia, though rodents were found to carry antibodies. In Europe, two hantaviruses – Puumala and Dobrava-Belgrade viruses – are known to cause HFRS. Puumala usually causes a generally mild disease, nephropathia epidemica , which typically presents with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision. Dobrava infections are similar, except that they often also have hemorrhagic complications. [ citation needed ] Puumala virus is carried by its rodent host, the bank vole ( Clethrionomys glareolus ), and is present throughout most of Europe, except for the Mediterranean region. Four Dobrava virus genotypes are known, each carried by a different rodent species. Genotype Dobrava is found in the yellow-necked mouse ( Apodemus flavicollis ), genotypes Saaremaa and Kurkino in the striped field mouse ( Apodemus agrarius ), and genotype Sochi in the Black Sea field mouse ( Apodemus ponticus ). [ citation needed ] In 2017 alone, the Robert Koch Institute (RKI) in Germany received 1,713 notifications of hantavirus infections. The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . Agents of HPS found in South America include the Andes virus (also called Oran, Castelo de Sonhos – Portuguese for "Castle of Dreams", Lechiguanas, Juquitiba, Araraquara, and Bermejo virus, among many other synonyms), which is the only hantavirus that has shown an interpersonal form of transmission, and the Laguna Negra virus , an extremely close relative of the previously known Rio Mamore virus. [ citation needed ] Rodents that have been shown to carry hantaviruses include Abrothrix longipilis and Oligoryzomys longicaudatus . In 2010, a novel hantavirus, Sangassou virus , was isolated in Africa, which causes HFRS. In China, Hong Kong, the Korean Peninsula, and Russia, HFRS is caused by Hantaan, Puumala, and Seoul viruses. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. In March 2020, a man from Yunnan tested positive for hantavirus. He died while travelling to Shandong for work on a chartered bus. According to the Global Times reports, around 32 other people have been tested for the virus. As of 2005 [ update ] , no human infections have been reported in Australia, though rodents were found to carry antibodies. In Europe, two hantaviruses – Puumala and Dobrava-Belgrade viruses – are known to cause HFRS. Puumala usually causes a generally mild disease, nephropathia epidemica , which typically presents with fever, headache, gastrointestinal symptoms, impaired renal function, and blurred vision. Dobrava infections are similar, except that they often also have hemorrhagic complications. [ citation needed ] Puumala virus is carried by its rodent host, the bank vole ( Clethrionomys glareolus ), and is present throughout most of Europe, except for the Mediterranean region. Four Dobrava virus genotypes are known, each carried by a different rodent species. Genotype Dobrava is found in the yellow-necked mouse ( Apodemus flavicollis ), genotypes Saaremaa and Kurkino in the striped field mouse ( Apodemus agrarius ), and genotype Sochi in the Black Sea field mouse ( Apodemus ponticus ). [ citation needed ] In 2017 alone, the Robert Koch Institute (RKI) in Germany received 1,713 notifications of hantavirus infections. The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . The primary cause of the disease in Canada is Sin Nombre virus-infected deer mice. Between 1989 and 2014, 109 confirmed cases were reported, with the death rate estimated at 29%. The virus exists in deer mice nationwide, but cases were concentrated in western Canada (British Columbia, Alberta, Saskatchewan, and Manitoba) with only one case in eastern Canada. In Canada, "[a]ll cases occurred in rural settings and approximately 70% of the cases have been associated with domestic and farming activities." In the United States, minor cases of HPS include Sin Nombre orthohantavirus , New York orthohantavirus , Bayou orthohantavirus , and possibly Black Creek Canal orthohantavirus . [ citation needed ] As of January 2017 [ update ] , 728 cases of hantavirus had been reported in the United States cumulatively since 1995, across 36 states, not including cases with presumed exposure outside the United States. More than 96% of cases have occurred in states west of the Mississippi River . The top 10 states by number of cases reported (which differs slightly from a count ordered by the state of original exposure ) were New Mexico (109), Colorado (104), Arizona (78), California (61), Washington (50), Texas (45), Montana (43), Utah (38), Idaho (21), and Oregon (21); 36% of the total reported cases have resulted in death. In Mexico, rodents have been found to carry hantaviruses include Thomas's giant deer mouse (Megadontomys thomasi) , the pack rat Neotoma picta , Orizaba deer mouse (Peromyscus beatae) , Western harvest mouse (Reithrodontomys megalotis) and Sumichrast's harvest mouse (Reithrodontomys sumichrasti) . Agents of HPS found in South America include the Andes virus (also called Oran, Castelo de Sonhos – Portuguese for "Castle of Dreams", Lechiguanas, Juquitiba, Araraquara, and Bermejo virus, among many other synonyms), which is the only hantavirus that has shown an interpersonal form of transmission, and the Laguna Negra virus , an extremely close relative of the previously known Rio Mamore virus. [ citation needed ] Rodents that have been shown to carry hantaviruses include Abrothrix longipilis and Oligoryzomys longicaudatus . Hantavirus HFRS was likely first referenced in China in the 12th century. The first clinical recognition was in 1931 in northeast China. Around the same time in the 1930s, NE was identified in Sweden. HFRS came to the recognition of western physicians during the Korean War between 1951 and 1954 when more than 3,000 United Nations soldiers fell ill in an outbreak. In 1976, the first pathogenic hantavirus, the Hantaan orthohantavirus , was isolated from rodents near the Hantan River in South Korea . Other prominent hantaviruses that cause HFRS, including the Dobrava-Belgrade orthohantavirus , Puumala orthohantavirus , and Seoul orthohantavirus , were identified in the years after then and are collectively referred to as the Old World hantaviruses. In 1993, an outbreak of HCPS , then unrecognized, occurred in the Four Corners region of the United States and led to the discovery of the Sin Nombre orthohantavirus . Since then, approximately 43 hantavirus strains, of which 20 are pathogenic, have been found in the Americas and are referred to as the New World hantaviruses. This includes the Andes orthohantavirus , one of the primary causes of HCPS in South America and the only hantavirus known to be capable of person-to-person transmission. In late medieval England a mysterious sweating sickness swept through the country in 1485 just before the Battle of Bosworth Field . Noting that the symptoms overlap with hantavirus pulmonary syndrome, several scientists have theorized that the virus may have been the cause of the disease. The hypothesis was criticized because sweating sickness was recorded as being transmitted from human to human, whereas hantaviruses were not known to spread in this way.

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Rift Valley fever

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List of systemic diseases with ocular manifestations

An ocular manifestation of a systemic disease is an eye condition that directly or indirectly results from a disease process in another part of the body. There are many diseases known to cause ocular or visual changes. Diabetes , for example, is the leading cause of new cases of blindness in those aged 20–74, with ocular manifestations such as diabetic retinopathy and macular edema affecting up to 80% of those who have had the disease for 15 years or more. [ citation needed ] Other diseases such as acquired immunodeficiency syndrome (AIDS) and hypertension are commonly found to have associated ocular symptoms.

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Rift Valley fever

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Ross River virus

Ross River virus ( RRV ) is a small encapsulated single-strand RNA Alphavirus endemic to Australia, Papua New Guinea and other islands in the South Pacific. It is responsible for a type of mosquito -borne, non-lethal but extremely debilitating tropical disease known as Ross River fever , previously termed "epidemic polyarthritis ". There is no known cure, and it can last in the host's system for up to 20 years. The virus is suspected to be enzootic in populations of various native Australian mammals, and has been found on occasion in horses. Taxonomically, Ross River virus belongs to the virus genus Alphavirus , which is part of the family Togaviridae . The alphaviruses are a group of small enveloped single-strand positive-sense RNA viruses. RRV belongs to a subgroup of "Old World" (Eurasian-African-Australasian) alphaviruses, and belongs to the SF antigenic complex of the genus Alphavirus. The virions (virus particles) themselves contain their genome in a protein capsid 700 à in diameter. They are characterised by the presence of two glycoproteins (E1 and E2) embedded as trimeric dimers in a host-derived lipid envelope . Because RRV is transmitted by mosquitos , it is considered an arbovirus , a non-taxonomic term for viruses borne by arthropod vectors .In 1928, an outbreak of acute febrile arthritis was recorded in Narrandera and Hay in New South Wales , Australia. In 1943, several outbreaks of arthralgia and arthritis were described in the Northern Territory , Queensland and the Schouten Islands , off the northern coast of Papua New Guinea . The name "epidemic polyarthritis" was coined for the disease. In 1956, an epidemic occurred in the Murray Valley which was compared to "acute viral polyarthritis" caused by the Chikungunya virus . The Australian disease seemed to progress in a milder fashion. In 1956, serological testing suggested an unknown new species of alphavirus (group A arbovirus) was the likely culprit. In July and August 1956 and 1957, a virus recovered from mosquitoes collected near Tokyo , Japan , and was dubbed Sagiyama virus . For a time, it was thought to be a separate species, but is now considered conspecific with Ross River virus . In 1959, a new alphavirus was identified in samples from a mosquito ( Aedes vigilax ) trapped in the Ross River , located in Townsville , Queensland, Australia. Further serological testing showed that patients who had suffered "epidemic polyarthritis" in Queensland had antibodies to the virus. The new virus was named Ross River virus , and the disease Ross River fever . The virus itself was first isolated in 1972 using suckling mice . It was found that RRV isolated from human serum could kill mice. However, the serum containing the virus that was used had come from an Aboriginal boy from Edward River , North Queensland. The child had a fever and a rash but no arthritis, making the link between RRV and Ross River fever less than concrete. The largest-ever outbreak of the virus was in 1979–1980 and occurred in the western Pacific. The outbreak involved the islands of Fiji , Samoa , the Cook Islands , and New Caledonia . However, RRV was later isolated in humans following a series of epidemic polyarthritis outbreaks in Fiji , Samoa and the Cook Islands during 1979. RRV was isolated in an Australian patient suffering from Ross River fever in 1985. In 2010, Ross River virus was found to have made its way to the Aundh area in Pune , India , and spread to other parts of the city. The RRV infection is characterised by inflammation and pain to multiple joints. Hydration by sufficient fluid intake is recommended, to ensure that the fever does not rise to very dangerous levels. It is also recommended that a doctor be consulted immediately as regular paracetamol gives only temporary reprieve from the fever. [ citation needed ]In rural and regional areas of Australia, the continued prevalence of Ross River virus is thought to be supported by natural reservoirs such as large marsupial mammals. Antibodies to Ross River virus have been found in a wide variety of placental and marsupial mammals, and also in a few bird species. It is not presently known what reservoir hosts support Ross River virus in metropolitan areas such as Brisbane . The southern saltmarsh mosquito ( Aedes camptorhynchus ), which is known to carry the Ross River virus , was discovered in Napier, New Zealand , in 1998. Due to an 11-year program by the New Zealand Ministry of Health , and later the Ministry of Agriculture & Fisheries , the species was declared completely eradicated from New Zealand in July 2010. As of September 2006, there has never been a report of a case of Ross River virus acquired within New Zealand. Separate mosquito species may act as vector, widespread across areas and seasonal/geographical locations. In southern and northern regions, the Aedes group ( A. camptorhynchus and A. vigilax ) are the main RRV carriers. However, inland the Culex annulirostris is the main carrier with Aedes mosquitoes becoming active during wet seasons. Due to the expansion and housing demand in the south west of Western Australia , residential development is occurring closer to wetlands in spite of the fact that the ecosystem is known for mosquito breeding. Particularly in the Peel region where living near water is desirable for aesthetic value. Over the decade of June 2011 – 2012 the population increased by 44,000 residents averaging a rate of 4.5 per cent per annum. In June 2013 the Peel region accounted for approximately five per cent of the State's population and predicted to account for around 6.7 per cent of Western Australia's population by 2031. A study comparing the risk of contracting Ross River virus (RRV) and the distance of the dwellings from Muddy Lakes. The reports showed within a one kilometre buffer zone there were approximately 1550 mosquitos in traps per night with 89% of them being Ae. camptorhynchus decreasing to approximately 450 mosquitos with 57% Ae. camptorhynchus at the six kilometre buffer zone. The study suggests that there is a significantly higher risk of contracting RRV when living closer to Muddy Lakes however, there was a rise in the two kilometre buffer zone of 3700 mosquitos with 94% Ae. camptorhynchus . A similar trend in the study same study conducted in the Peel region resulting in less mosquitoes the further away the buffer distance. In 1995–96 Leschenault and Capel-Busselton were affected by an outbreak of 524 cases of RRV disease. Although this occurred around a decade ago, the data analysed the total RRV cases per 1000 persons for each 500m buffer zone. This shows an elevated risk of contracting the disease if living in close proximity to the Leschenault Estuary , within 2 km being the strongest disease risk gradient. Evidence shows that there is a strong correlation between contracting RRV when living in close proximity to wetlands in the south west of Western Australia. However, due to continuous growth and development of residential areas around these wetlands it is expected that problems with RRV disease will occur.There are several factors that can contribute to an individual's risk for Ross River virus in Australia. These risks were trialed in a study conducted in tropical Australia which illustrate that factors such as camping, light coloured clothing, exposure to certain flora and fauna and specific protective mechanisms are able to increase or decrease the likelihood of contracting the virus. By increasing the frequency of camping the individual's risk increases eight-fold, suggesting that an increased exposure to wildlife increases risk. This is shown by the narrow 95% confidence interval of 1.07–4.35 within the study. For example, an individual's exposure to kangaroos , wallabies and bromeliad plants also increased risk, suggesting that they are reservoirs for infection, breeding sites for mosquitoes and potential vectors of the virus. Ross River virus antibodies have been found in captive populations of tammar wallabies and wallaroos in urban areas in New South Wales, Australia, and are potential reservoirs for the virus. Although these areas show a higher risk for the virus, humans should still enjoy the wildlife but consider that preventive mechanisms as increasingly important while camping.Ross River virus can be easily prevented through small behavioural mechanisms which should be of high importance in tropical areas and during participation of outdoor activities. Firstly, insect repellent should be rigorously used as to prevent bites from insects that specifically include mosquitoes which are vectors that carry the disease. A study in tropical Australia shows a very narrow 95% confidence interval of 0.20–1.00 for a decrease in Ross River virus risk as a result of increased use of insect repellent, suggesting a strong correlation between the two. Following, burning citronella candles are based on the same principle, that it repels insects that are vectors of the virus. Burning such candles also show a strong correlation with decreased Ross River virus risk shown in the same study with a narrow 95% confidence interval of 0.10–0.78. Secondly, wearing light coloured clothing decrease the risk of Ross River virus three-fold. This is again based on the repelling of vectors such as mosquitoes through the use of bright colours. Lastly, high risk areas should be minimised by mechanisms of prevention that are applied within households. For example, screens should be fitted to windows and doors to prevent entry of insects carrying the virus and potential breeding areas such as open water containers or water holding plants should be removed. Therefore, specific climatic environments should be assessed for high risk factors and the appropriate precautions should be taken in response.The study of RRV has been recently facilitated by a mouse model. Inbred mice infected with RRV develop hind-limb arthritis/arthralgia. The disease in mice, similar to humans, is characterised by an inflammatory infiltrate including macrophages which are immunopathogenic and exacerbate disease. Furthermore, recent data indicate that the serum component, C3, directly contributes to disease since mice deficient in the C3 protein do not suffer from severe disease following infection. Ross River virus can cause multiple symptoms in someone who is infected, the most common being arthritis or joint pain. Other symptoms include a rash on the limbs of the body, which often occurs roughly 10 days after arthritis begins. Lymph nodes may enlarge, most commonly in the arm pits or groin region, and rarely a feeling of 'pins and needles' in the persons hands and feet, but only occurs in a small number of people. The virus also causes moderate symptoms in horses . The symptoms of Ross River virus are important to recognise for early diagnosis and therefore early treatment. Symptoms have been illustrated in a case report of an infected Thuringian traveller returning from South-East Australia. This case showed flu-like symptoms that include fever , chills , headache and pains in the body. Additionally, joint pain arose in which some joints become swollen and joint stiffness was particularly noticeable. A clinical examination of the infected individual shows a significant decrease of specific antibodies despite the normal blood count levels. A rash is a good indication that is likely to occur but usually disappears after ten days. The symptoms of Ross River virus are important to be aware of so that early treatment can be administered before the virus worsens. The time between catching the disease and experiencing symptoms is anywhere between three days to three weeks, usually it takes about 1–2 weeks. A person can be tested for Ross River virus by a blood test , other illnesses may need to be excluded before diagnosis. Testing for Ross River virus should occur in patients who are experiencing acute polyarthritis, tiredness and/or rashes (~90%) with a history of travel within areas prone to infection from the virus. Serology (blood tests) is the appropriate manner by which to diagnose Ross River virus . Within 7 days of infection, the virus produces Immunoglobulin M (IgM) and is a presumptive positive diagnosis. IgM may persist for months or even years and therefore false positives may be triggered by Barmah Forest virus , rubella , Q fever or rheumatoid factor . To completely test for Ross River virus , a second serology test must be conducted 10–14 days after the first. The patient may then be declared positive for Ross River virus infection if there is a 4-fold increase of IgM antibody count. Ross River fever is also known as Ross River virus infection or Ross River virus disease . Ross River virus is named after the Ross River in Townsville, which is the place where it was first identified. Ross River fever is the most common mosquito-borne disease in Australia, and nearly 5000 people are reported to be infected with the virus each year.

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Rift Valley fever

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List of biosafety level 4 organisms

Biosafety level 4 (BSL-4) organisms are dangerous or exotic agents which pose high risk of life-threatening disease, aerosol-transmitted lab infections, or related agents with unknown risk of transmission. [ citation needed ]Biosafety level 4 laboratories are designed for diagnostic work and research on easily respiratory-acquired viruses which can often cause severe and/or fatal disease. What follows is a list of select agents that have specific biocontainment requirements according to US federal law. Organisms include those harmful to human health , or to animal health . The Plant Protection and Quarantine programs (PPQ) of the Animal and Plant Health Inspection Service (APHIS) are listed in 7 CFR Part 331. The Department of Health and Human Services (HHS) lists are located at 42 CFR Part 73.3 and 42 CFR Part 73.4. The USDA animal safety list is located at 9 CFR Subchapter B. Not all select agents require BSL-4 handling, namely select bacteria and toxins, but most select agent viruses do (with the notable exception of SARS-CoV-1 which can be handled in BSL3). Many non-select agent viruses are often handled in BSL-4 according to facility SOPs or when dealing with new viruses closely related to viruses that require BSL-4. For instance, Andes orthohantavirus and MERS-CoV are both non-select agents that are often handled in BSL-4 because they cause severe and fatal disease in humans. Newly characterized viruses closely related to select agents and/or BSL-4 viruses (for example newly discovered henipaviruses or ebolaviruses ) are typically handled in BSL-4 even if they aren't yet known to be readily transmissible or cause severe disease. [ citation needed ]Globally, there are no official agreements on what agents must be handled in BSL-4. However, select agents and toxins originating or ending in US BSL-4 labs must adhere to US select agent laws. [ citation needed ]

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Rift Valley fever

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

EcoHealth Alliance

New York City, New York EcoHealth Alliance is an US-based non-governmental organization with a stated mission of protecting people, animals, and the environment from emerging infectious diseases . The nonprofit focuses on research aimed at preventing pandemics and promoting conservation in hotspot regions worldwide. The EcoHealth Alliance focuses on diseases caused by deforestation and increased interaction between humans and wildlife . The organization has researched the emergence of diseases such as Severe Acute Respiratory Syndrome (SARS), Nipah virus , Middle East respiratory syndrome (MERS), Rift Valley fever , the Ebola virus , and COVID-19 . The EcoHealth Alliance also advises the World Organization for Animal Health (OIE), the International Union for Conservation of Nature (IUCN), the United Nations Food and Agriculture Organization (FAO), and the World Health Organization (WHO) on global wildlife trade , threats of disease, and the environmental damage posed by these. Following the outbreak of the COVID-19 pandemic , EcoHealth's ties with the Wuhan Institute of Virology were put into question in relation to investigations into the origin of COVID-19 . Citing these concerns, the National Institutes of Health (NIH) withdrew funding to the organization in April 2020. Significant criticism followed this decision, including a joint letter signed by 77 Nobel laureates and 31 scientific societies. The NIH later reinstated funding to the organization as one of 11 institutions partnering in the Centers for Research in Emerging Infectious Diseases (CREID) initiative in August 2020, but all activities funded by the grant remain suspended. In 2022, the NIH terminated the EcoHealth Alliance grant, stating that "EcoHealth Alliance had not been able to hand over lab notebooks and other records from its Wuhan partner that relate to controversial experiments involving modified bat viruses , despite multiple requests." In 2023, an audit by the Office of Inspector General of the Department of Health and Human Services found that "NIH did not effectively monitor or take timely action to address" compliance problems with the EcoHealth Alliance. In December 2023, the EcoHealth Alliance denied allegations that it double-billed the NIH and United States Agency for International Development for research in China. Founded under the name Wildlife Preservation Trust International in 1971 by British naturalist , author , and television personality , Gerald Durrell , it then became The Wildlife Trust in 1999. In the fall of 2010, the organization changed its name to EcoHealth Alliance. The rebrand reflected a change in the organization's focus, moving solely from a conservation nonprofit, which focused mainly on the captive breeding of endangered species , to an environmental health organization with its foundation in conservation. The organization held an early professional conservation medicine meeting in 1996. In 2002, they published an edited volume on the field through Oxford University Press : Conservation Medicine: Ecological Health in Practice. In February 2008, they published a paper in Nature entitled "Global trends in emerging infectious diseases" which featured an early rendition of a global disease hotspot map. Using epidemiological , social, and environmental data from the past 50 years, the map outlined regions of the globe most at risk for emergent disease threats. EcoHealth Alliance's funding comes mostly from U.S. federal agencies such as the Department of Defense , Department of Homeland Security , and U.S. Agency for International Development . Between 2011 and 2020, its annual budget fluctuated between US$9 and US$15 million per year. Following the outbreak of the COVID-19 pandemic , EcoHealth Alliance has been the subject of controversy and increased scrutiny due to its ties to the Wuhan Institute of Virology (WIV)—which has been at the center of speculation since early 2020 that SARS-CoV-2 may have escaped in a lab incident. Prior to the pandemic, EcoHealth Alliance was the only U.S.-based organization researching coronavirus evolution and transmission in China, where they partnered with the WIV, among others. EcoHealth president Peter Daszak co-authored a February 2020 letter in The Lancet condemning " conspiracy theories suggesting that COVID-19 does not have a natural origin". However, Daszak failed to disclose EcoHealth's ties to the WIV, which some observers noted as an apparent conflict of interest . In June 2021, The Lancet published an addendum in which Daszak disclosed his cooperation with researchers in China. In April 2020, the NIH ordered EcoHealth Alliance to cease spending the remaining $369,819 from its current NIH grant at the request of the Trump administration, pressuring them by stating "it must hand over information and materials from the Chinese research facility to resume funding for suspended grant" in reference to the Wuhan Institute of Virology. The canceled grant was supposed to run through 2024. Funding from NIH resumed in August 2020 after an uproar from "77 U.S. Nobel laureates and 31 scientific societies". Work conducted at the Wuhan Institute of Virology under an NIH grant to the EHA has been at the center of political controversies during the pandemic. One such controversy centered on whether any experiments conducted under the grant could be accurately described as " gain-of-function " (GoF) research. NIH officials (including Anthony Fauci ) unequivocally denied during 2020 congressional hearings that the EHA had conducted GoF research with NIH funding. In October 2021, the EHA submitted a progress report detailing the results of a past experiment where some laboratory mice lost more weight than expected after being infected with a modified bat coronavirus. The NIH subsequently sent a letter to the congressional House Committee on Energy and Commerce describing this experiment, but did not refer to it as "gain-of-function." Whether such research qualifies as "gain-of-function" is a matter of considerable debate among relevant experts. Following the outbreak of the COVID-19 pandemic , EcoHealth Alliance has been the subject of controversy and increased scrutiny due to its ties to the Wuhan Institute of Virology (WIV)—which has been at the center of speculation since early 2020 that SARS-CoV-2 may have escaped in a lab incident. Prior to the pandemic, EcoHealth Alliance was the only U.S.-based organization researching coronavirus evolution and transmission in China, where they partnered with the WIV, among others. EcoHealth president Peter Daszak co-authored a February 2020 letter in The Lancet condemning " conspiracy theories suggesting that COVID-19 does not have a natural origin". However, Daszak failed to disclose EcoHealth's ties to the WIV, which some observers noted as an apparent conflict of interest . In June 2021, The Lancet published an addendum in which Daszak disclosed his cooperation with researchers in China. In April 2020, the NIH ordered EcoHealth Alliance to cease spending the remaining $369,819 from its current NIH grant at the request of the Trump administration, pressuring them by stating "it must hand over information and materials from the Chinese research facility to resume funding for suspended grant" in reference to the Wuhan Institute of Virology. The canceled grant was supposed to run through 2024. Funding from NIH resumed in August 2020 after an uproar from "77 U.S. Nobel laureates and 31 scientific societies". Work conducted at the Wuhan Institute of Virology under an NIH grant to the EHA has been at the center of political controversies during the pandemic. One such controversy centered on whether any experiments conducted under the grant could be accurately described as " gain-of-function " (GoF) research. NIH officials (including Anthony Fauci ) unequivocally denied during 2020 congressional hearings that the EHA had conducted GoF research with NIH funding. In October 2021, the EHA submitted a progress report detailing the results of a past experiment where some laboratory mice lost more weight than expected after being infected with a modified bat coronavirus. The NIH subsequently sent a letter to the congressional House Committee on Energy and Commerce describing this experiment, but did not refer to it as "gain-of-function." Whether such research qualifies as "gain-of-function" is a matter of considerable debate among relevant experts. EcoHealth Alliance partners with USAID on the PREDICT subset of USAID's EPT (Emerging Pandemic Threats) program. PREDICT seeks to identify which emerging infectious diseases are of the greatest risk to human health. Many of EcoHealth Alliance's international collaborations with in-country organizations and institutions fall under the PREDICT umbrella. Scientists in the field collect samples from local fauna in order to track the spread of potentially harmful pathogens and to stop them from becoming outbreaks . Scientists also train local technicians and veterinarians in animal sampling and information gathering. Active countries include Bangladesh , Cameroon , China, Democratic Republic of the Congo , Egypt , Ethiopia , Guinea , India , Indonesia , Jordan , Kenya , Liberia , Malaysia , Myanmar , Nepal , Sierra Leone , Sudan , South Sudan , Thailand , Uganda , and Vietnam . IDEEAL (Infectious Disease Emergence and Economics of Altered Landscapes Program) attempts to investigate the impact of deforestation and land-use change on the risk of zoonoses in Sabah, Malaysia . This project focuses on the local palm oil industry in particular. The study also offers to the country's corporate leaders and policymakers long-term alternatives to large-scale deforestation. The program is headquartered at the Malaysian Development Health Research Unit (DHRU), which was developed in collaboration with the Malaysian University of Sabah . A growing body of research indicates that bats are an important factor in both ecosystem health and disease emergence. A number of hypotheses have been proposed for the high number of zoonoses that have come from bat populations in recent decades. One group of researchers hypothesized "that flight, a factor common to all bats but to no other mammals, provides an intensive selective force for coexistence with viral parasites through a daily cycle that elevates metabolism and body temperature analogous to the fever response in other mammals. On an evolutionary scale, this host-virus interaction might have resulted in the large diversity of zoonotic viruses in bats, possibly through bat viruses adapting to be more tolerant of the fever response and less virulent to their natural hosts." According to the FAO (Food and Agriculture Organization), roughly 18 million acres of forest (roughly the size of Panama ) are lost every year due to deforestation . Increased contact between humans and the animal species whose habitat is being destroyed has led to increases in zoonotic disease. EcoHealth Alliance scientists are testing species for pathogens in areas with very little, moderate, and complete deforestation in order to track potential outbreaks. This data is used to promote the preservation of natural lands and diminish the negative effects of land-use change . Project DEFUSE was a rejected DARPA grant application, which proposed to sample bat coronaviruses from various locations in China. To evaluate whether bat coronaviruses might spill over into the human population, the grantees proposed to create chimeric coronaviruses which were mutated in different locations, before evaluating their ability to infect human cells in the laboratory. One proposed alteration was to modify bat coronaviruses to insert a cleavage site for the Furin protease at the S1/S2 junction of the spike (S) viral protein. Another part of the grant aimed to create noninfectious protein-based vaccines containing just the spike protein of dangerous coronaviruses. These vaccines would then be administered to bats in caves in southern China to help prevent future outbreaks. Co-investigators on the rejected proposal included Ralph Baric from UNC , Linfa Wang from Duke–NUS Medical School in Singapore, and Shi Zhengli from the Wuhan Institute of Virology . EcoHealth Alliance partners with USAID on the PREDICT subset of USAID's EPT (Emerging Pandemic Threats) program. PREDICT seeks to identify which emerging infectious diseases are of the greatest risk to human health. Many of EcoHealth Alliance's international collaborations with in-country organizations and institutions fall under the PREDICT umbrella. Scientists in the field collect samples from local fauna in order to track the spread of potentially harmful pathogens and to stop them from becoming outbreaks . Scientists also train local technicians and veterinarians in animal sampling and information gathering. Active countries include Bangladesh , Cameroon , China, Democratic Republic of the Congo , Egypt , Ethiopia , Guinea , India , Indonesia , Jordan , Kenya , Liberia , Malaysia , Myanmar , Nepal , Sierra Leone , Sudan , South Sudan , Thailand , Uganda , and Vietnam .IDEEAL (Infectious Disease Emergence and Economics of Altered Landscapes Program) attempts to investigate the impact of deforestation and land-use change on the risk of zoonoses in Sabah, Malaysia . This project focuses on the local palm oil industry in particular. The study also offers to the country's corporate leaders and policymakers long-term alternatives to large-scale deforestation. The program is headquartered at the Malaysian Development Health Research Unit (DHRU), which was developed in collaboration with the Malaysian University of Sabah .A growing body of research indicates that bats are an important factor in both ecosystem health and disease emergence. A number of hypotheses have been proposed for the high number of zoonoses that have come from bat populations in recent decades. One group of researchers hypothesized "that flight, a factor common to all bats but to no other mammals, provides an intensive selective force for coexistence with viral parasites through a daily cycle that elevates metabolism and body temperature analogous to the fever response in other mammals. On an evolutionary scale, this host-virus interaction might have resulted in the large diversity of zoonotic viruses in bats, possibly through bat viruses adapting to be more tolerant of the fever response and less virulent to their natural hosts." According to the FAO (Food and Agriculture Organization), roughly 18 million acres of forest (roughly the size of Panama ) are lost every year due to deforestation . Increased contact between humans and the animal species whose habitat is being destroyed has led to increases in zoonotic disease. EcoHealth Alliance scientists are testing species for pathogens in areas with very little, moderate, and complete deforestation in order to track potential outbreaks. This data is used to promote the preservation of natural lands and diminish the negative effects of land-use change .Project DEFUSE was a rejected DARPA grant application, which proposed to sample bat coronaviruses from various locations in China. To evaluate whether bat coronaviruses might spill over into the human population, the grantees proposed to create chimeric coronaviruses which were mutated in different locations, before evaluating their ability to infect human cells in the laboratory. One proposed alteration was to modify bat coronaviruses to insert a cleavage site for the Furin protease at the S1/S2 junction of the spike (S) viral protein. Another part of the grant aimed to create noninfectious protein-based vaccines containing just the spike protein of dangerous coronaviruses. These vaccines would then be administered to bats in caves in southern China to help prevent future outbreaks. Co-investigators on the rejected proposal included Ralph Baric from UNC , Linfa Wang from Duke–NUS Medical School in Singapore, and Shi Zhengli from the Wuhan Institute of Virology .

Wiki

Rift Valley fever

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Israel–Somaliland relations

Israel–Somaliland relations refers to the relationship between the Republic of Somaliland and the State of Israel . The two countries have no formal diplomatic relations. Israel was one of 35 countries that recognised Somaliland 's brief independence in 1960. In February 2010, Israeli Foreign Ministry spokesperson Yigal Palmor was quoted in the Haaretz Daily that his government was ready to recognise Somaliland again. Although, he stated that the Somaliland government has not contacted the Israeli government to seek ties. In 1995, former President Egal of Somaliland also wrote a letter to Prime Minister Yitzhak Rabin seeking to establish diplomatic ties between the two countries. In September 2001, it was also reported Somaliland was looking towards Tel Aviv after Saudi Arabia banned imports of livestock from the country due to Rift Valley fever . During this time several Israeli businessmen were also in the nation's capital Hargeisa . However, President Kahin who succeeded Egal is reported to have avoided approaching Israel to prevent straining fragile relations with the Arabs and Muslim world, which it heavily relies on its livestock trade. In August 2020, Somaliland expressed its support for the Israel–United Arab Emirates normalization agreement .

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Rift Valley fever

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Oropouche fever

Oropouche fever is a tropical viral infection transmitted by biting midges and mosquitoes from the blood of sloths to humans . This disease is named after the region where it was first discovered and isolated at the Trinidad Regional Virus Laboratory in 1955 by the Oropouche River in Trinidad and Tobago . Oropouche fever is caused by a specific arbovirus , the Oropouche virus (OROV), of the Bunyaviridae family. Large epidemics are common and very swift, one of the earliest largest having occurred at the city of Belém , in the Brazilian Amazon state of Pará , with 11,000 recorded cases. In the Brazilian Amazon, oropouche is the second most frequent viral disease, after dengue fever. Several epidemics have generated more than 263,000 cases, of which 130,000 alone occurred in the period from 1978 to 1980. Presently, in Brazil alone it is estimated that more than half a million cases have occurred. Nevertheless, clinics in Brazil may not have adequate testing reliability as they rely on symptoms rather than PCR viral sequencing, which is expensive and time consuming, in many cases there may be co-infection with other similar mosquito-borne viruses. Oropouche fever is characterized as an acute febrile illness, meaning that it begins with a sudden onset of a fever followed by severe clinical symptoms. It typically takes 4 to 8 days from the incubation period to first start noticing signs of infection , beginning from the bite of the infected mosquito or midge. Fevers are the most common symptom with temperatures as high as 40 °C (104 °F) . Clinical symptoms include chills, headache, myalgia, arthralgia, dizziness, photophobia, vomiting, joint pains, epigastric pain , and rashes. There also have been some cases where rashes resembles rubella and patients presented systematic symptoms including nausea , vomiting , diarrhea , conjunctive congestion , epigastric pain, and retro-orbitial pain. The initial febrile episode typically passes after a few days, but it is very common to have a reoccurrence of these symptoms with a lesser intensity. Studies have shown this typically happens in about 60% of cases. The oropouche virus is an emerging infectious agent that causes the illness oropouche fever. This virus is an arbovirus and is transmitted among sloths, marsupials, primates, and birds through the mosquitoes Aedes serratus and Culex quinquefaciatus . The oropouche virus has evolved to an urban cycle infecting humans though midges as its main transporting vector. OROV was first described in Trinidad in 1955 when the prototype strain was isolated from the blood of a febrile human patient and from Coquillettidia venezuelensis mosquitoes . In Brazil, OROV was first described in 1960 when it was isolated from a three-toed sloth ( Bradypus tridactylus ) and Ochlerotatus serratus mosquitoes captured nearby during the construction of the Belém-Brasilia Highway . The oropouche virus is responsible for causing massive, explosive outbreaks in Latin American countries, making oropouche fever the second most common arboviral infection seen in Brazil. So far the only reported cases of Oropouche fever have been in Brazil, Panama, Peru, and Trinidad and Tobago. ORO fever occurs mainly during the rainy seasons because there is an increase in breeding sites in the vector populations. There has also been reports of the oropouche epidemics during the dry season but this is most likely due to the high population density of mosquitoes from the past rainy season. Moreover, during the dry season there is a deceased chance of outbreaks which decreases the amount of midges this is because the amount of outbreaks is related to the number of human population that has not yet been exposed to this virus. Oropouche fever is caused by the oropouche virus (OROV) that belongs to the Peribunyaviridae family of arboviruses. This virus is a single-stranded, negative sense RNA virus which is the cause of this disease. There are no specific ultrastructural studies of the oropouche virus in human tissues that have been recorded to this date. It is likely that this viral agent shares similar morphological characteristics with other members of the Orthobunyavirus genus. Members of the Orthobunyavirus genus have a three part, single-stranded, negative sense RNA genome of small (S), medium (M) and large (L) RNA segments. These segments function to encode nucleocapsids , glycoproteins and the RNA polymerase in that sequential order. Through phylogenetic analysis of nucleocapsid genes in different oropouche virus strains, it has been revealed that there are three unique genotypes (I, II, III) that are currently spreading through Central and South America. Genetic reassortment is said to be one of the most important mechanisms in explaining the viral biodiversity in orthobunyaviruses. This occurs when two genetically related viruses infect the same cell at the same time forming a progeny virus and this virus holds various components of genetic L, M and S segments from the two parental viruses. In reassortment, the S and L segments are the ones that are usually exchanged between species further, the S segment, that is coded by the nucleocapsid protein, and the L polymerase function together to create a replication of the viral genome. Due to this, one segment will restrict the molecular evolution of another segment and this is said to be inherited as a pair. On the contrary, the M segment codes for viral glycoproteins and these could be more prone to mutations due to a higher selective pressure in their coding region because these proteins are major host range determinants. There is not a significant amount of information about regarding the natural pathogenesis of OROV infections because there have been no recorded fatalities to date. It is known that within 2–4 days from the initial onset of systematic symptoms in humans, the presence of this virus is detected in the blood. In some cases this virus has also been recovered from the cerebrospinal fluid, but the route of invasion to the central nervous system remains unclear. To further understand the pathogenesis of how this virus manifests in the body experimental studies using murine models have been performed. BALB/c neonate mice were treated with this virus subcutaneously and presented clinical symptoms five days after inoculation . The mice revealed a high concentration of the replicating virus in the brain along with inflammation of the meninges and apoptosis of neurons without encephalitis, which is inflammation of the brain due to an infection. These findings confirmed the neurotropism of this virus, which means that this virus is capable of infecting nerve cells. Immunohistochemistry was used to reveal how this virus had access to the central nervous system. The findings indicated that the OROV infection starts from the posterior parts of the brain and progresses toward the forebrain. The oropouche virus spreads through the neural routes during early stages of the infection, reaching the spinal cord and traveling upward to the brain through brainstem with little inflammation. As the infection progresses, the virus crosses the blood-brain barrier and spreads to the brain parenchyma leading to severe manifestations of encephalitis . Damage to the brain parenchyma can result in the loss of cognitive ability or death. Genetic reassortment is said to be one of the most important mechanisms in explaining the viral biodiversity in orthobunyaviruses. This occurs when two genetically related viruses infect the same cell at the same time forming a progeny virus and this virus holds various components of genetic L, M and S segments from the two parental viruses. In reassortment, the S and L segments are the ones that are usually exchanged between species further, the S segment, that is coded by the nucleocapsid protein, and the L polymerase function together to create a replication of the viral genome. Due to this, one segment will restrict the molecular evolution of another segment and this is said to be inherited as a pair. On the contrary, the M segment codes for viral glycoproteins and these could be more prone to mutations due to a higher selective pressure in their coding region because these proteins are major host range determinants. There is not a significant amount of information about regarding the natural pathogenesis of OROV infections because there have been no recorded fatalities to date. It is known that within 2–4 days from the initial onset of systematic symptoms in humans, the presence of this virus is detected in the blood. In some cases this virus has also been recovered from the cerebrospinal fluid, but the route of invasion to the central nervous system remains unclear. To further understand the pathogenesis of how this virus manifests in the body experimental studies using murine models have been performed. BALB/c neonate mice were treated with this virus subcutaneously and presented clinical symptoms five days after inoculation . The mice revealed a high concentration of the replicating virus in the brain along with inflammation of the meninges and apoptosis of neurons without encephalitis, which is inflammation of the brain due to an infection. These findings confirmed the neurotropism of this virus, which means that this virus is capable of infecting nerve cells. Immunohistochemistry was used to reveal how this virus had access to the central nervous system. The findings indicated that the OROV infection starts from the posterior parts of the brain and progresses toward the forebrain. The oropouche virus spreads through the neural routes during early stages of the infection, reaching the spinal cord and traveling upward to the brain through brainstem with little inflammation. As the infection progresses, the virus crosses the blood-brain barrier and spreads to the brain parenchyma leading to severe manifestations of encephalitis . Damage to the brain parenchyma can result in the loss of cognitive ability or death. BALB/c neonate mice were treated with this virus subcutaneously and presented clinical symptoms five days after inoculation . The mice revealed a high concentration of the replicating virus in the brain along with inflammation of the meninges and apoptosis of neurons without encephalitis, which is inflammation of the brain due to an infection. These findings confirmed the neurotropism of this virus, which means that this virus is capable of infecting nerve cells. Immunohistochemistry was used to reveal how this virus had access to the central nervous system. The findings indicated that the OROV infection starts from the posterior parts of the brain and progresses toward the forebrain. The oropouche virus spreads through the neural routes during early stages of the infection, reaching the spinal cord and traveling upward to the brain through brainstem with little inflammation. As the infection progresses, the virus crosses the blood-brain barrier and spreads to the brain parenchyma leading to severe manifestations of encephalitis . Damage to the brain parenchyma can result in the loss of cognitive ability or death. Diagnosis of the oropouche infection is done through classic and molecular virology techniques. These include: Clinical diagnosis of oropouche fever is hard to perform due to the nonspecific nature of the disease, in many causes it can be confused with dengue fever or other arbovirus illness. Prevention strategies include reducing the breeding of midges through source reduction (removal and modification of breeding sites) and reducing contact between midges and people. This can be accomplished by reducing the number of natural and artificial water-filled habitats and encourage the midge larvae to grow. Oropouche fever is present in epidemics so the chances of one contracting it after being exposed to areas of midgets or mosquitoes is rare. Oropouche Fever has no cure or specific therapy so treatment is done by relieving the pain of the symptoms through symptomatic treatment . Certain oral analgesic and anti-inflammatory agents can help treat headaches and body pains. In extreme cases of oropouche fever the drug Ribavirin is recommended to help against the virus. This is called antiviral therapy . Treatments also consist of drinking plenty of fluids to prevent dehydration. Aspirin is not a recommended choice of drug because it can reduce blood clotting and may aggravate the hemorrhagic effects and prolong recovery time. [ citation needed ]The infection is usually self-limiting and complications are rare. This illness usually lasts for about a week but in extreme cases can be prolonged. Patients usually recover fully with no long term ill effects. There have been no recorded fatalities resulting from oropouche fever. One study has focused on identifying OROV through the use of RNA extraction from reverse transcription-polymerase chain reaction. This study revealed that OROV caused central nervous system infections in three patients. The three patients all had meningoencephalitis and also showed signs of clear lympho-monocytic cellular pattern in CSF , high protein, and normal to slightly decreased glucose levels indicating they had viral infections. Two of the patients already had underlying infections that can effect the CNS and immune system and in particular one of these patients has HIV/AIDS and the third patient has neurocysticercosis . Two patients were infected with OROV developed meningitis and it was theorized that this is due to them being immunocompromised. Through this it was revealed that it's possible that the invasion of the central nervous system by the oropouche virus can be performed by a previous blood-brain barrier damage.

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Rift Valley fever

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Ebola

Ebola , also known as Ebola virus disease ( EVD ) and Ebola hemorrhagic fever ( EHF ), is a viral hemorrhagic fever in humans and other primates , caused by ebolaviruses . Symptoms typically start anywhere between two days and three weeks after infection. The first symptoms are usually fever , sore throat , muscle pain , and headaches . These are usually followed by vomiting , diarrhoea , rash and decreased liver and kidney function, at which point some people begin to bleed both internally and externally. It kills between 25% and 90% of those infected – about 50% on average. Death is often due to shock from fluid loss , and typically occurs between six and 16 days after the first symptoms appear. Early treatment of symptoms increases the survival rate considerably compared to late start. An Ebola vaccine was approved by the US FDA in December 2019. The virus spreads through direct contact with body fluids , such as blood from infected humans or other animals, or from contact with items that have recently been contaminated with infected body fluids. There have been no documented cases, either in nature or under laboratory conditions, of spread through the air between humans or other primates . After recovering from Ebola, semen or breast milk may continue to carry the virus for anywhere between several weeks to several months. Fruit bats are believed to be the normal carrier in nature ; they are able to spread the virus without being affected by it. The symptoms of Ebola may resemble those of several other diseases, including malaria , cholera , typhoid fever , meningitis and other viral hemorrhagic fevers. Diagnosis is confirmed by testing blood samples for the presence of viral RNA , viral antibodies or the virus itself. Control of outbreaks requires coordinated medical services and community engagement, including rapid detection, contact tracing of those exposed, quick access to laboratory services, care for those infected, and proper disposal of the dead through cremation or burial. Prevention measures involve wearing proper protective clothing and washing hands when in close proximity to patients and while handling potentially infected bushmeat , as well as thoroughly cooking bushmeat. An Ebola vaccine was approved by the US FDA in December 2019. While there is no approved treatment for Ebola as of 2019 [ update ] , two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. Supportive efforts also improve outcomes. These include oral rehydration therapy (drinking slightly sweetened and salty water) or giving intravenous fluids , and treating symptoms. In October 2020, atoltivimab/maftivimab/odesivimab (Inmazeb) was approved for medical use in the United States to treat the disease caused by Zaire ebolavirus . Ebola was first identified in 1976, in two simultaneous outbreaks, one in Nzara (a town in South Sudan ) and the other in Yambuku ( the Democratic Republic of the Congo ), a village near the Ebola River , for which the disease was named. Ebola outbreaks occur intermittently in tropical regions of sub-Saharan Africa . Between 1976 and 2012, according to the World Health Organization , there were 24 outbreaks of Ebola resulting in a total of 2,387 cases, and 1,590 deaths . The largest Ebola outbreak to date was an epidemic in West Africa from December 2013 to January 2016, with 28,646 cases and 11,323 deaths. On 29 March 2016, it was declared to no longer be an emergency. Other outbreaks in Africa began in the Democratic Republic of the Congo in May 2017, and 2018. In July 2019, the World Health Organization declared the Congo Ebola outbreak a world health emergency . The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. The length of time between exposure to the virus and the development of symptoms ( incubation period ) is between 2 and 21 days, and usually between 4 and 10 days. However, recent estimates based on mathematical models predict that around 5% of cases may take longer than 21 days to develop. Symptoms usually begin with a sudden influenza -like stage characterised by fatigue , fever , weakness , decreased appetite , muscular pain , joint pain , headache, and sore throat. The fever is usually higher than 38.3 °C (101 °F) . This is often followed by nausea, vomiting, diarrhoea , abdominal pain, and sometimes hiccups . The combination of severe vomiting and diarrhoea often leads to severe dehydration . Next, shortness of breath and chest pain may occur, along with swelling , headaches , and confusion . In about half of the cases, the skin may develop a maculopapular rash , a flat red area covered with small bumps, five to seven days after symptoms begin. In some cases, internal and external bleeding may occur. This typically begins five to seven days after the first symptoms. All infected people show some decreased blood clotting . Bleeding from mucous membranes or from sites of needle punctures has been reported in 40–50% of cases. This may cause vomiting blood , coughing up of blood , or blood in stool . Bleeding into the skin may create petechiae , purpura , ecchymoses or haematomas (especially around needle injection sites). Bleeding into the whites of the eyes may also occur. Heavy bleeding is uncommon; if it occurs, it is usually in the gastrointestinal tract . The incidence of bleeding into the gastrointestinal tract was reported to be ~58% in the 2001 outbreak in Gabon, but in the 2014–15 outbreak in the US it was ~18%, possibly due to improved prevention of disseminated intravascular coagulation . Recovery may begin between seven and 14 days after first symptoms. Death, if it occurs, follows typically six to sixteen days from first symptoms and is often due to shock from fluid loss . In general, bleeding often indicates a worse outcome, and blood loss may result in death. People are often in a coma near the end of life. Those who survive often have ongoing muscular and joint pain, liver inflammation , and decreased hearing, and may have continued tiredness, continued weakness, decreased appetite, and difficulty returning to pre-illness weight. Problems with vision may develop. It is recommended that survivors of EVD wear condoms for at least twelve months after initial infection or until the semen of a male survivor tests negative for Ebola virus on two separate occasions. Survivors develop antibodies against Ebola that last at least 10 years, but it is unclear whether they are immune to additional infections. EVD in humans is caused by four of six viruses of the genus Ebolavirus . The four are Bundibugyo virus (BDBV), Sudan virus (SUDV), Taï Forest virus (TAFV) and one simply called Ebola virus (EBOV, formerly Zaire Ebola virus). EBOV, species Zaire ebolavirus , is the most dangerous of the known EVD-causing viruses, and is responsible for the largest number of outbreaks. The fifth and sixth viruses, Reston virus (RESTV) and Bombali virus (BOMV), are not thought to cause disease in humans, but have caused disease in other primates. All five viruses are closely related to marburgviruses . Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Ebolaviruses contain single-stranded, non-infectious RNA genomes . Ebolavirus genomes contain seven genes including 3'-UTR - NP - VP35 - VP40 - GP - VP30 - VP24 - L - 5'-UTR . The genomes of the five different ebolaviruses (BDBV, EBOV, RESTV, SUDV and TAFV) differ in sequence and the number and location of gene overlaps. As with all filoviruses , ebolavirus virions are filamentous particles that may appear in the shape of a shepherd's crook, of a "U" or of a "6," and they may be coiled, toroid or branched. In general, ebolavirions are 80 nanometers (nm) in width and may be as long as 14,000 nm. Their life cycle is thought to begin with a virion attaching to specific cell-surface receptors such as C-type lectins , DC-SIGN , or integrins , which is followed by fusion of the viral envelope with cellular membranes . The virions taken up by the cell then travel to acidic endosomes and lysosomes where the viral envelope glycoprotein GP is cleaved. This processing appears to allow the virus to bind to cellular proteins enabling it to fuse with internal cellular membranes and release the viral nucleocapsid . The Ebolavirus structural glycoprotein (known as GP1,2) is responsible for the virus' ability to bind to and infect targeted cells. The viral RNA polymerase , encoded by the L gene, partially uncoats the nucleocapsid and transcribes the genes into positive-strand mRNAs , which are then translated into structural and nonstructural proteins. The most abundant protein produced is the nucleoprotein, whose concentration in the host cell determines when L switches from gene transcription to genome replication. Replication of the viral genome results in full-length, positive-strand antigenomes that are, in turn, transcribed into genome copies of negative-strand virus progeny. Newly synthesised structural proteins and genomes self-assemble and accumulate near the inside of the cell membrane . Virions bud off from the cell, gaining their envelopes from the cellular membrane from which they bud. The mature progeny particles then infect other cells to repeat the cycle. The genetics of the Ebola virus are difficult to study because of EBOV's virulent characteristics. It is believed that between people, Ebola disease spreads only by direct contact with the blood or other body fluids of a person who has developed symptoms of the disease. Body fluids that may contain Ebola viruses include saliva, mucus, vomit, feces, sweat, tears, breast milk, urine and semen . The WHO states that only people who are very sick are able to spread Ebola disease in saliva , and the virus has not been reported to be transmitted through sweat. Most people spread the virus through blood, feces and vomit. Entry points for the virus include the nose, mouth, eyes, open wounds, cuts and abrasions. Ebola may be spread through large droplets ; however, this is believed to occur only when a person is very sick. This contamination can happen if a person is splashed with droplets. Contact with surfaces or objects contaminated by the virus, particularly needles and syringes, may also transmit the infection. The virus is able to survive on objects for a few hours in a dried state, and can survive for a few days within body fluids outside of a person. The Ebola virus may be able to persist for more than three months in the semen after recovery, which could lead to infections via sexual intercourse . Virus persistence in semen for over a year has been recorded in a national screening programme. Ebola may also occur in the breast milk of women after recovery, and it is not known when it is safe to breastfeed again. The virus was also found in the eye of one patient in 2014, two months after it was cleared from his blood. Otherwise, people who have recovered are not infectious. The potential for widespread infections in countries with medical systems capable of observing correct medical isolation procedures is considered low. Usually when someone has symptoms of the disease, they are unable to travel without assistance. Dead bodies remain infectious; thus, people handling human remains in practices such as traditional burial rituals or more modern processes such as embalming are at risk. Of the cases of Ebola infections in Guinea during the 2014 outbreak, 69% are believed to have been contracted via unprotected (or unsuitably protected) contact with infected corpses during certain Guinean burial rituals. Health-care workers treating people with Ebola are at greatest risk of infection. The risk increases when they do not have appropriate protective clothing such as masks, gowns, gloves and eye protection; do not wear it properly; or handle contaminated clothing incorrectly. This risk is particularly common in parts of Africa where the disease mostly occurs and health systems function poorly. There has been transmission in hospitals in some African countries that reuse hypodermic needles. Some health-care centres caring for people with the disease do not have running water. In the United States the spread to two medical workers treating infected patients prompted criticism of inadequate training and procedures. Human-to-human transmission of EBOV through the air has not been reported to occur during EVD outbreaks, and airborne transmission has only been demonstrated in very strict laboratory conditions, and then only from pigs to primates , but not from primates to primates. Spread of EBOV by water, or food other than bushmeat, has not been observed. No spread by mosquitos or other insects has been reported. Other possible methods of transmission are being studied. Airborne transmission among humans is theoretically possible due to the presence of Ebola virus particles in saliva, which can be discharged into the air with a cough or sneeze, but observational data from previous epidemics suggests the actual risk of airborne transmission is low. A number of studies examining airborne transmission broadly concluded that transmission from pigs to primates could happen without direct contact because, unlike humans and primates, pigs with EVD get very high ebolavirus concentrations in their lungs, and not their bloodstream. Therefore, pigs with EVD can spread the disease through droplets in the air or on the ground when they sneeze or cough. By contrast, humans and other primates accumulate the virus throughout their body and specifically in their blood, but not very much in their lungs. It is believed that this is the reason researchers have observed pig to primate transmission without physical contact, but no evidence has been found of primates being infected without actual contact, even in experiments where infected and uninfected primates shared the same air. Although it is not entirely clear how Ebola initially spreads from animals to humans, the spread is believed to involve direct contact with an infected wild animal or fruit bat. Besides bats, other wild animals that are sometimes infected with EBOV include several species of monkeys such as baboons , great apes ( chimpanzees and gorillas ), and duikers (a species of antelope ). Animals may become infected when they eat fruit partially eaten by bats carrying the virus. Fruit production, animal behavior and other factors may trigger outbreaks among animal populations. Evidence indicates that both domestic dogs and pigs can also be infected with EBOV. Dogs do not appear to develop symptoms when they carry the virus, and pigs appear to be able to transmit the virus to at least some primates. Although some dogs in an area in which a human outbreak occurred had antibodies to EBOV, it is unclear whether they played a role in spreading the disease to people. The natural reservoir for Ebola has yet to be confirmed; however, bats are considered to be the most likely candidate. Three types of fruit bats ( Hypsignathus monstrosus , Epomops franqueti and Myonycteris torquata ) were found to possibly carry the virus without getting sick. As of 2013 [ update ] , whether other animals are involved in its spread is not known. Plants, arthropods , rodents , and birds have also been considered possible viral reservoirs. Bats were known to roost in the cotton factory in which the first cases of the 1976 and 1979 outbreaks were observed, and they have also been implicated in Marburg virus infections in 1975 and 1980. Of 24 plant and 19 vertebrate species experimentally inoculated with EBOV, only bats became infected. The bats displayed no clinical signs of disease, which is considered evidence that these bats are a reservoir species of EBOV. In a 2002–2003 survey of 1,030 animals including 679 bats from Gabon and the Republic of the Congo , immunoglobulin G (IgG) immune defense molecules indicative of Ebola infection were found in three bat species; at various periods of study, between 2.2 and 22.6% of bats were found to contain both RNA sequences and IgG molecules indicating Ebola infection. Antibodies against Zaire and Reston viruses have been found in fruit bats in Bangladesh , suggesting that these bats are also potential hosts of the virus and that the filoviruses are present in Asia. Between 1976 and 1998, in 30,000 mammals, birds, reptiles, amphibians and arthropods sampled from regions of EBOV outbreaks, no Ebola virus was detected apart from some genetic traces found in six rodents (belonging to the species Mus setulosus and Praomys ) and one shrew ( Sylvisorex ollula ) collected from the Central African Republic . However, further research efforts have not confirmed rodents as a reservoir. Traces of EBOV were detected in the carcasses of gorillas and chimpanzees during outbreaks in 2001 and 2003, which later became the source of human infections. However, the high rates of death in these species resulting from EBOV infection make it unlikely that these species represent a natural reservoir for the virus. Deforestation has been mentioned as a possible contributor to recent outbreaks, including the West African Ebola virus epidemic . Index cases of EVD have often been close to recently deforested lands. Like other filoviruses , EBOV replicates very efficiently in many cells , producing large amounts of virus in monocytes , macrophages , dendritic cells and other cells including liver cells , fibroblasts , and adrenal gland cells . Viral replication triggers high levels of inflammatory chemical signals and leads to a septic state . EBOV is thought to infect humans through contact with mucous membranes or skin breaks. After infection, endothelial cells (cells lining the inside of blood vessels), liver cells, and several types of immune cells such as macrophages, monocytes , and dendritic cells are the main targets of attack. Following infection, immune cells carry the virus to nearby lymph nodes where further reproduction of the virus takes place. From there the virus can enter the bloodstream and lymphatic system and spread throughout the body. Macrophages are the first cells infected with the virus, and this infection results in programmed cell death . Other types of white blood cells , such as lymphocytes , also undergo programmed cell death leading to an abnormally low concentration of lymphocytes in the blood. This contributes to the weakened immune response seen in those infected with EBOV. Endothelial cells may be infected within three days after exposure to the virus. The breakdown of endothelial cells leading to blood vessel injury can be attributed to EBOV glycoproteins . This damage occurs due to the synthesis of Ebola virus glycoprotein (GP), which reduces the availability of specific integrins responsible for cell adhesion to the intercellular structure and causes liver damage, leading to improper clotting . The widespread bleeding that occurs in affected people causes swelling and shock due to loss of blood volume . The dysfunctional bleeding and clotting commonly seen in EVD has been attributed to increased activation of the extrinsic pathway of the coagulation cascade due to excessive tissue factor production by macrophages and monocytes. After infection, a secreted glycoprotein , small soluble glycoprotein (sGP or GP) is synthesised. EBOV replication overwhelms protein synthesis of infected cells and the host immune defences. The GP forms a trimeric complex , which tethers the virus to the endothelial cells. The sGP forms a dimeric protein that interferes with the signalling of neutrophils , another type of white blood cell. This enables the virus to evade the immune system by inhibiting early steps of neutrophil activation. [ medical citation needed ] Furthermore, the virus is capable of hijacking cellular metabolism. Studies have shown that Ebola virus-like particles can reprogram metabolism in both vascular and immune cells. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. Filoviral infection also interferes with proper functioning of the innate immune system . EBOV proteins blunt the human immune system's response to viral infections by interfering with the cells' ability to produce and respond to interferon proteins such as interferon-alpha , interferon-beta , and interferon gamma . The VP24 and VP35 structural proteins of EBOV play a key role in this interference. When a cell is infected with EBOV, receptors located in the cell's cytosol (such as RIG-I and MDA5 ) or outside of the cytosol (such as Toll-like receptor 3 (TLR3) , TLR7 , TLR8 and TLR9 ) recognise infectious molecules associated with the virus. On TLR activation, proteins including interferon regulatory factor 3 and interferon regulatory factor 7 trigger a signalling cascade that leads to the expression of type 1 interferons . The type 1 interferons are then released and bind to the IFNAR1 and IFNAR2 receptors expressed on the surface of a neighbouring cell. Once interferon has bound to its receptors on the neighbouring cell, the signalling proteins STAT1 and STAT2 are activated and move to the cell's nucleus . This triggers the expression of interferon-stimulated genes , which code for proteins with antiviral properties. EBOV's V24 protein blocks the production of these antiviral proteins by preventing the STAT1 signalling protein in the neighbouring cell from entering the nucleus. The VP35 protein directly inhibits the production of interferon-beta. By inhibiting these immune responses, EBOV may quickly spread throughout the body. When EVD is suspected, travel, work history, and exposure to wildlife are important factors with respect to further diagnostic efforts. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. Possible non-specific laboratory indicators of EVD include a low platelet count ; an initially decreased white blood cell count followed by an increased white blood cell count ; elevated levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST); and abnormalities in blood clotting often consistent with disseminated intravascular coagulation (DIC) such as a prolonged prothrombin time , partial thromboplastin time , and bleeding time . Filovirions such as EBOV may be identified by their unique filamentous shapes in cell cultures examined with electron microscopy . The specific diagnosis of EVD is confirmed by isolating the virus, detecting its RNA or proteins, or detecting antibodies against the virus in a person's blood. Isolating the virus by cell culture , detecting the viral RNA by polymerase chain reaction (PCR) and detecting proteins by enzyme-linked immunosorbent assay (ELISA) are methods best used in the early stages of the disease and also for detecting the virus in human remains. Detecting antibodies against the virus is most reliable in the later stages of the disease and in those who recover. IgM antibodies are detectable two days after symptom onset and IgG antibodies can be detected six to 18 days after symptom onset. During an outbreak, isolation of the virus with cell culture methods is often not feasible. In field or mobile hospitals, the most common and sensitive diagnostic methods are real-time PCR and ELISA. In 2014, with new mobile testing facilities deployed in parts of Liberia, test results were obtained 3–5 hours after sample submission. In 2015, a rapid antigen test which gives results in 15 minutes was approved for use by WHO. It is able to confirm Ebola in 92% of those affected and rule it out in 85% of those not affected. Early symptoms of EVD may be similar to those of other diseases common in Africa, including malaria and dengue fever . The symptoms are also similar to those of other viral haemorrhagic fevers such as Marburg virus disease , Crimean–Congo haemorrhagic fever , and Lassa fever . The complete differential diagnosis is extensive and requires consideration of many other infectious diseases such as typhoid fever , shigellosis , rickettsial diseases , cholera , sepsis , borreliosis , EHEC enteritis , leptospirosis , scrub typhus , plague , Q fever , candidiasis , histoplasmosis , trypanosomiasis , visceral leishmaniasis , measles , and viral hepatitis among others. Non-infectious diseases that may result in symptoms similar to those of EVD include acute promyelocytic leukaemia , haemolytic uraemic syndrome , snake envenomation , clotting factor deficiencies/platelet disorders, thrombotic thrombocytopenic purpura , hereditary haemorrhagic telangiectasia , Kawasaki disease , and warfarin poisoning. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. An Ebola vaccine , rVSV-ZEBOV , was approved in the United States in December 2019. It appears to be fully effective ten days after being given. It was studied in Guinea between 2014 and 2016. More than 100,000 people have been vaccinated against Ebola as of 2019 [ update ] . The WHO reported that approximately 345,000 people were given the vaccine during the Kivu Ebola epidemic from 2018 to 2020. Community awareness of the benefits on survival chances of admitting cases early is important for the infected and infection control People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. People who care for those infected with Ebola should wear protective clothing including masks, gloves, gowns and goggles. The U.S. Centers for Disease Control (CDC) recommend that the protective gear leaves no skin exposed. These measures are also recommended for those who may handle objects contaminated by an infected person's body fluids. In 2014, the CDC began recommending that medical personnel receive training on the proper suit-up and removal of personal protective equipment (PPE); in addition, a designated person, appropriately trained in biosafety, should be watching each step of these procedures to ensure they are done correctly. In Sierra Leone, the typical training period for the use of such safety equipment lasts approximately 12 days. In 2022 in Uganda, lighter personal protection equipment has become available as well as possibilities to monitor and communicate with patients from windows in the treatment tents until it is necessary to enter if e.g. a patient's oxygen levels drop. The infected person should be in barrier-isolation from other people. All equipment, medical waste, patient waste and surfaces that may have come into contact with body fluids need to be disinfected . During the 2014 outbreak, kits were put together to help families treat Ebola disease in their homes, which included protective clothing as well as chlorine powder and other cleaning supplies. Education of caregivers in these techniques, and providing such barrier-separation supplies has been a priority of Doctors Without Borders . Ebolaviruses can be eliminated with heat (heating for 30 to 60 minutes at 60 °C or boiling for five minutes). To disinfect surfaces, some lipid solvents such as some alcohol-based products, detergents, sodium hypochlorite (bleach) or calcium hypochlorite (bleaching powder), and other suitable disinfectants may be used at appropriate concentrations. Education of the general public about the risk factors for Ebola infection and of the protective measures individuals may take to prevent infection is recommended by the World Health Organization . These measures include avoiding direct contact with infected people and regular hand washing using soap and water. Bushmeat , an important source of protein in the diet of some Africans, should be handled and prepared with appropriate protective clothing and thoroughly cooked before consumption. Some research suggests that an outbreak of Ebola disease in the wild animals used for consumption may result in a corresponding human outbreak. Since 2003, such animal outbreaks have been monitored to predict and prevent Ebola outbreaks in humans. If a person with Ebola disease dies, direct contact with the body should be avoided. Certain burial rituals , which may have included making various direct contacts with a dead body, require reformulation so that they consistently maintain a proper protective barrier between the dead body and the living. Social anthropologists may help find alternatives to traditional rules for burials. Transportation crews are instructed to follow a certain isolation procedure, should anyone exhibit symptoms resembling EVD. As of August 2014 [ update ] , the WHO does not consider travel bans to be useful in decreasing spread of the disease. In October 2014, the CDC defined four risk levels used to determine the level of 21-day monitoring for symptoms and restrictions on public activities. In the United States, the CDC recommends that restrictions on public activity, including travel restrictions, are not required for the following defined risk levels: having been in a country with widespread Ebola disease transmission and having no known exposure (low risk); or having been in that country more than 21 days ago (no risk) encounter with a person showing symptoms; but not within three feet of the person with Ebola without wearing PPE; and no direct contact with body fluids having had brief skin contact with a person showing symptoms of Ebola disease when the person was believed to be not very contagious (low risk) in countries without widespread Ebola disease transmission: direct contact with a person showing symptoms of the disease while wearing PPE (low risk) contact with a person with Ebola disease before the person was showing symptoms (no risk). The CDC recommends monitoring for the symptoms of Ebola disease for those both at "low risk" and at higher risk. In laboratories where diagnostic testing is carried out, biosafety level 4-equivalent containment is required. Laboratory researchers must be properly trained in BSL-4 practices and wear proper PPE. Isolation refers to separating those who are sick from those who are not. Quarantine refers to separating those who may have been exposed to a disease until they either show signs of the disease or are no longer at risk. Quarantine, also known as enforced isolation, is usually effective in decreasing spread. Governments often quarantine areas where the disease is occurring or individuals who may transmit the disease outside of an initial area. In the United States, the law allows quarantine of those infected with ebolaviruses. Contact tracing is considered important to contain an outbreak. It involves finding everyone who had close contact with infected individuals and monitoring them for signs of illness for 21 days. If any of these contacts comes down with the disease, they should be isolated, tested and treated. Then the process is repeated, tracing the contacts' contacts. As of 2019 [ update ] two treatments ( atoltivimab/maftivimab/odesivimab and ansuvimab ) are associated with improved outcomes. The U.S. Food and Drug Administration (FDA) advises people to be careful of advertisements making unverified or fraudulent claims of benefits supposedly gained from various anti-Ebola products. In October 2020, the U.S. Food and Drug Administration (FDA) approved atoltivimab/maftivimab/odesivimab with an indication for the treatment of infection caused by Zaire ebolavirus . Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. Treatment is primarily supportive in nature. Early supportive care with rehydration and symptomatic treatment improves survival. Rehydration may be via the oral or intravenous route. These measures may include pain management , and treatment for nausea , fever , and anxiety . The World Health Organization (WHO) recommends avoiding aspirin or ibuprofen for pain management, due to the risk of bleeding associated with these medications. Blood products such as packed red blood cells , platelets , or fresh frozen plasma may also be used. Other regulators of coagulation have also been tried including heparin in an effort to prevent disseminated intravascular coagulation and clotting factors to decrease bleeding. Antimalarial medications and antibiotics are often used before the diagnosis is confirmed, though there is no evidence to suggest such treatment helps. Several experimental treatments are being studied . Where hospital care is not possible, the WHO's guidelines for home care have been relatively successful. Recommendations include using towels soaked in a bleach solution when moving infected people or bodies and also applying bleach on stains. It is also recommended that the caregivers wash hands with bleach solutions and cover their mouth and nose with a cloth. Intensive care is often used in the developed world. This may include maintaining blood volume and electrolytes (salts) balance as well as treating any bacterial infections that may develop. Dialysis may be needed for kidney failure , and extracorporeal membrane oxygenation may be used for lung dysfunction. EVD has a risk of death in those infected of between 25% and 90%. As of September 2014 [ update ] , the average risk of death among those infected is 50%. The highest risk of death was 90% in the 2002–2003 Republic of the Congo outbreak. Early admission significantly increases survival rates Death, if it occurs, follows typically six to sixteen days after symptoms appear and is often due to low blood pressure from fluid loss . Early supportive care to prevent dehydration may reduce the risk of death. If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . If an infected person survives, recovery may be quick and complete. However, a large portion of survivors develop post-Ebola virus syndrome after the acute phase of the infection. Prolonged cases are often complicated by the occurrence of long-term problems, such as inflammation of the testicles , joint pains , fatigue, hearing loss, mood and sleep disturbances, muscular pain , abdominal pain, menstrual abnormalities , miscarriages , skin peeling , or hair loss . Inflammation and swelling of the uveal layer of the eye is the most common eye complication in survivors of Ebola virus disease. Eye symptoms, such as light sensitivity , excess tearing , and vision loss have been described. Ebola can stay in some body parts like the eyes, breasts, and testicles after infection. Sexual transmission after recovery has been suspected. If sexual transmission occurs following recovery it is believed to be a rare event. One case of a condition similar to meningitis has been reported many months after recovery, as of October 2015 [ update ] . The disease typically occurs in outbreaks in tropical regions of Sub-Saharan Africa . From 1976 (when it was first identified) through 2013, the WHO reported 2,387 confirmed cases with 1,590 overall fatalities. The largest outbreak to date was the Ebola virus epidemic in West Africa , which caused a large number of deaths in Guinea , Sierra Leone , and Liberia . The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The first known outbreak of EVD was identified only after the fact. It occurred between June and November 1976, in Nzara, South Sudan (then part of Sudan ), and was caused by Sudan virus (SUDV). The Sudan outbreak infected 284 people and killed 151. The first identifiable case in Sudan occurred on 27 June in a storekeeper in a cotton factory in Nzara , who was hospitalised on 30 June and died on 6 July. Although the WHO medical staff involved in the Sudan outbreak knew that they were dealing with a heretofore unknown disease, the actual "positive identification" process and the naming of the virus did not occur until some months later in Zaire . On 26 August 1976, the second outbreak of EVD began in Yambuku , a small rural village in Mongala District in northern Zaire (now known as the Democratic Republic of the Congo ). This outbreak was caused by EBOV, formerly designated Zaire ebolavirus , a different member of the genus Ebolavirus than in the first Sudan outbreak. The first person infected with the disease was the village school's headmaster Mabalo Lokela , who began displaying symptoms on 26 August 1976. Lokela had returned from a trip to Northern Zaire near the border of the Central African Republic , after visiting the Ebola River between 12 and 22 August. He was originally believed to have malaria and was given quinine . However, his symptoms continued to worsen, and he was admitted to Yambuku Mission Hospital on 5 September. Lokela died on 8 September 14 days after he began displaying symptoms. Soon after Lokela's death, others who had been in contact with him also died, and people in Yambuku began to panic. The country's Minister of Health and Zaire President Mobutu Sese Seko declared the entire region, including Yambuku and the country's capital, Kinshasa , a quarantine zone. No-one was permitted to enter or leave the area, and roads, waterways, and airfields were placed under martial law . Schools, businesses and social organisations were closed. The initial response was led by Congolese doctors, including Jean-Jacques Muyembe-Tamfum , one of the discoverers of Ebola. Muyembe took a blood sample from a Belgian nun; this sample would eventually be used by Peter Piot to identify the previously unknown Ebola virus. Muyembe was also the first scientist to come into direct contact with the disease and survive. Researchers from the Centers for Disease Control and Prevention (CDC), including Piot, co-discoverer of Ebola, later arrived to assess the effects of the outbreak, observing that "the whole region was in panic." Piot concluded that Belgian nuns had inadvertently started the epidemic by giving unnecessary vitamin injections to pregnant women without sterilizing the syringes and needles. The outbreak lasted 26 days and the quarantine lasted two weeks. Researchers speculated that the disease disappeared due to the precautions taken by locals, the quarantine of the area, and discontinuing of the injections. During this outbreak, Ngoy Mushola recorded the first clinical description of EVD in Yambuku , where he wrote the following in his daily log: "The illness is characterised with a high temperature of about 39 °C (102 °F) , haematemesis , diarrhoea with blood, retrosternal abdominal pain, prostration with 'heavy' articulations, and rapid evolution death after a mean of three days." The virus responsible for the initial outbreak, first thought to be the Marburg virus , was later identified as a new type of virus related to the genus Marburgvirus . Virus strain samples isolated from both outbreaks were named "Ebola virus" after the Ebola River , near the first-identified viral outbreak site in Zaire. Reports conflict about who initially coined the name: either Karl Johnson of the American CDC team or Belgian researchers. Subsequently, a number of other cases were reported, almost all centred on the Yambuku mission hospital or close contacts of another case. In all, 318 cases and 280 deaths (an 88% fatality rate) occurred in Zaire. Although the two outbreaks were at first believed connected, scientists later realised that they were caused by two distinct ebolaviruses, SUDV and EBOV. The second major outbreak occurred in Zaire (now the Democratic Republic of the Congo , DRC), in 1995, affecting 315 and killing 254. In 2000, Uganda had an outbreak infecting 425 and killing 224; in this case, the Sudan virus was found to be the Ebola species responsible for the outbreak. In 2003, an outbreak in the DRC infected 143 and killed 128, a 90% death rate, the highest of a genus Ebolavirus outbreak to date. In 2004, a Russian scientist died from Ebola after sticking herself with an infected needle. Between April and August 2007, a fever epidemic in a four-village region of the DRC was confirmed in September to have been cases of Ebola. Many people who attended the recent funeral of a local village chief died. The 2007 outbreak eventually infected 264 individuals and killed 187. On 30 November 2007, the Uganda Ministry of Health confirmed an outbreak of Ebola in the Bundibugyo District in Western Uganda. After confirming samples tested by the United States National Reference Laboratories and the Centers for Disease Control, the World Health Organization (WHO) confirmed the presence of a new species of genus Ebolavirus , which was tentatively named Bundibugyo. The WHO reported 149 cases of this new strain and 37 of those led to deaths. The WHO confirmed two small outbreaks in Uganda in 2012, both caused by the Sudan variant. The first outbreak affected seven people, killing four, and the second affected 24, killing 17. On 17 August 2012, the Ministry of Health of the DRC reported an outbreak of the Ebola-Bundibugyo variant in the eastern region. Other than its discovery in 2007, this was the only time that this variant has been identified as responsible for an outbreak. The WHO revealed that the virus had sickened 57 people and killed 29. The probable cause of the outbreak was tainted bush meat hunted by local villagers around the towns of Isiro and Viadana. In 2014, an outbreak occurred in the DRC. Genome-sequencing showed that this outbreak was not related to the 2014–15 West Africa Ebola virus outbreak , but was the same EBOV species, the Zaire species. It began in August 2014, and was declared over in November with 66 cases and 49 deaths. This was the 7th outbreak in the DRC, three of which occurred during the period when the country was known as Zaire . In March 2014, the World Health Organization (WHO) reported a major Ebola outbreak in Guinea , a West African nation. Researchers traced the outbreak to a one-year-old child who died in December 2013. The disease rapidly spread to the neighbouring countries of Liberia and Sierra Leone . It was the largest Ebola outbreak ever documented, and the first recorded in the region. On 8 August 2014, the WHO declared the epidemic an international public health emergency. Urging the world to offer aid to the affected regions, its Director-General said, "Countries affected to date simply do not have the capacity to manage an outbreak of this size and complexity on their own. I urge the international community to provide this support on the most urgent basis possible." By mid-August 2014, Doctors Without Borders reported the situation in Liberia's capital, Monrovia , was "catastrophic" and "deteriorating daily". They reported that fears of Ebola among staff members and patients had shut down much of the city's health system, leaving many people without medical treatment for other conditions. In a 26 September statement, WHO said, "The Ebola epidemic ravaging parts of West Africa is the most severe acute public health emergency seen in modern times. Never before in recorded history has a biosafety level four pathogen infected so many people so quickly, over such a broad geographical area, for so long." Intense contact tracing and strict isolation largely prevented further spread of the disease in the countries that had imported cases. It caused significant mortality, with a considerable case fatality rate . [note 1] By the end of the epidemic, 28,616 people had been infected; of these, 11,310 had died, for a case-fatality rate of 40%. As of 8 May 2016 [ update ] , 28,646 suspected cases and 11,323 deaths were reported; however, the WHO said that these numbers may be underestimated. Because they work closely with the body fluids of infected patients, healthcare workers were especially vulnerable to infection; in August 2014, the WHO reported that 10% of the dead were healthcare workers. In September 2014, it was estimated that the countries' capacity for treating Ebola patients was insufficient by the equivalent of 2,122 beds; by December there were a sufficient number of beds to treat and isolate all reported Ebola cases, although the uneven distribution of cases was causing serious shortfalls in some areas. On 28 January 2015, the WHO reported that for the first time since the week ending 29 June 2014, there had been fewer than 100 new confirmed cases reported in a week in the three most-affected countries. The response to the epidemic then moved to a second phase, as the focus shifted from slowing transmission to ending the epidemic. On 8 April 2015, the WHO reported only 30 confirmed cases, the lowest weekly total since the third week of May 2014. On 29 December 2015, 42 days after the last person tested negative for a second time, Guinea was declared free of Ebola transmission. At that time, a 90-day period of heightened surveillance was announced by that agency. "This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission ...", the organisation stated in a news release. A new case was detected in Sierra Leone on 14 January 2016. However, the outbreak was declared no longer an emergency on 29 March 2016. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 19 September, Eric Duncan flew from his native Liberia to Texas; five days later he began showing symptoms and visited a hospital but was sent home. His condition worsened and he returned to the hospital on 28 September, where he died on 8 October. Health officials confirmed a diagnosis of Ebola on 30 September – the first case in the United States. In early October, Teresa Romero, a 44-year-old Spanish nurse, contracted Ebola after caring for a priest who had been repatriated from West Africa. This was the first transmission of the virus to occur outside Africa. Romero tested negative for the disease on 20 October, suggesting that she may have recovered from Ebola infection. On 12 October, the Centers for Disease Control and Prevention (CDC) confirmed that a nurse in Texas, Nina Pham , who had treated Duncan tested positive for the Ebola virus, the first known case of transmission in the United States. On 15 October, a second Texas health-care worker who had treated Duncan was confirmed to have the virus. Both of these people recovered. An unrelated case involved a doctor in New York City, who returned to the United States from Guinea after working with Médecins Sans Frontières and tested positive for Ebola on 23 October. The person recovered and was discharged from Bellevue Hospital on 11 November. On 24 December 2014, a laboratory in Atlanta , Georgia reported that a technician had been exposed to Ebola. On 29 December 2014, Pauline Cafferkey , a British nurse who had just returned to Glasgow from Sierra Leone, was diagnosed with Ebola at Glasgow's Gartnavel General Hospital . After initial treatment in Glasgow, she was transferred by air to RAF Northolt , then to the specialist high-level isolation unit at the Royal Free Hospital in London for longer-term treatment. On 11 May 2017, the DRC Ministry of Public Health notified the WHO about an outbreak of Ebola. Four people died, and four people survived; five of these eight cases were laboratory-confirmed. A total of 583 contacts were monitored. On 2 July 2017, the WHO declared the end of the outbreak. On 14 May 2018, the World Health Organization reported that "the Democratic Republic of Congo reported 39 suspected, probable or confirmed cases of Ebola between 4 April and 13 May, including 19 deaths." Some 393 people identified as contacts of Ebola patients were being followed up. The outbreak centred on the Bikoro , Iboko, and Wangata areas in Equateur province, including in the large city of Mbandaka . The DRC Ministry of Public Health approved the use of an experimental vaccine. On 13 May 2018, WHO Director-General Tedros Adhanom Ghebreyesus visited Bikoro. Reports emerged that maps of the area were inaccurate, not so much hampering medical providers as epidemiologists and officials trying to assess the outbreak and containment efforts. The 2018 outbreak in the DRC was declared over on 24 July 2018. On 1 August 2018, the world's 10th Ebola outbreak was declared in North Kivu province of the Democratic Republic of the Congo. It was the first Ebola outbreak in a military conflict zone, with thousands of refugees in the area. By November 2018, nearly 200 Congolese had died of Ebola, about half of them from the city of Beni , where armed groups are fighting over the region's mineral wealth, impeding medical relief efforts. By March 2019, this became the second largest Ebola outbreak ever recorded, with more than 1,000 cases and insecurity continuing to be the major resistance to providing an adequate response. As of 4 June 2019 [ update ] , the WHO reported 2025 confirmed and probable cases with 1357 deaths. In June 2019, two people died of Ebola in neighbouring Uganda . In July 2019, an infected man travelled to Goma , home to more than two million people. One week later, on 17 July 2019, the WHO declared the Ebola outbreak a global health emergency , the fifth time such a declaration has been made by the organisation. A government spokesman said that half of the Ebola cases are unidentified, and he added that the current outbreak could last up to three years. On 25 June 2020, the second biggest EVD outbreak ever was declared over. On 1 June 2020, the Congolese health ministry announced a new DRC outbreak of Ebola in Mbandaka , Équateur Province , a region along the Congo River. Genome sequencing suggests that this outbreak, the 11th outbreak since the virus was first discovered in the country in 1976, is unrelated to the one in North Kivu Province or the previous outbreak in the same area in 2018. It was reported that six cases had been identified; four of the people had died. It is expected that more people will be identified as surveillance activities increase. By 15 June the case count had increased to 17 with 11 deaths, with more than 2,500 people having been vaccinated. The 11th EVD outbreak was officially declared over on 19 November 2020. By the time the Équateur outbreak ended, it had 130 confirmed cases with 75 recoveries and 55 deaths.On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 7 February 2021, the Congolese health ministry announced a new case of Ebola near Butembo, North Kivu detected a day before. The case was a 42-year-old woman who had symptoms of Ebola in Biena on 1 February 2021. A few days after, she died in a hospital in Butembo. The WHO said that more than 70 people with contact with the woman had been tracked. On 11 February 2021, another woman who had contact with the previous woman died in the same town, and the number of traced contacts increased to 100. A day after, a third case was detected in Butembo. On 3 May 2021, the 12th EVD outbreak was declared over, resulting in 12 cases and six deaths. Heightened surveillance will continue for 90 days after the declaration, in case of resurgence. In February 2021, Sakoba Keita, head of Guinea's national health agency confirmed that three people had died of Ebola in the south-eastern region near the city of Nzérékoré. A further five people also tested positive. Keita also confirmed more testing was underway, and attempts to trace and isolate further cases had begun. On 14 February, the Guinean government declared an Ebola epidemic. The outbreak may have started following reactivation of a latent case in a survivor of an earlier outbreak. As of 4 May 2021, 23 cases were reported, with no new cases or deaths since 3 April 2021. A 42-day countdown period was started on 8 May 2021, and on 19 June, the outbreak was declared over. On 14 August 2021, The Ministry of Health of Cote d'Ivoire confirmed the country's first case of Ebola since 1994. This came after the Institut Pasteur in Cote d'Ivoire confirmed the Ebola Virus Disease in samples collected from a patient, who was hospitalized in the commercial capital of Abidjan , after arriving from Guinea. However, on 31 August 2021, the WHO found that, after further tests in a laboratory in Lyon , the patient did not have Ebola. The cause of her disease is still being analyzed. On 23 April 2022, a case of Ebola was confirmed in the DRC in the Equateur province. The case was a 31-year-old man whose symptoms began on 5 April, but did not seek treatment for over a week. On 21 April, he was admitted to an Ebola treatment centre and died later that day. By 24 May 2022, there were 5 recorded deaths in the DRC. On 15 August, the fifth case was buried, and the outbreak was declared over, 42 days after, on 4 July 2022. In September 2022, Uganda reported 7 cases infected with the Ebola Sudan strain , but by mid-October the count had increased to 63. In November 2022, the outbreak in Uganda continued - still without a vaccine. On 10 January 2023, the outbreak was considered over after no new cases had been reported for 42 days; the outbreak killed nearly 80 people. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebolavirus is classified as a biosafety level 4 agent, as well as a Category A bioterrorism agent by the Centers for Disease Control and Prevention. It has the potential to be weaponised for use in biological warfare , and was investigated by Biopreparat for such use, but might be difficult to prepare as a weapon of mass destruction because the virus becomes ineffective quickly in open air. Fake emails pretending to be Ebola information from the WHO or the Mexican government have, in 2014, been misused to spread computer malware. The BBC reported in 2015 that "North Korean state media has suggested the disease was created by the U.S. military as a biological weapon." Richard Preston 's 1995 best-selling book, The Hot Zone , dramatised the Ebola outbreak in Reston, Virginia. William Close 's 1995 Ebola: A Documentary Novel of Its First Explosion and 2002 Ebola: Through the Eyes of the People focused on individuals' reactions to the 1976 Ebola outbreak in Zaire. Tom Clancy 's 1996 novel, Executive Orders , involves a Middle Eastern terrorist attack on the United States using an airborne form of a deadly Ebola virus strain named "Ebola Mayinga" (see Mayinga N'Seka ). As the Ebola virus epidemic in West Africa developed in 2014, a number of popular self-published and well-reviewed books containing sensational and misleading information about the disease appeared in electronic and printed formats. The authors of some such books admitted that they lacked medical credentials and were not technically qualified to give medical advice. The World Health Organization and the United Nations stated that such misinformation had contributed to the spread of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks." In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. Ebola has a high mortality rate among primates. Frequent outbreaks of Ebola may have resulted in the deaths of 5,000 gorillas. Outbreaks of Ebola may have been responsible for an 88% decline in tracking indices of observed chimpanzee populations in the 420 km 2 Lossi Sanctuary between 2002 and 2003. Transmission among chimpanzees through meat consumption constitutes a significant risk factor, whereas contact between the animals, such as touching dead bodies and grooming, is not. Recovered gorilla carcasses have contained multiple Ebola virus strains, suggesting multiple introductions of the virus. Bodies decompose quickly and carcasses are not infectious after three to four days. Contact between gorilla groups is rare, suggesting that transmission among gorilla groups is unlikely, and that outbreaks result from transmission between viral reservoirs and animal populations. In 2012, it was demonstrated that the virus can travel without contact from pigs to nonhuman primates, although the same study failed to achieve transmission in that manner between primates. Dogs may become infected with EBOV but not develop symptoms. Dogs in some parts of Africa scavenge for food, and they sometimes eat EBOV-infected animals and also the corpses of humans. A 2005 survey of dogs during an EBOV outbreak found that although they remain asymptomatic, about 32 percent of dogs closest to an outbreak showed a seroprevalence for EBOV versus nine percent of those farther away. The authors concluded that there were "potential implications for preventing and controlling human outbreaks."In late 1989, Hazelton Research Products' Reston Quarantine Unit in Reston, Virginia , had an outbreak of fatal illness amongst certain lab monkeys. This lab outbreak was initially diagnosed as simian haemorrhagic fever virus (SHFV) and occurred amongst a shipment of crab-eating macaque monkeys imported from the Philippines. Hazelton's veterinary pathologist in Reston sent tissue samples from dead animals to the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) at Fort Detrick, Maryland , where an ELISA test indicated the antibodies present in the tissue were a response to Ebola virus and not SHFV. An electron microscopist from USAMRIID discovered filoviruses similar in appearance, in crystalloid aggregates and as single filaments with a shepherd's hook, to Ebola in the tissue samples sent from Hazelton Research Products' Reston Quarantine Unit. A US Army team headquartered at USAMRIID euthanised the surviving monkeys, and brought all the dead monkeys to Fort Detrick for study by the Army's veterinary pathologists and virologists, and eventual disposal under safe conditions. Blood samples were taken from 178 animal handlers during the incident. Of those, six animal handlers eventually seroconverted , including one who had cut himself with a bloody scalpel. Despite its status as a Level‑4 organism and its apparent pathogenicity in monkeys, when the handlers did not become ill, the CDC concluded that the virus had a very low pathogenicity to humans. The Philippines and the United States had no previous cases of Ebola infection, and upon further isolation, researchers concluded it was another strain of Ebola, or a new filovirus of Asian origin, which they named Reston ebolavirus (RESTV) after the location of the incident. Reston virus (RESTV) can be transmitted to pigs. Since the initial outbreak it has since been found in nonhuman primates in Pennsylvania, Texas, and Italy, where the virus had infected pigs. According to the WHO, routine cleaning and disinfection of pig (or monkey) farms with sodium hypochlorite or detergents should be effective in inactivating the Reston ebolavirus . Pigs that have been infected with RESTV tend to show symptoms of the disease. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome. As of July 2015 [ update ] , no medication has been proven safe and effective for treating Ebola. By the time the Ebola virus epidemic in West Africa began in 2013, there were at least nine different candidate treatments. Several trials were conducted in late 2014, and early 2015, but some were abandoned due to lack of efficacy or lack of people to study. As of August 2019 [ update ] , two experimental treatments known as atoltivimab/maftivimab/odesivimab and ansuvimab were found to be 90% effective. The diagnostic tests currently available require specialised equipment and highly trained personnel. Since there are few suitable testing centres in West Africa, this leads to delay in diagnosis. On 29 November 2014, a new 15-minute Ebola test was reported that if successful, "not only gives patients a better chance of survival, but it prevents transmission of the virus to other people." The new equipment, about the size of a laptop and solar-powered, allows testing to be done in remote areas. On 29 December 2014, the U.S. Food and Drug Administration (FDA) approved the LightMix Ebola Zaire rRT-PCR test for patients with symptoms of Ebola. Animal models and in particular non-human primates are being used to study different aspects of Ebola virus disease. Developments in organ-on-a-chip technology have led to a chip-based model for Ebola haemorrhagic syndrome.

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Rift Valley fever

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

Prevention of viral hemorrhagic fever

Prevention of viral hemorrhagic fever is similar for the different viruses. There are a number of different viral hemorrhagic fevers including Ebola virus disease , Lassa fever , Rift valley fever , Marburg virus disease , Crimean-Congo haemorrhagic fever (CCHF) and yellow fever . Lassa, Ebola, Marburg and CCHF can be spread by direct contact with the body fluids of those infected. Thus the content here covers the prevention of Ebola .The use of standard precautions is recommended with all patients in a healthcare environment. This includes a minimum level of standard precautions for use with all people regardless of their infection status, routine handwashing practices, safe handling and disposal of used needles and syringes, and intensifying standard precautions. It also includes VHF isolation precautions when needed. Limited supplies and resources may prevent a health facility from using all the standard precautions all the time. However, health facilities should establish and maintain a basic, practical level of standard precautions that can be used routinely with patients in their health facility. This requires a source of clean water, routine handwashing before and after any contact with a person who has fever, and safe handling and disposal of sharp instruments and equipment. Washing hands with soap and water eliminates microorganisms from the skin and hands. This provides some protection against transmission of VHF and other diseases. This requires at least cake soap cut into small pieces, soap dishes with openings that allow water to drain away, running water or a bucket kept full with clean water, a bucket for collecting rinse water and a ladle for dipping, if running water is not available, and one-use towels. The handwashing technique that is recommended is to place a piece of soap in the palm of one hand, wash the opposite hand and forearm, rub the surfaces vigorously for at least 10 seconds, move soap to the opposite hand and repeat, use clean water to rinse both hands and then the forearms, dry the hands and forearms with a clean one-use towel, or let rinsed hands and forearms air-dry. Reusable needles and syringes are not recommended. If reusable needles and syringes are used, clean, disinfect and sterilize them before reuse. Needles and syringes used with VHF patients require special care. Cleaning staff should wear two pairs of gloves when handling needles and syringes used with any patient with a known or suspected VHF. In an outbreak situation, several cases occur around the same time. They may be grouped together, and there may be person-to-person transmission. An initial diagnosis of a VHF can be made based on the signs and symptoms of the specific VHF. Suspecting a VHF during a non-outbreak situation in a single case is more difficult. The early symptoms of a VHF include high fever and headache. These are also symptoms for many infections seen at the health facility. Most people who present with fever do not have a VHF. Their fever is more often caused by malaria , typhoid fever , dysentery , severe bacterial infection or other fever-producing illnesses usually seen in the area. The health worker probably will not suspect a VHF until more severe signs develop and the patient does not respond to recommended treatment for other illnesses. However, health workers should be aware of the possibility of VHF in a non-outbreak situation. As soon as a VHF is suspected, VHF isolation precautions should begin. This will help reduce the number of people exposed to the VHF. Isolating the VHF patient will restrict patient access to health facility staff trained to use VHF isolation precautions. Establish a barrier between the VHF patient and uninfected patients, other health facility staff, and visitors. When a VHF case is suspected in the health facility, the following protective clothing should be worn in the isolation area: A scrub suit or inner layer of clothing (an old shirt and trousers brought from home) A pair of thin gloves Rubber boots or overshoes (only if the floor is soiled) A gown or outer layer of clothing (surgical or disposable gown with long sleeves and cuffs) A plastic apron worn over both layers of clothes A second pair of thin or thick gloves. Wearing a second pair of gloves provides an added measure of safety during patient care and when handling contaminated supplies A HEPA-filter (high-efficiency particulate air respirator) or other biosafety mask (or surgical mask if HEPA-filter or other biosafety mask is not available) Cotton head covering Clear eyeglasses or non-fogging goggles When protective clothing is not available or is in short supply, adaptations must be made and used. There are specific recommendation regarding the putting on of protective clothing including: Before entering the changing room, remove jewelry, wallets and other valuables. Remove street clothes and hang them on a hook. Put on the scrub suit or set of old clothes. Enter the changing room. Put on rubber boots. Put on each boot and tuck the trouser leg inside the boot. If overboots are used, tape the top of the boot to the leg with plastic tape. This will help prevent spills from running inside the boots. Put on the first pair of gloves. Look at your hands for cut or broken skin. If the skin is cut or broken, refrain from direct patient contact. Put on one glove at a time. If the scrub suit or set of old clothes has long sleeves, place the edge of each glove under the cuff. When only one pair of gloves is worn, place the edge of the glove over the cuff or gown. If gloves are not available, use plastic bags. Put on one layer now. Attach and close the first layer with tape or elastic bands Put on the outer gown. Pick up the gown from the inside. This is especially important if the gown is being reused Put on the plastic or rubber apron. Put on the second pair of gloves Put on the mask and head cover Put on the protective eyewear. Attach the eyeglasses or goggles behind the head with string or cord to prevent the eyewear from falling off. Introduction Trained oberserver Removing own clothing Examining equipment Hand cleaning Boot covers Inner gloves Coverall N95 respirator surgical hood Outer apron Outer gloves Face shield Verification There are also specific recommendations regarding the removal of protective clothing including: Disinfect the outer pair of gloves, wash the gloved hands in soap and water, dip the gloved hands in 1:100 bleach solution (see below) for one minute Disinfect the apron. Spray or wipe it with 1:100 bleach solution. Disinfect the boots. Use a sprayer containing 1:100 bleach solution to spray boots or hold the foot over a pan or basin and ask another health worker to pour 1:100 bleach solution over the boots or step into a shallow pan containing 1:100 bleach solution and wipe boots on a bleach-drenched cloth Remove the outer pair of gloves Remove the apron and outer gown Disinfect the gloved hands after contact with apron and outer gown. Remove the eyewear, head cover and mask. Remove the boots. Place a towel that has been soaked in 1:100 bleach solution on the floor for health facility staff to stand on when removing boots Remove the inner pair of gloves. Remove inner layer of clothes and dress in street clothes. Wash hands with soap and clean water before leaving the changing roomThere are specific recommendation regarding the putting on of protective clothing including: Before entering the changing room, remove jewelry, wallets and other valuables. Remove street clothes and hang them on a hook. Put on the scrub suit or set of old clothes. Enter the changing room. Put on rubber boots. Put on each boot and tuck the trouser leg inside the boot. If overboots are used, tape the top of the boot to the leg with plastic tape. This will help prevent spills from running inside the boots. Put on the first pair of gloves. Look at your hands for cut or broken skin. If the skin is cut or broken, refrain from direct patient contact. Put on one glove at a time. If the scrub suit or set of old clothes has long sleeves, place the edge of each glove under the cuff. When only one pair of gloves is worn, place the edge of the glove over the cuff or gown. If gloves are not available, use plastic bags. Put on one layer now. Attach and close the first layer with tape or elastic bands Put on the outer gown. Pick up the gown from the inside. This is especially important if the gown is being reused Put on the plastic or rubber apron. Put on the second pair of gloves Put on the mask and head cover Put on the protective eyewear. Attach the eyeglasses or goggles behind the head with string or cord to prevent the eyewear from falling off. Introduction Trained oberserver Removing own clothing Examining equipment Hand cleaning Boot covers Inner gloves Coverall N95 respirator surgical hood Outer apron Outer gloves Face shield VerificationThere are also specific recommendations regarding the removal of protective clothing including: Disinfect the outer pair of gloves, wash the gloved hands in soap and water, dip the gloved hands in 1:100 bleach solution (see below) for one minute Disinfect the apron. Spray or wipe it with 1:100 bleach solution. Disinfect the boots. Use a sprayer containing 1:100 bleach solution to spray boots or hold the foot over a pan or basin and ask another health worker to pour 1:100 bleach solution over the boots or step into a shallow pan containing 1:100 bleach solution and wipe boots on a bleach-drenched cloth Remove the outer pair of gloves Remove the apron and outer gown Disinfect the gloved hands after contact with apron and outer gown. Remove the eyewear, head cover and mask. Remove the boots. Place a towel that has been soaked in 1:100 bleach solution on the floor for health facility staff to stand on when removing boots Remove the inner pair of gloves. Remove inner layer of clothes and dress in street clothes. Wash hands with soap and clean water before leaving the changing roomDisinfection kills almost all bacteria, fungi, viruses, and protozoa. It reduces the number of microorganisms to make equipment and surfaces safer for use. When VHF is suspected in the health facility, all medical, nursing, laboratory and cleaning staff should disinfect: Hands and skin after contact with a VHF patient or infectious body fluids Gloved hands after contact with each VHF patient or after contact with infectious body fluids (when gloves cannot be changed) Thermometers, stethoscopes and other medical instruments after use with each VHF patient Spills of infectious body fluids on the walls and floors Patient excreta and containers contaminated by patient excreta Reusable supplies such as protective clothing and patient bedding Used needles and syringes Two strengths of solution are recommended. 1:10 bleach solution is a strong solution used to disinfect excreta and bodies. It is also used to prepare the 1:100 bleach solution. 1:100 bleach solution is used to disinfect surfaces, medical equipment, patient bedding, reusable protective clothing before it is laundered, rinsing gloves between contact with each patient, rinsing gloves, apron and boots before leaving the patient's room, disinfecting contaminated waste for disposal The dilutions mentioned pertain to a starting concentration of 5% active chlorine , so the 1:10 solution is 0.5% and the 1:100 is 0.05%. These solutions must be prepared new each day as they lose their strength after 24 hours. Two strengths of solution are recommended. 1:10 bleach solution is a strong solution used to disinfect excreta and bodies. It is also used to prepare the 1:100 bleach solution. 1:100 bleach solution is used to disinfect surfaces, medical equipment, patient bedding, reusable protective clothing before it is laundered, rinsing gloves between contact with each patient, rinsing gloves, apron and boots before leaving the patient's room, disinfecting contaminated waste for disposal The dilutions mentioned pertain to a starting concentration of 5% active chlorine , so the 1:10 solution is 0.5% and the 1:100 is 0.05%. These solutions must be prepared new each day as they lose their strength after 24 hours. Direct, unprotected contact during disposal of infectious waste can result in accidental transmission of VHF. For this reason, all contaminated waste produced in the care of the VHF patient must be disposed of safely. All non-reusable items should be destroyed so they cannot be used again. Burning should be carried out at least daily. Liquid waste, including patient excreta, can be disposed of in an isolated latrine or toilet set aside for VHF cases. Burning is the recommended method for disposal of other VHF-contaminated waste. A safe and inexpensive disposal system can be made by using an incinerator or a pit for burning. Use fuel to accelerate the burning and ensure that all waste is completely destroyed. There is risk of transmission in the health facility when a VHF patient dies because the bodies and body fluids of deceased VHF patients remain contagious for several days after death. Family and community members are also at risk if burial practices involve touching and washing the body. Burial should take place as soon as possible after the body is prepared in the health facility. Health facility staff should prepare the body safely and instruct families on what is and is not safe. To prepare the body, protective clothing is recommended per usually with a second pair of thick rubber gloves. The body and the area around it is sprayed with 1:10 bleach solution. The body is placed in a " body bag " (mortuary sack) and it is closed securely. The body bag is sprayed with 1:10 bleach solution. The body is then transported to the burial site as soon as possible. Any person who must touch or carry the body during transport should wear the same protective clothing as is worn in the isolation area. The grave should be at least 2 meters deep. Viewing the body is not possible and the burial ceremony should be limited to family only. The interior of the vehicle where the body was carried should be rinsed with 1:10 bleach solution. Community education and involvement is an important part of the prevention of the spread of VHF.

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Rift Valley fever

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

Climate change and infectious diseases

Global climate change has increased the occurrence of some infectious diseases . Infectious diseases whose transmission is impacted by climate change include, for example, vector-borne diseases like dengue fever , malaria , tick-borne diseases , leishmaniasis , zika fever , chikungunya and Ebola . One mechanism contributing to increased disease transmission is that climate change is altering the geographic range and seasonality of the insects (or disease vectors ) that can carry the diseases. Scientists stated a clear observation in 2022: "the occurrence of climate-related food-borne and waterborne diseases has increased (very high confidence)." : 11 Infectious diseases that are sensitive to climate can be grouped into: vector-borne diseases (transmitted via mosquitos , ticks etc.), waterborne diseases (transmitted via viruses or bacteria through water), and food-borne diseases. : 1107 Climate change is affecting the distribution of these diseases due to the expanding geographic range and seasonality of these diseases and their vectors. : 9 Like other ways in which climate change affects on human health , climate change exacerbates existing inequalities and challenges in managing infectious disease. Mosquito-borne diseases that are sensitive to climate include malaria , lymphatic filariasis , Rift Valley fever , yellow fever , dengue fever, Zika virus , and chikungunya . Scientists found in 2022 that rising temperatures are increasing the areas where dengue fever, malaria and other mosquito-carried diseases are able to spread. : 1062 Warmer temperatures are also advancing to higher elevations, allowing mosquitoes to survive in places that were previously inhospitable to them. : 1045 This risks malaria making a return to areas where it was previously eradicated. Ticks are changing their geographic range because of rising temperatures, and this puts new populations at risk. Ticks can spread lyme disease and tick-borne encephalitis . It is expected that climate change will increase the incidence of these diseases in the Northern Hemisphere. : 1094 For example, a review of the literature found that "In the USA, a 2°C warming could increase the number of lyme disease cases by over 20% over the coming decades and lead to an earlier onset and longer length of the annual Lyme disease season". : 1094 Waterborne diseases are caused by a pathogen transmitted through water. The symptoms of waterborne diseases typically include diarrhea , fever and other flu-like symptoms, neurological disorders, and liver damage. Changes in climate have a large effect on the distribution of microbial species. These communities are very complex and can be extremely sensitive to external climate stimuli. There are a range of waterborne diseases and parasites that will pose greater health risks in future. This will vary by region. For example, in Africa Cryptosporidium spp. and Giardia duodenalis ( protozoan parasites ) will increase. This is due to increasing temperatures and drought. : 1095 Scientist also expect that disease outbreaks caused by vibrio (in particular the bacterium that causes cholera , called vibrio cholerae ) are increasing in occurrence and intensity. : 1107 One reason is that the area of coastline with suitable conditions for vibrio bacteria has increased due to changes in sea surface temperature and sea surface salinity caused by climate change. : 12 These pathogens can cause gastroenteritis , cholera, wound infections, and sepsis . The increasing occurrence of higher temperature days, heavy rainfall events and flooding due to climate change could lead to an increase in cholera risks. : 1045In 1988, little was known about the effects of climate change on human health . As of 2023, the evidence has grown significantly and is for example summarised in the Sixth Assessment Report of the Intergovernmental Panel on Climate Change . The scientific understanding about the potential health risks and observed health impacts caused by climate change is now better understood. One category of health risks is that of infectious diseases . A study concluded in 2022 that "58% (that is, 218 out of 375) of infectious diseases confronted by humanity worldwide have been at some point aggravated by climatic hazards". The World Health Organization considers climate change as one of the greatest threats to human health. Infectious diseases have played a significant role in human history, impacting the rise and fall of civilizations and facilitating the conquest of new territories. During recent decades, there are significant regional changes in vector and pathogen distribution reported in temperate, peri‐Arctic, Arctic, and tropical highland regions. Climate change is only one factor in the spread of human diseases. Many other key factors affect the spread and severity of human diseases as well, including mobility of people, animals, and goods; control measures in place; availability of effective drugs; quality of public health services; human behavior; and political stability and conflicts. The effects of climate change on health will impact most populations over the next few decades. However, Africa, and specifically, the African Highlands, are susceptible to being particularly negatively affected. For example, with regards to malaria, in 2010, 91% of the global burden due to malaria deaths occurred in Africa. Several spatiotemporal models have been studied to assess the potential effect of projected climate scenarios on malaria transmission in Africa. It is expected that the most significant climate change effects are confined to specific regions, including the African Highlands. Climate change may lead to dramatic increases in prevalence of a variety of infectious diseases. Beginning in the mid-'70s, an "emergence, resurgence and redistribution of infectious diseases" has occurred. Reasons for this are likely multi-causal, dependent on a variety of social, environmental and climatic factors, however, many argue that the "volatility of infectious disease may be one of the earliest biological expressions of climate instability". Infectious diseases (also called pathogenic diseases) depend on "a pathogen and a person coming into contact, and the extent to which peoples' resistance is diminished, or the pathogen is strengthened, by a climatic hazard ." Climatic hazards, which can be strengthened by climate change, include for example warming of land and oceans, heatwaves and marine heatwaves , floods, drought, storms, land cover change, fires and so forth. Possible pathways that can increase the infectious disease occurrence and which are affected by climate change include: Infectious diseases that are sensitive to climate can be grouped into: Climate change is affecting the distribution of these diseases due to the expanding geographic range and seasonality of these diseases and their vectors. : 9 Though many infectious diseases are affected by changes in climate, vector-borne diseases, such as malaria, dengue fever and leishmaniasis, present the strongest causal relationship. One reason for that is that temperature and rainfall play a key role in the distribution, magnitude, and viral capacity of mosquitoes, who are primary vectors for many vectors borne diseases. Observation and research detect a shift of pests and pathogens in the distribution away from the equator and towards Earth's poles. Climate change affects vector-borne diseases by affecting the survival, distribution and behavior of vectors such as mosquitoes, ticks and rodents. : 29 The viruses, bacteria and protozoa are carried by these vectors transferring them from one carrier to another. Vector and pathogen can adapt to the climate fluctuations by shifting and expanding their geographic ranges, which can alter the rate of new cases of disease depending on vector-host interaction, host immunity and pathogen evolution. This means that climate change affects infectious diseases by changing the length of the transmission season and their geographical range. Climate change is leading to latitudinal and altitudinal temperature increases. Global warming projections indicate that surface air warming for a "high scenario" is 4 C, with a likely range of 2.4–6.4 C by 2100. A temperature increase of this size would alter the biology and the ecology of many mosquito vectors and the dynamics of the diseases they transmit such as malaria. Changes in climate and global warming have significant influences on the biology and distribution of vector-borne diseases , parasites , fungi , and their associated illnesses. Regional changes resulting from changing weather conditions and patterns within temperate climates will stimulate the reproduction of certain insect species that are vectors for disease. One major disease-spreading insect is the mosquito , which can carry diseases like malaria , West Nile virus , and dengue fever . With regional temperatures changing due to climate change the range of mosquitos will change as well. The range of mosquitoes will move farther north and south, and places will have a longer period of mosquito habitability than at present, leading to an increase in the mosquito population in these areas. This range shift has already been seen in highland Africa. Since 1970, the incidence of malaria in high elevation areas in East Africa has increased greatly. This has been proven to be caused by the warming of regional climates. The vectors of transmission are the major reason for the increased ranges and infection of these diseases. If the vector has a range shift, so do the associated diseases; if the vector increases in activity due to changes in climate, then there is an effect on the transmission of disease. However it will be hard to classify exactly why the range shifts or an increase in infection rates occurs as there are many other factors to consider besides climate change, such as human migration , poverty , infrastructure quality, and land usage ; but climate change is still potentially a key factor. Environmental changes, climate variability , and climate change are such factors that could affect biology and disease ecology of Anopheles vectors and their disease transmission potential. Anopheles mosquitoes in highland areas are to experience a larger shift in their metabolic rate due to climate change. This climate change is due to the deforestation in the highland areas where these mosquitos' dwell. When the temperature rises, the larvae take a shorter time to mature and, consequently, a greater capacity to produce more offspring. In turn this could potentially lead to an increase in malaria transmission when infected humans are available. Environmental changes such as deforestation could also increase local temperatures in the highlands thus could enhance the vectorial capacity of the anopheles. Anopheles mosquitoes are responsible for the transmission of a number of diseases in the world, such as, malaria, lymphatic filariasis and viruses that can cause such ailments, like the O'nyong'nyong virus . High temperatures can alter the survival, replication, and virulence of a pathogen. Higher temperatures can also increase the pathogen yields in animal reservoirs. During the warmer summer months an increase in yield of bacteria from drinking water delivery systems has been recorded. During times of warmer temperatures water consumption rates are also typically higher. These together increase the probability of pathogen ingestion and infection. With an increase in not only temperature, but also higher nutrient concentrations due to runoff there will be an increase in cyanobacterial blooms. The warming oceans and lakes are leading to more frequent harmful algal blooms . Also, during droughts, surface waters are even more susceptible to harmful algal blooms and microorganisms. Algal blooms increase water turbidity, suffocating aquatic plants, and can deplete oxygen, killing fish. Some kinds of blue-green algae (cyanobacteria) create neurotoxins , hepatoxins, cytotoxins or endotoxins that can cause serious and sometimes fatal neurological, liver and digestive diseases in humans. Cyanobacteria grow best in warmer temperatures (especially above 25 degrees Celsius), and so areas of the world that are experiencing general warming as a result of climate change are also experiencing harmful algal blooms more frequently and for longer periods of time. Climate change is forecast to have substantial effects on the water cycle , with an increase in both frequency and intensity of droughts and heavy precipitation events. A literature review in 2016 found that generally there is an increase in diarrheal disease (except for viral diarrheal disease) during or after certain weather conditions: elevated ambient temperature, heavy rainfall, and flooding. These three weather conditions are predicted to increase (or to intensify) with climate change in future. There is already now a high current baseline rate of the diarrheal diseases in developing countries. Climate change therefore poses a real risk of an uptick in these diseases for those regions. Climate change affects vector-borne diseases by affecting the survival, distribution and behavior of vectors such as mosquitoes, ticks and rodents. : 29 The viruses, bacteria and protozoa are carried by these vectors transferring them from one carrier to another. Vector and pathogen can adapt to the climate fluctuations by shifting and expanding their geographic ranges, which can alter the rate of new cases of disease depending on vector-host interaction, host immunity and pathogen evolution. This means that climate change affects infectious diseases by changing the length of the transmission season and their geographical range. Climate change is leading to latitudinal and altitudinal temperature increases. Global warming projections indicate that surface air warming for a "high scenario" is 4 C, with a likely range of 2.4–6.4 C by 2100. A temperature increase of this size would alter the biology and the ecology of many mosquito vectors and the dynamics of the diseases they transmit such as malaria. Changes in climate and global warming have significant influences on the biology and distribution of vector-borne diseases , parasites , fungi , and their associated illnesses. Regional changes resulting from changing weather conditions and patterns within temperate climates will stimulate the reproduction of certain insect species that are vectors for disease. One major disease-spreading insect is the mosquito , which can carry diseases like malaria , West Nile virus , and dengue fever . With regional temperatures changing due to climate change the range of mosquitos will change as well. The range of mosquitoes will move farther north and south, and places will have a longer period of mosquito habitability than at present, leading to an increase in the mosquito population in these areas. This range shift has already been seen in highland Africa. Since 1970, the incidence of malaria in high elevation areas in East Africa has increased greatly. This has been proven to be caused by the warming of regional climates. The vectors of transmission are the major reason for the increased ranges and infection of these diseases. If the vector has a range shift, so do the associated diseases; if the vector increases in activity due to changes in climate, then there is an effect on the transmission of disease. However it will be hard to classify exactly why the range shifts or an increase in infection rates occurs as there are many other factors to consider besides climate change, such as human migration , poverty , infrastructure quality, and land usage ; but climate change is still potentially a key factor. Environmental changes, climate variability , and climate change are such factors that could affect biology and disease ecology of Anopheles vectors and their disease transmission potential. Anopheles mosquitoes in highland areas are to experience a larger shift in their metabolic rate due to climate change. This climate change is due to the deforestation in the highland areas where these mosquitos' dwell. When the temperature rises, the larvae take a shorter time to mature and, consequently, a greater capacity to produce more offspring. In turn this could potentially lead to an increase in malaria transmission when infected humans are available. Environmental changes such as deforestation could also increase local temperatures in the highlands thus could enhance the vectorial capacity of the anopheles. Anopheles mosquitoes are responsible for the transmission of a number of diseases in the world, such as, malaria, lymphatic filariasis and viruses that can cause such ailments, like the O'nyong'nyong virus . High temperatures can alter the survival, replication, and virulence of a pathogen. Higher temperatures can also increase the pathogen yields in animal reservoirs. During the warmer summer months an increase in yield of bacteria from drinking water delivery systems has been recorded. During times of warmer temperatures water consumption rates are also typically higher. These together increase the probability of pathogen ingestion and infection. With an increase in not only temperature, but also higher nutrient concentrations due to runoff there will be an increase in cyanobacterial blooms. The warming oceans and lakes are leading to more frequent harmful algal blooms . Also, during droughts, surface waters are even more susceptible to harmful algal blooms and microorganisms. Algal blooms increase water turbidity, suffocating aquatic plants, and can deplete oxygen, killing fish. Some kinds of blue-green algae (cyanobacteria) create neurotoxins , hepatoxins, cytotoxins or endotoxins that can cause serious and sometimes fatal neurological, liver and digestive diseases in humans. Cyanobacteria grow best in warmer temperatures (especially above 25 degrees Celsius), and so areas of the world that are experiencing general warming as a result of climate change are also experiencing harmful algal blooms more frequently and for longer periods of time. Climate change is forecast to have substantial effects on the water cycle , with an increase in both frequency and intensity of droughts and heavy precipitation events. A literature review in 2016 found that generally there is an increase in diarrheal disease (except for viral diarrheal disease) during or after certain weather conditions: elevated ambient temperature, heavy rainfall, and flooding. These three weather conditions are predicted to increase (or to intensify) with climate change in future. There is already now a high current baseline rate of the diarrheal diseases in developing countries. Climate change therefore poses a real risk of an uptick in these diseases for those regions. Increased rainfall could increase the number of mosquitos indirectly by expanding larval habitat and food supply. Malaria, which kills about 300,000 children (under age 5) annually, poses an imminent threat through temperature increase. Models suggest, conservatively, that the risk of malaria will increase 5–15% by 2100 due to climate change. In Africa alone, according to the MARA Project (Mapping Malaria Risk in Africa), there is a projected increase of 16–28% in person-month exposures to malaria by 2100. Climate is an influential driving force of vector-borne diseases such as malaria. Malaria is especially susceptible to the effects of climate change because mosquitoes lack the mechanisms to regulate their internal temperature. This implies that there is a limited range of climatic conditions within which the pathogen (malaria) and vector (a mosquito) can survive, reproduce, and infect hosts. Vector-borne diseases, such as malaria, have distinctive characteristics that determine pathogenicity . These include the survival and reproduction rate of the vector, the level of vector activity (i.e. the biting or feeding rate), and the development and reproduction rate of the pathogen within the vector or host. Changes in climate factors substantially affect reproduction, development, distribution, and seasonal transmissions of malaria. Malaria is a mosquito-borne parasitic disease that infects humans and other animals caused by microorganisms in the Plasmodium family. It begins with a bite from an infected female mosquito, which introduces the parasite through its saliva and into the infected host's circulatory system. It then travels through the bloodstream into the liver, where it can mature and reproduce. Dengue fever is an infectious disease caused by dengue viruses known to be in the tropical regions. It is transmitted by the mosquito Aedes , or A. aegypti. Dengue incidence has increased in the last few decades and is projected to continue to do so with changing climate conditions. > Dengue can be fatal. Dengue fever is spread by the bite of the female mosquito known as Aedes aegypti. The female mosquito is a highly effective vector of this disease. The evidence for the spread of dengue fever is that climate change is altering the geographic range and seasonality of the mosquito that can carry dengue. Because there are multiple drivers of transmission, it is easier to model and project changes in the geographic range and seasonality. The drivers for the recent spread of this disease are globalization, trade, urbanization, population growth, increased international travel, and climate change. The same trends also led to the spread of different serotypes of the disease to new areas, and to the emergence of dengue hemorrhagic fever . The World Health Organization (WHO) has reported an increase from a thousand to one million confirmed cases between 1955 and 2007. The presence and number of Aedes aegypti mosquitoes is strongly influenced by the amount of water-bearing containers or pockets of stagnant water in an area, daily temperature and variation in temperature, moisture, and solar radiation. While dengue fever is primarily considered a tropical and subtropical disease , the geographic ranges of the Aedes aegypti are expanding. The cases of dengue fever have increased dramatically since the 1970s and it continues to become more prevalent. Dengue is ranked as the most important vector-borne viral disease in the world. An estimated 50–100 million dengue fever infections occur annually. In just the past 50 years, transmission has increased drastically with new cases of the disease (incidence) increasing 30-fold. The number of reported cases has continually increased along with dengue spreading to new areas. Tick-borne disease , which affect humans and other animals, are caused by infectious agents transmitted by tick bites. A high humidity of greater than 85% is ideal for a tick to start and finish its life cycle. Studies have indicated that temperature and vapor play a significant role in determining the range for tick population. More specifically, maximum temperature has been found to play the most influential variable in sustaining tick populations. Higher temperatures augment both hatching and developmental rates while hindering overall survival. Temperature is so important to overall survival that an average monthly minimum temperature of below -7 °C in the winter can prevent an area from maintaining established populations. The effect of climate on the tick life cycle is one of the more difficult projections to make in relation to climate and vector-borne disease. Unlike other vectors, tick life cycles span multiple seasons as they mature from larva to nymph to adult. Further, infection and spread of diseases such as Lyme disease happens across the multiple stages and different classes of vertebrate hosts, adding additional variables to consider. Although it is a European species from the Lyme borreliosis spirochetes, Borrelia garinii was documented from infected ticks on seabirds in North America. Further research is needed to improve evolutionary models predicting distributional changes in this tick-borne system in the face of climate change. Infection of ticks happen in the larval/nymph stage (after the first blood meal) when they are exposed to Borrelia burgdorferi (the spirochete responsible for Lyme disease ), but transmission to humans doesn't occur until the adult stages. The expansion of tick populations is concurrent with global climatic change. Species distribution models of recent years indicate that the deer tick, known as I. scapularis, is pushing its distribution to higher latitudes of the Northeastern United States and Canada, as well as pushing and maintaining populations in the South Central and Northern Midwest regions of the United States. Climate models project further expansion of tick habit north into Canada as progressing Northwest from the Northeastern United States. Additionally, however, tick populations are expected to retreat from the Southeastern coast of the U.S., but this has not yet been observed. It's estimated that coinciding with this expansion, increased average temperatures may double tick populations by 2020 as well as bring an earlier start to the tick exposure season. In the face of these expanding threats, strong collaboration between government officials and environmental scientists is necessary for advancing preventive and reactive response measures. Without acknowledging the climate changes that make environments more habitable for disease carriers, policy and infrastructure will lag behind vector borne disease spread. In the United States, the Centers for Disease Control and Prevention (CDC) is conducting a grant program called Building Resilience Against Climate Effects (BRACE) which details a 5 step process for combating climate effects like tick borne disease spread. As in other vector-borne diseases , one of the reasons climate changes can affect the incidence of leishmaniasis is the susceptibility of the sandfly vectors to changes in temperature, rainfall and humidity; these conditions will alter their range of distribution and seasonality. For example, modelling studies have predicted that climate change will increase suitable conditions for Phlebotomus vector species in Central Europe. Another model that looked at the distribution of Lutzomyia longipalpis , an important visceral leishmaniasis vector, suggested an increased range of this species in the Amazon Basin. A different study model that factored data on climate, policy and socio-economic changes of land use, found that the effects were different for cutaneous and visceral leishmaniasis, emphasizing the importance of considering each disease and region separately. Parasite development inside the sandfly can also be affected by temperature changes. For instance, Leishmania peruviana infections were lost during sandfly defecation when the infected vector was kept at higher temperatures, whereas in the same experiment Leishmania infantum and Leishmania braziliensis temperature seemed to make no difference. Leishmaniasis is a neglected tropical disease , caused by parasites of the genus Leishmania and transmitted by sandflies; it is distributed mostly in tropical and subtropical regions around the world, wherever the sand fly vector and reservoir hosts are present. The WHO estimates 12 million people around the world are living with leishmaniasis. Risk factors for the spread of this disease include poverty, urbanization, deforestation , and climate change. The Ebola virus has been infecting people from time to time, leading to outbreaks in several African countries. The average case fatality rate of the Ebola virus is approximately 40% and there have been more than 28,600 cases with 11,310 deaths. Many researchers are linking deforestation to the disease, observing that change in the landscape increases wildlife contact with humans. Recent studies are holding climate change indirectly liable for the uptick in Ebola: Seasonal droughts alongside strong winds, thunderstorms, heat waves, floods, landslides, and a change in rainfall patterns also impact wildlife migration. These conditions pull them away from their natural environment and closer to human proximity. One example of an Ebola outbreak caused by climate change or a shift in nature was seen during the drought of Central Africa. This ultimately amplified food insecurity leading West African communities to eat animals such as bats who were infected with the virus. Zika virus , a vector-borne virus was historically presented in cluster outbreaks in the tropical regions of Africa and Asia. Zika fever epidemics have affected larger populations including Micronesia and South Pacific Islands in 2007, and the Americas in 2013. Brazil has experienced one of the largest outbreaks of Zika virus with approximately 1.5 million cases reported in 2015. Pregnant women infected with Zika virus are at a higher risk of giving birth to children with congenital malformations, including microcephaly. In the context of climate change and temperature rise, it is predicted that Zika virus will affect more than 1.3 billion people by 2050. This is largely due to the expansion of environments conducive to vector growth and life cycles, such as those with temperatures ranging from 23.9 °C to 34 °C. Mosquito behaviors are also affected by the change in temperature including increased breeding and biting rates. Furthermore, extreme climate patterns, including drought, floods and heatwaves are known to exacerbate the proliferation of mosquito breeding ground and as a result, escalate the rate of virus-borne diseases. There is no direct evidence that the spread of COVID-19 is worsened or is caused by climate change, although investigations continue. As of 2020 [ update ] , the World Health Organization summarized the current knowledge about the issue as follows: "There is no evidence of a direct connection between climate change and the emergence or transmission of COVID-19 disease. [...] However, climate change may indirectly affect the COVID-19 response, as it undermines environmental determinants of health, and places additional stress on health systems." A 2021 study found possible links between climate change and transmission of COVID-19 by bats. The authors found that climate-driven changes in the distribution and richness of bat species increased the likelihood of bat-borne coronaviruses in the Yunnan province, Myanmar, and Laos. This region was also the habitat of Sunda pangolins and masked palm civits which were suspected as intermediate hosts of COVID-19 between bats and humans. The authors suggest, therefore, that climate change possibly contributed to some extent to the emergence of the pandemic. Climate changed might induce changes to bat habitats which may have driven them closer to populated areas. Increased aridity and drought periods are predicted to push bats out of their endemic areas and into populated areas. This creates a knock-on effect of increasing their interactions with humans and hence the likelihood of zoonotic disease transfer. Scientist expect that disease outbreaks caused by vibrio (in particular the bacterium that causes cholera , called vibrio cholerae ) are increasing in occurrence and intensity. : 1107 One reason is that the area of coastline with suitable conditions for vibrio bacteria has increased due to changes in sea surface temperature and sea surface salinity caused by climate change. : 12 These pathogens can cause gastroenteritis , cholera , wound infections, and sepsis . It has been observed that in the period of 2011–21, the "area of coastline suitable for Vibrio bacterial transmission has increased by 35% in the Baltics , 25% in the Atlantic Northeast, and 4% in the Pacific Northwest. : 12 Furthermore, the increasing occurrence of higher temperature days, heavy rainfall events and flooding due to climate change could lead to an increase in cholera risks. : 1045 Vibrio illnesses are a waterborne disease and are increasing worldwide. Vibrio infections are recently being reported where historically it did not occur. The warming climate seems to be playing a substantial role in the increase in cases and area of occurrence. Vibrio infections are caused by consuming raw or undercooked seafood, or by exposing an open wound to contaminated sea water. Vibrio infections are most likely to occur during the warm season, May through October. One of the most commonly transmitted waterborne disease categories are the diarrhea diseases. These diseases are transmitted through unsafe drinking water or recreational water contact. Diarrheal diseases account for 10–12% of deaths in children under five, as the second leading cause of death in children this age. They are also the second leading cause of death in low and middle income countries. Diarrhea diseases account for an estimated 1.4–1.9 million deaths worldwide. Fungal infections will also see an increase due to the warming of certain climates. For example, the fungus Cryptococcus gattii has been found in Canada but is normally found in warmer climates such as in Australia . There are now two strains of this fungus in the northwestern part of North America, affecting many terrestrial animals. The spread of this fungus is hypothesized to be linked to climate change. There is concern about the emergence of new diseases from the fungal kingdom. Mammals have endothermy and homeothermy , which allows them to maintain elevated body temperature through life; but it can be defeated if the fungi were to adapt to higher temperatures and survive in the body. Fungi that are pathogenic for insects can be experimentally adapted to replicate at mammalian temperatures through cycles of progressive warming. This demonstrates that fungi are able to adapt rapidly to higher temperatures. The emergence of Candida auris on three continents is proposed to be as a result of global warming and has raised the danger that increased warmth by itself will trigger adaptations on certain microbes to make them pathogenic for humans. It is projected that interspecies viral sharing , that can lead to novel viral spillovers , will increase due to ongoing climate change-caused geographic range-shifts of mammals (most importantly bats ). Risk hotspots would mainly be located at "high elevations, in biodiversity hotspots, and in areas of high human population density in Asia and Africa". Climate change may also lead to new infectious diseases due to changes in microbial and vector geographic range. Microbes that are harmful to humans can adapt to higher temperatures, which will allow them to build better tolerance against human endothermy defences. Increased rainfall could increase the number of mosquitos indirectly by expanding larval habitat and food supply. Malaria, which kills about 300,000 children (under age 5) annually, poses an imminent threat through temperature increase. Models suggest, conservatively, that the risk of malaria will increase 5–15% by 2100 due to climate change. In Africa alone, according to the MARA Project (Mapping Malaria Risk in Africa), there is a projected increase of 16–28% in person-month exposures to malaria by 2100. Climate is an influential driving force of vector-borne diseases such as malaria. Malaria is especially susceptible to the effects of climate change because mosquitoes lack the mechanisms to regulate their internal temperature. This implies that there is a limited range of climatic conditions within which the pathogen (malaria) and vector (a mosquito) can survive, reproduce, and infect hosts. Vector-borne diseases, such as malaria, have distinctive characteristics that determine pathogenicity . These include the survival and reproduction rate of the vector, the level of vector activity (i.e. the biting or feeding rate), and the development and reproduction rate of the pathogen within the vector or host. Changes in climate factors substantially affect reproduction, development, distribution, and seasonal transmissions of malaria. Malaria is a mosquito-borne parasitic disease that infects humans and other animals caused by microorganisms in the Plasmodium family. It begins with a bite from an infected female mosquito, which introduces the parasite through its saliva and into the infected host's circulatory system. It then travels through the bloodstream into the liver, where it can mature and reproduce. Dengue fever is an infectious disease caused by dengue viruses known to be in the tropical regions. It is transmitted by the mosquito Aedes , or A. aegypti. Dengue incidence has increased in the last few decades and is projected to continue to do so with changing climate conditions. > Dengue can be fatal. Dengue fever is spread by the bite of the female mosquito known as Aedes aegypti. The female mosquito is a highly effective vector of this disease. The evidence for the spread of dengue fever is that climate change is altering the geographic range and seasonality of the mosquito that can carry dengue. Because there are multiple drivers of transmission, it is easier to model and project changes in the geographic range and seasonality. The drivers for the recent spread of this disease are globalization, trade, urbanization, population growth, increased international travel, and climate change. The same trends also led to the spread of different serotypes of the disease to new areas, and to the emergence of dengue hemorrhagic fever . The World Health Organization (WHO) has reported an increase from a thousand to one million confirmed cases between 1955 and 2007. The presence and number of Aedes aegypti mosquitoes is strongly influenced by the amount of water-bearing containers or pockets of stagnant water in an area, daily temperature and variation in temperature, moisture, and solar radiation. While dengue fever is primarily considered a tropical and subtropical disease , the geographic ranges of the Aedes aegypti are expanding. The cases of dengue fever have increased dramatically since the 1970s and it continues to become more prevalent. Dengue is ranked as the most important vector-borne viral disease in the world. An estimated 50–100 million dengue fever infections occur annually. In just the past 50 years, transmission has increased drastically with new cases of the disease (incidence) increasing 30-fold. The number of reported cases has continually increased along with dengue spreading to new areas.Tick-borne disease , which affect humans and other animals, are caused by infectious agents transmitted by tick bites. A high humidity of greater than 85% is ideal for a tick to start and finish its life cycle. Studies have indicated that temperature and vapor play a significant role in determining the range for tick population. More specifically, maximum temperature has been found to play the most influential variable in sustaining tick populations. Higher temperatures augment both hatching and developmental rates while hindering overall survival. Temperature is so important to overall survival that an average monthly minimum temperature of below -7 °C in the winter can prevent an area from maintaining established populations. The effect of climate on the tick life cycle is one of the more difficult projections to make in relation to climate and vector-borne disease. Unlike other vectors, tick life cycles span multiple seasons as they mature from larva to nymph to adult. Further, infection and spread of diseases such as Lyme disease happens across the multiple stages and different classes of vertebrate hosts, adding additional variables to consider. Although it is a European species from the Lyme borreliosis spirochetes, Borrelia garinii was documented from infected ticks on seabirds in North America. Further research is needed to improve evolutionary models predicting distributional changes in this tick-borne system in the face of climate change. Infection of ticks happen in the larval/nymph stage (after the first blood meal) when they are exposed to Borrelia burgdorferi (the spirochete responsible for Lyme disease ), but transmission to humans doesn't occur until the adult stages. The expansion of tick populations is concurrent with global climatic change. Species distribution models of recent years indicate that the deer tick, known as I. scapularis, is pushing its distribution to higher latitudes of the Northeastern United States and Canada, as well as pushing and maintaining populations in the South Central and Northern Midwest regions of the United States. Climate models project further expansion of tick habit north into Canada as progressing Northwest from the Northeastern United States. Additionally, however, tick populations are expected to retreat from the Southeastern coast of the U.S., but this has not yet been observed. It's estimated that coinciding with this expansion, increased average temperatures may double tick populations by 2020 as well as bring an earlier start to the tick exposure season. In the face of these expanding threats, strong collaboration between government officials and environmental scientists is necessary for advancing preventive and reactive response measures. Without acknowledging the climate changes that make environments more habitable for disease carriers, policy and infrastructure will lag behind vector borne disease spread. In the United States, the Centers for Disease Control and Prevention (CDC) is conducting a grant program called Building Resilience Against Climate Effects (BRACE) which details a 5 step process for combating climate effects like tick borne disease spread. As in other vector-borne diseases , one of the reasons climate changes can affect the incidence of leishmaniasis is the susceptibility of the sandfly vectors to changes in temperature, rainfall and humidity; these conditions will alter their range of distribution and seasonality. For example, modelling studies have predicted that climate change will increase suitable conditions for Phlebotomus vector species in Central Europe. Another model that looked at the distribution of Lutzomyia longipalpis , an important visceral leishmaniasis vector, suggested an increased range of this species in the Amazon Basin. A different study model that factored data on climate, policy and socio-economic changes of land use, found that the effects were different for cutaneous and visceral leishmaniasis, emphasizing the importance of considering each disease and region separately. Parasite development inside the sandfly can also be affected by temperature changes. For instance, Leishmania peruviana infections were lost during sandfly defecation when the infected vector was kept at higher temperatures, whereas in the same experiment Leishmania infantum and Leishmania braziliensis temperature seemed to make no difference. Leishmaniasis is a neglected tropical disease , caused by parasites of the genus Leishmania and transmitted by sandflies; it is distributed mostly in tropical and subtropical regions around the world, wherever the sand fly vector and reservoir hosts are present. The WHO estimates 12 million people around the world are living with leishmaniasis. Risk factors for the spread of this disease include poverty, urbanization, deforestation , and climate change. The Ebola virus has been infecting people from time to time, leading to outbreaks in several African countries. The average case fatality rate of the Ebola virus is approximately 40% and there have been more than 28,600 cases with 11,310 deaths. Many researchers are linking deforestation to the disease, observing that change in the landscape increases wildlife contact with humans. Recent studies are holding climate change indirectly liable for the uptick in Ebola: Seasonal droughts alongside strong winds, thunderstorms, heat waves, floods, landslides, and a change in rainfall patterns also impact wildlife migration. These conditions pull them away from their natural environment and closer to human proximity. One example of an Ebola outbreak caused by climate change or a shift in nature was seen during the drought of Central Africa. This ultimately amplified food insecurity leading West African communities to eat animals such as bats who were infected with the virus. Zika virus , a vector-borne virus was historically presented in cluster outbreaks in the tropical regions of Africa and Asia. Zika fever epidemics have affected larger populations including Micronesia and South Pacific Islands in 2007, and the Americas in 2013. Brazil has experienced one of the largest outbreaks of Zika virus with approximately 1.5 million cases reported in 2015. Pregnant women infected with Zika virus are at a higher risk of giving birth to children with congenital malformations, including microcephaly. In the context of climate change and temperature rise, it is predicted that Zika virus will affect more than 1.3 billion people by 2050. This is largely due to the expansion of environments conducive to vector growth and life cycles, such as those with temperatures ranging from 23.9 °C to 34 °C. Mosquito behaviors are also affected by the change in temperature including increased breeding and biting rates. Furthermore, extreme climate patterns, including drought, floods and heatwaves are known to exacerbate the proliferation of mosquito breeding ground and as a result, escalate the rate of virus-borne diseases. There is no direct evidence that the spread of COVID-19 is worsened or is caused by climate change, although investigations continue. As of 2020 [ update ] , the World Health Organization summarized the current knowledge about the issue as follows: "There is no evidence of a direct connection between climate change and the emergence or transmission of COVID-19 disease. [...] However, climate change may indirectly affect the COVID-19 response, as it undermines environmental determinants of health, and places additional stress on health systems." A 2021 study found possible links between climate change and transmission of COVID-19 by bats. The authors found that climate-driven changes in the distribution and richness of bat species increased the likelihood of bat-borne coronaviruses in the Yunnan province, Myanmar, and Laos. This region was also the habitat of Sunda pangolins and masked palm civits which were suspected as intermediate hosts of COVID-19 between bats and humans. The authors suggest, therefore, that climate change possibly contributed to some extent to the emergence of the pandemic. Climate changed might induce changes to bat habitats which may have driven them closer to populated areas. Increased aridity and drought periods are predicted to push bats out of their endemic areas and into populated areas. This creates a knock-on effect of increasing their interactions with humans and hence the likelihood of zoonotic disease transfer. Scientist expect that disease outbreaks caused by vibrio (in particular the bacterium that causes cholera , called vibrio cholerae ) are increasing in occurrence and intensity. : 1107 One reason is that the area of coastline with suitable conditions for vibrio bacteria has increased due to changes in sea surface temperature and sea surface salinity caused by climate change. : 12 These pathogens can cause gastroenteritis , cholera , wound infections, and sepsis . It has been observed that in the period of 2011–21, the "area of coastline suitable for Vibrio bacterial transmission has increased by 35% in the Baltics , 25% in the Atlantic Northeast, and 4% in the Pacific Northwest. : 12 Furthermore, the increasing occurrence of higher temperature days, heavy rainfall events and flooding due to climate change could lead to an increase in cholera risks. : 1045 Vibrio illnesses are a waterborne disease and are increasing worldwide. Vibrio infections are recently being reported where historically it did not occur. The warming climate seems to be playing a substantial role in the increase in cases and area of occurrence. Vibrio infections are caused by consuming raw or undercooked seafood, or by exposing an open wound to contaminated sea water. Vibrio infections are most likely to occur during the warm season, May through October. One of the most commonly transmitted waterborne disease categories are the diarrhea diseases. These diseases are transmitted through unsafe drinking water or recreational water contact. Diarrheal diseases account for 10–12% of deaths in children under five, as the second leading cause of death in children this age. They are also the second leading cause of death in low and middle income countries. Diarrhea diseases account for an estimated 1.4–1.9 million deaths worldwide. Fungal infections will also see an increase due to the warming of certain climates. For example, the fungus Cryptococcus gattii has been found in Canada but is normally found in warmer climates such as in Australia . There are now two strains of this fungus in the northwestern part of North America, affecting many terrestrial animals. The spread of this fungus is hypothesized to be linked to climate change. There is concern about the emergence of new diseases from the fungal kingdom. Mammals have endothermy and homeothermy , which allows them to maintain elevated body temperature through life; but it can be defeated if the fungi were to adapt to higher temperatures and survive in the body. Fungi that are pathogenic for insects can be experimentally adapted to replicate at mammalian temperatures through cycles of progressive warming. This demonstrates that fungi are able to adapt rapidly to higher temperatures. The emergence of Candida auris on three continents is proposed to be as a result of global warming and has raised the danger that increased warmth by itself will trigger adaptations on certain microbes to make them pathogenic for humans. It is projected that interspecies viral sharing , that can lead to novel viral spillovers , will increase due to ongoing climate change-caused geographic range-shifts of mammals (most importantly bats ). Risk hotspots would mainly be located at "high elevations, in biodiversity hotspots, and in areas of high human population density in Asia and Africa". Climate change may also lead to new infectious diseases due to changes in microbial and vector geographic range. Microbes that are harmful to humans can adapt to higher temperatures, which will allow them to build better tolerance against human endothermy defences. Climate change and increasing temperatures will also impact the health of wildlife animals as well. Specifically, climate change will impact wildlife disease, specifically affecting "geographic range and distribution of wildlife diseases, plant and animal phenology, wildlife host-pathogen interactions, and disease patterns in wildlife". The health of wild animals, particularly birds, is assumed to be a better indicator of early climate change effects because very little or no control measures are undertaken to protect them. Northern geographic shifts of disease vectors and parasitic disease in the Northern Hemisphere have likely been due to global warming. The geographic range of a lung parasite that impacts ungulates like caribou and mountain goats, Parelaphostrongylus odocoilei , has been shifting northward since 1995, and a tick vector for Lyme disease and other tick-borne zoonotic diseases known as Ixodes scapularis has been expanding its presence northward as well. It is also predicted that climate warming will also lead to changes in disease distribution at certain altitudes. At high elevation in the Hawaiian Islands, for example, it is expected that climate warming will allow for year-round transmission of avian malaria . This increased opportunity for transmission will likely be devastating to endangered native Hawaiian birds at those altitudes that have little or no resistance to the disease. Phenology is the study of seasonal cycles, and with climate change the seasonal biologic cycles of many animals have already been affected. For example, the transmission of tick-borne encephalitis (TBE) is higher to humans when early spring temperatures are warmer. The warmer temperatures result in an overlap in feeding activity of ticks who are infected with the virus (nymphal) with ticks who aren't (larval). This overlapped feeding leads to more of the uninfected larval ticks acquiring the infection and therefore increases the risk of humans being infected with TBE. On the other hand, cooler spring temperatures would result in less overlapped feeding activity, and would therefore decrease the risk of zoonotic transmission of TBE. The transmission of pathogens can be achieved through either direct contact from a diseased animal to another, or indirectly through a host like infected prey or a vector. Higher temperatures as a result of climate change results in an increased presence of disease producing agents in hosts and vectors, and also increases the "survival of animals that harbor disease". Survival of Parelaphostrongylus tenuis , a brain worm of white-tailed deer that affects moose, could be increased due to the higher temperatures and milder winters that are caused by climate change. In moose, this brain causes neurological disease and eventually ends up being fatal. Moose are already facing heat stress due to climate change, and may have increased susceptibility to parasitic and infectious diseases like the brain worm. Predicting the impact climate change might have on disease patterns in different geographic regions can be difficult, because its effects likely have high variability. This has been more evident in marine ecosystems than terrestrial environments, where massive decline in coral reefs has been observed due to disease spread. Northern geographic shifts of disease vectors and parasitic disease in the Northern Hemisphere have likely been due to global warming. The geographic range of a lung parasite that impacts ungulates like caribou and mountain goats, Parelaphostrongylus odocoilei , has been shifting northward since 1995, and a tick vector for Lyme disease and other tick-borne zoonotic diseases known as Ixodes scapularis has been expanding its presence northward as well. It is also predicted that climate warming will also lead to changes in disease distribution at certain altitudes. At high elevation in the Hawaiian Islands, for example, it is expected that climate warming will allow for year-round transmission of avian malaria . This increased opportunity for transmission will likely be devastating to endangered native Hawaiian birds at those altitudes that have little or no resistance to the disease. Phenology is the study of seasonal cycles, and with climate change the seasonal biologic cycles of many animals have already been affected. For example, the transmission of tick-borne encephalitis (TBE) is higher to humans when early spring temperatures are warmer. The warmer temperatures result in an overlap in feeding activity of ticks who are infected with the virus (nymphal) with ticks who aren't (larval). This overlapped feeding leads to more of the uninfected larval ticks acquiring the infection and therefore increases the risk of humans being infected with TBE. On the other hand, cooler spring temperatures would result in less overlapped feeding activity, and would therefore decrease the risk of zoonotic transmission of TBE. The transmission of pathogens can be achieved through either direct contact from a diseased animal to another, or indirectly through a host like infected prey or a vector. Higher temperatures as a result of climate change results in an increased presence of disease producing agents in hosts and vectors, and also increases the "survival of animals that harbor disease". Survival of Parelaphostrongylus tenuis , a brain worm of white-tailed deer that affects moose, could be increased due to the higher temperatures and milder winters that are caused by climate change. In moose, this brain causes neurological disease and eventually ends up being fatal. Moose are already facing heat stress due to climate change, and may have increased susceptibility to parasitic and infectious diseases like the brain worm. Predicting the impact climate change might have on disease patterns in different geographic regions can be difficult, because its effects likely have high variability. This has been more evident in marine ecosystems than terrestrial environments, where massive decline in coral reefs has been observed due to disease spread. Vector-borne diseases seriously affect the health of domestic animals and livestock (e.g., trypanosomiasis , Rift Valley Fever , and bluetongue ). Therefore, climate change will also indirectly affect the health of humans through its multifaceted impacts on food security, including livestock and plant crops. Mosquitoes also carry diseases like Dirofilaria immitis which affect dogs (dog heartworm). Therefore, tropical diseases will probably migrate and become endemic in many other ecosystems due to an increase in mosquito range. While climate-induced heat stress can directly reduce domestic animals' immunity against all diseases, climatic factors also impact the distribution of many livestock pathogens themselves. For instance, Rift Valley fever outbreaks in East Africa are known to be more intense during the times of drought or when there is an El Nino . Another example is that of helminths in Europe which have now spread further towards the poles, with higher survival rate and higher reproductive capacity ( fecundity ). : 231 Detailed long-term records of both livestock diseases and various agricultural interventions in Europe mean that demonstrating the role of climate change in the increased helminth burden in livestock is actually easier than attributing the impact of climate change on diseases which affect humans. : 231 Temperature increases are also likely to benefit Culicoides imicola , a species of midge which spreads bluetongue virus . Without a significant improvement in epidemiological control measures, what is currently considered an once-in-20-years outbreak of bluetongue would occur as frequently as once in five or seven years by midcentury under all but the most optimistic warming scenario. Rift Valley Fever outbreaks in East African livestock are also expected to increase. : 747 Ixodes ricinus , a tick which spreads pathogens like Lyme disease and tick-borne encephalitis , is predicted to become 5–7% more prevalent on livestock farms in Great Britain, depending on the extent of future climate change. The policy implications of climate change and infectious diseases fall into two categories: Enacting policy that will reduce greenhouse gas emissions, thus slowing down climate change, and Mitigating problems that have already arisen, and will inevitably continue to develop, due to climate change. Addressing both of these areas is of importance, as those in the poorest countries face the greatest burden. Additionally, when countries are forced to contend with a disease like malaria (for example), their prospects for economic growth are slowed. This contributes to continued and worsening global inequality. Policies are required that will significantly increase investments in public health in developing countries. This achieves two goals, the first being better outcomes related to diseases like malaria in the affected area, and the second being an overall better health environment for populations. It is also important to focus on " one-health approaches." This means collaborating on an interdisciplinary level, across various geographic areas, to come up with workable solutions. As is the case when responding to the effects of climate change, vulnerable populations including children and the elderly will need to be prioritized by any intervention. The United Nations Environment Programme states that: "The most fundamental way to protect ourselves from zoonotic diseases is to prevent destruction of nature. Where ecosystems are healthy and bio-diverse, they are resilient, adaptable and help to regulate diseases." Significant progress has been achieved in terms of surveillance systems, disease and vector control measures, vaccine development, diagnostic tests, and mathematical risk modeling/mapping in recent decades. A tool that has been used to predict this distribution trend is the Dynamic Mosquito Simulation Process (DyMSiM). DyMSiM uses epidemiological and entomological data and practices to model future mosquito distributions based upon climate conditions and mosquitos living in the area. This modeling technique helps identify the distribution of specific species of mosquito, some of which are more susceptible to viral infection than others. [ citation needed ] Scientists are carrying out attribution studies, to find the degree to which climate change affects the spread of infectious diseases. There is also a need for scenario modeling which can help further our understanding of future climate change consequences on infectious disease rates. Surveillance and monitoring of infectious diseases and their vectors is important to better understand these diseases. Governments should accurately model changes in vector populations as well as the burden of disease, educate the public on ways to mitigate infection, and prepare health systems for the increasing disease load.Significant progress has been achieved in terms of surveillance systems, disease and vector control measures, vaccine development, diagnostic tests, and mathematical risk modeling/mapping in recent decades. A tool that has been used to predict this distribution trend is the Dynamic Mosquito Simulation Process (DyMSiM). DyMSiM uses epidemiological and entomological data and practices to model future mosquito distributions based upon climate conditions and mosquitos living in the area. This modeling technique helps identify the distribution of specific species of mosquito, some of which are more susceptible to viral infection than others. [ citation needed ] Scientists are carrying out attribution studies, to find the degree to which climate change affects the spread of infectious diseases. There is also a need for scenario modeling which can help further our understanding of future climate change consequences on infectious disease rates. Surveillance and monitoring of infectious diseases and their vectors is important to better understand these diseases. Governments should accurately model changes in vector populations as well as the burden of disease, educate the public on ways to mitigate infection, and prepare health systems for the increasing disease load.

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Rift Valley fever

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Emerging infectious disease

An emerging infectious disease ( EID ) is an infectious disease whose incidence has increased recently (in the past 20 years), and could increase in the near future. The minority that are capable of developing efficient transmission between humans can become major public and global concerns as potential causes of epidemics or pandemics . Their many impacts can be economic and societal , as well as clinical. EIDs have been increasing steadily since at least 1940. For every decade since 1940, there has been a consistent increase in the number of EID events from wildlife-related zoonosis . Human activity is the primary driver of this increase, with loss of biodiversity a leading mechanism. Emerging infections account for at least 12% of all human pathogens . EIDs can be caused by newly identified microbes , including novel species or strains of virus (e.g. novel coronaviruses , ebolaviruses , HIV ). Some EIDs evolve from a known pathogen, as occurs with new strains of influenza . EIDs may also result from spread of an existing disease to a new population in a different geographic region, as occurs with West Nile fever outbreaks . Some known diseases can also emerge in areas undergoing ecologic transformation (as in the case of Lyme disease ). Others can experience a resurgence as a re-emerging infectious disease , like tuberculosis (following drug resistance ) or measles . Nosocomial (hospital-acquired) infections, such as methicillin-resistant Staphylococcus aureus are emerging in hospitals, and are extremely problematic in that they are resistant to many antibiotics. Of growing concern are adverse synergistic interactions between emerging diseases and other infectious and non-infectious conditions leading to the development of novel syndemics . Many EID are zoonotic , deriving from pathogens present in animals, with only occasional cross-species transmission into human populations. For instance, most emergent viruses are zoonotic (whereas other novel viruses may have been circulating in the species without being recognized, as occurred with hepatitis C ).The French doctor Charles Anglada (1809–1878) wrote a book in 1869 on extinct and new diseases. He did not distinguish infectious diseases from others (he uses the terms reactive and affective diseases, to mean diseases with an external or internal cause, more or less meaning diseases with or without an observable external cause). He writes in the introduction: A widely held opinion among physicians admits the invariability of pathologies. All the illnesses which have existed or which have an outbreak around us are categorized according to arrested and preconceived types, and must enter one way or the other into the frameworks established by the nosologists. History and observation protest wildly against this prejudice, and this is what they teach: Diseases which have disappeared and whose traces are confined to the archives of science, are followed by other diseases, unknown to the contemporary generation, and which come for the first time to assert their rights. In other words, there are extinct and new diseases. Charles Nicolle , laureate of the Nobel Prize in Physiology or Medicine elaborated the concept of emergence of diseases in his 1930 book Naissance, vie et mort des maladies infectieuses (Birth, Life and Death of Infectious Diseases), and later in Destin des maladies infectieuses (Fate of Infectious Diseases) published in 1933 which served as lecture notes for his teaching of a second year course at the Collège de France . In the introduction of the book he sets out the program of the lectures: It is this historical existence, this destiny that will be the subject of our talks. I will have to answer, to the extent that our current knowledge allows, questions that you have asked yourself, that every thoughtful or simply curious mind asks: have the infectious diseases that we observe today always existed? Or have some of them appeared in the course of history? Can we assume that new ones will appear? Can we assume that some of these diseases will disappear? Have some of them already disappeared? Finally, what will become of humanity and domestic animals if, as a result of more and more frequent contacts between people, the number of infectious diseases continues to increase? The term emerging disease has been in use in scientific publications since the beginning of the 1960s at least and is used in the modern sense by David Sencer in his 1971 article "Emerging Diseases of Man and Animals" where in the first sentence of the introduction he implicitly defines emerging diseases as "infectious diseases of man and animals currently emerging as public health problems" and as a consequence also includes re-emerging diseases: Infectious diseases of man and animals currently emerging as public health problems include some old acquaintances and some that are new in respect to identity or concept. He also notes that some infectious agents are newly considered as diseases because of changing medical technologies: But there are also many familiar organisms formerly considered nonpathogenic that are now associated with nosocomial infections, use of artificial kidneys, and the acceptance or rejection of organ transplants, for example. He concludes the introduction with a word of caution: And so infectious disease, one of man's oldest enemies, survives as an adversary that calls forth our best efforts. However, to many people in the 1960s and 1970s the emergence of new diseases appeared as a marginal problem, as illustrated by the introduction to the 1962 edition of Natural History of Infectious Disease by Macfarlane Burnet : to write about infectious disease is almost to write of something that has passed into history as well as the epilogue of the 1972 edition: On the basis of what has happened in the last thirty years, can we forecast any likely developments for the 1970s? If for the present we retain a basic optimism and assume no major catastrophes occur [...] the most likely forecast about the future of infectious disease is that it will be very dull. There may be some wholly unexpected emergence of a new and dangerous infectious disease, but nothing of the sort has marked the past fifty years. The concept gained more interest at the end of the 1980s as a reaction to the AIDS epidemic . On the side of epistemology, Mirko Grmek worked on the concept of emerging diseases while writing his book on the history of AIDS and later in 1993 published an article about the concept of emerging disease as a more precise notion than the term "new disease" that was mostly used in France at that time to qualify AIDS among others. Also under the shock of the emergence of AIDS, epidemiologists wanted to take a more active approach to anticipate and prevent the emergence of new diseases. Stephen S. Morse from The Rockefeller University in New York was chair and principal organizer of the NIAID / NIH Conference "Emerging Viruses: The Evolution of Viruses and Viral Diseases" held 1–3 May 1989 in Washington, DC. In the article summarizing the conference the authors write: Challenged by the sudden appearance of AIDS as a major public health crisis [...] jointly sponsored the conference "Emerging Viruses: The Evolution of Viruses and Viral Diseases" [...] It was convened to consider the mechanisms of viral emergence and possible strategies for anticipating, detecting, and preventing the emergence of new viral diseases in the future. They further note: Surprisingly, most emergent viruses are zoonotic, with natural animal reservoirs a more frequent source of new viruses than is the sudden evolution of a new entity. The most frequent factor in emergence is human behavior that increases the probability of transfer of viruses from their endogenous animal hosts to man. In a 1991 paper Morse underlines how the emergence of new infectious diseases (of which the public became aware through the AIDS epidemic) is the opposite of the then generally expected retreat of these diseases: The striking successes achieved with antibiotics, together with widespread application of vaccines for many previously feared viral diseases, made it appear to many physicians and the public that infectious diseases were retreating and would in time be fully conquered. Although this view was disputed by virologists and many specialists in infectious diseases, it had become a commonplace to suggest that infectious diseases were about to become a thing of the past [...]. As a direct consequence of the 1989 conference on emerging viruses, the Institute Of Medicine convened in February 1991 the 19-member multidisciplinary Committee on Emerging Microbial Threats to Health, co-chaired by Joshua Lederberg and Robert Shope , to conduct an 18-month study. According to the report produced by the committee in 1992, its charge "was to identify significant emerging infectious diseases, determine what might be done to deal with them, and recommend how similar future threats might be confronted to lessen their impact on public health." The report recommended setting up a surveillance program to recognize emerging diseases and proposed methods of intervention in case an emergent disease was discovered. A well-designed, well-implemented surveillance program can detect unusual clusters of disease, document the geographic and demographic spread of an outbreak, and estimate the magnitude of the problem. It can also help to describe the natural history of a disease, identify factors responsible for emergence, facilitate laboratory and epidemiological research, and assess the success of specific intervention efforts. The proposed interventions were based on the following: the U.S. public health system, research and training, vaccine and drug development, vector control, public education and behavioral change. A few years after the 1989 Emerging Viruses conference and the 1992 IOM report, the Program for Monitoring Emerging Diseases (ProMED) was formed by a group of scientists as a follow-up in 1994 and the Centres for Disease Control (CDC) launched the Emerging Infectious Diseases journal in 1995. A decade later the IOM convened the Committee on Emerging Microbial Threats to Health in the 21st Century which published its conclusions in 2003. In April 2000 the WHO organized a meeting on Global Outbreak Alert and Response, which was the founding act of the Global Outbreak Alert and Response Network . In 2014, the Western African Ebola virus epidemic demonstrated how ill-prepared the world was to handle such an epidemic. In response, the Coalition for Epidemic Preparedness Innovation was launched at the World Economic Forum in 2017 with the objective of accelerating the development of vaccines against emerging infectious diseases to be able to offer them to affected populations during outbreaks. CEPI promotes the idea that a proactive approach is required to "create a world in which epidemics are no longer a threat to humanity". One way to classify emerging infections diseases is by time and how humans were involved in the emergence: The 1992 IOM report distinguished 6 factors contributing to emergence of new diseases (Microbial adaptation and change; Economic development and land use; Human demographics and behavior; International travel and commerce; Technology and industry; Breakdown of public health measures) which were extended to 13 factors in the 2003 report (Chapter 3 of the report detailing each of them) Microbial adaptation and change Human susceptibility to infection Climate and weather Changing ecosystems Human demographics and behavior Economic development and land use International travel and commerce Technology and industry Breakdown of public health measures Poverty and social inequality War and famine Lack of political will Intent to harm Their classification serves as a basis for many others. The following table gives examples for different factors:Emerging infectious diseases between human, animal have become a significant concern in recent years, playing a crucial role in the occurrence and spread of diseases. Human population growth, increased proximity to wildlife, and climate change have created favorable conditions for the transmission of zoonotic diseases, leading to outbreaks such as Zika, Ebola, and COVID-19. The One Health approach, which integrates animal, human, and environmental health, has emerged as a crucial tool for monitoring and mitigating the spread of infectious diseases. Zoonotic diseases , originating from animal sources, pose a significant threat to human health. Up to 75% of emerging infectious diseases are zoonotic, originating from viruses and other pathogens that are transmitted from animals to humans. Understanding the mechanisms of transmission, the role of wildlife trade, and the importance of surveillance and early detection is crucial for mitigating the impact of zoonotic diseases on human health. Surveillance efforts involving wastewater have been identified as valuable tools for detecting early warning signs of disease emergence and providing timely interventions. The U.S. National Institute of Allergy and Infectious Diseases (NIAID) maintains a list of Biodefense and Emerging Infectious Diseases. The list is categorized by biodefense risk, which is mostly based on biological warfare and bioterrorism considerations. As of 2004, it recognized the following emerging and re-emerging diseases. Re-emerging: Diseases with bioterrorism potential, CDC category A (most dangerous): Diseases with bioterrorism potential, CDC category B: Diseases with bioterrorism potential, CDC category C (least dangerous): Since 2004, NIAID has added to its biodefense emerging pathogen list: In December 2015, the World Health Organization held a workshop on prioritization of pathogens "for accelerated R&D for severe emerging diseases with potential to generate a public health emergency, and for which no, or insufficient, preventive and curative solutions exist." The result was a list containing the following six diseases: These were selected based on the following measures: Human transmissibility (including population immunity, behavioural factors, etc.) Severity or case fatality rate Spillover potential Evolutionary potential Available countermeasures Difficulty of detection or control Public health context of the affected area(s) Potential scope of outbreak (risk of international spread) Potential societal impacts In 2007 Mark Woolhouse and Eleanor Gaunt established a list of 87 human pathogens first reported in the period between 1980 and 2005. These were classified according to their types. known in 2005 reported from 1980 to 2005 The following table summarizes the major outbreaks since 1998 caused by emerging or re-emerging infectious diseases. The U.S. National Institute of Allergy and Infectious Diseases (NIAID) maintains a list of Biodefense and Emerging Infectious Diseases. The list is categorized by biodefense risk, which is mostly based on biological warfare and bioterrorism considerations. As of 2004, it recognized the following emerging and re-emerging diseases. Re-emerging: Diseases with bioterrorism potential, CDC category A (most dangerous): Diseases with bioterrorism potential, CDC category B: Diseases with bioterrorism potential, CDC category C (least dangerous): Since 2004, NIAID has added to its biodefense emerging pathogen list: In December 2015, the World Health Organization held a workshop on prioritization of pathogens "for accelerated R&D for severe emerging diseases with potential to generate a public health emergency, and for which no, or insufficient, preventive and curative solutions exist." The result was a list containing the following six diseases: These were selected based on the following measures: Human transmissibility (including population immunity, behavioural factors, etc.) Severity or case fatality rate Spillover potential Evolutionary potential Available countermeasures Difficulty of detection or control Public health context of the affected area(s) Potential scope of outbreak (risk of international spread) Potential societal impactsIn 2007 Mark Woolhouse and Eleanor Gaunt established a list of 87 human pathogens first reported in the period between 1980 and 2005. These were classified according to their types. known in 2005 reported from 1980 to 2005The following table summarizes the major outbreaks since 1998 caused by emerging or re-emerging infectious diseases. Methicillin-resistant Staphylococcus aureus (MRSA) evolved from methicillin-susceptible Staphylococcus aureus (MSSA), otherwise known as common S. aureus . Many people are natural carriers of S. aureus , without being affected in any way. MSSA was treatable with the antibiotic methicillin until it acquired the gene for antibiotic resistance. Through genetic mapping of various strains of MRSA, scientists have found that MSSA acquired the mecA gene in the 1960s, which accounts for its pathogenicity, before this it had a predominantly commensal relationship with humans. It is theorized that when this S. aureus strain that had acquired the mecA gene was introduced into hospitals, it came into contact with other hospital bacteria that had already been exposed to high levels of antibiotics. When exposed to such high levels of antibiotics, the hospital bacteria suddenly found themselves in an environment that had a high level of selection for antibiotic resistance, and thus resistance to multiple antibiotics formed within these hospital populations. When S. aureus came into contact with these populations, the multiple genes that code for antibiotic resistance to different drugs were then acquired by MRSA, making it nearly impossible to control. It is thought that MSSA acquired the resistance gene through the horizontal gene transfer , a method in which genetic information can be passed within a generation, and spread rapidly through its own population as was illustrated in multiple studies. Horizontal gene transfer speeds the process of genetic transfer since there is no need to wait an entire generation time for gene to be passed on. Since most antibiotics do not work on MRSA, physicians have to turn to alternative methods based in Darwinian medicine . However, prevention is the most preferred method of avoiding antibiotic resistance. By reducing unnecessary antibiotic use in human and animal populations, antibiotics resistance can be slowed. On 16 July 2021, the Director-General of WHO announced the formation of the Scientific Advisory Group for Origins of Novel Pathogens (SAGO), which is to be a permanent advisory body of the organisation. The Group was formed with a broad objective to examine emerging infectious diseases, including COVID-19 . According to the WHO Director-General, "SAGO will play a vital role in the next phase of studies into the origins of SARS-CoV-2, as well as the origins of future new pathogens." Methicillin-resistant Staphylococcus aureus (MRSA) evolved from methicillin-susceptible Staphylococcus aureus (MSSA), otherwise known as common S. aureus . Many people are natural carriers of S. aureus , without being affected in any way. MSSA was treatable with the antibiotic methicillin until it acquired the gene for antibiotic resistance. Through genetic mapping of various strains of MRSA, scientists have found that MSSA acquired the mecA gene in the 1960s, which accounts for its pathogenicity, before this it had a predominantly commensal relationship with humans. It is theorized that when this S. aureus strain that had acquired the mecA gene was introduced into hospitals, it came into contact with other hospital bacteria that had already been exposed to high levels of antibiotics. When exposed to such high levels of antibiotics, the hospital bacteria suddenly found themselves in an environment that had a high level of selection for antibiotic resistance, and thus resistance to multiple antibiotics formed within these hospital populations. When S. aureus came into contact with these populations, the multiple genes that code for antibiotic resistance to different drugs were then acquired by MRSA, making it nearly impossible to control. It is thought that MSSA acquired the resistance gene through the horizontal gene transfer , a method in which genetic information can be passed within a generation, and spread rapidly through its own population as was illustrated in multiple studies. Horizontal gene transfer speeds the process of genetic transfer since there is no need to wait an entire generation time for gene to be passed on. Since most antibiotics do not work on MRSA, physicians have to turn to alternative methods based in Darwinian medicine . However, prevention is the most preferred method of avoiding antibiotic resistance. By reducing unnecessary antibiotic use in human and animal populations, antibiotics resistance can be slowed.On 16 July 2021, the Director-General of WHO announced the formation of the Scientific Advisory Group for Origins of Novel Pathogens (SAGO), which is to be a permanent advisory body of the organisation. The Group was formed with a broad objective to examine emerging infectious diseases, including COVID-19 . According to the WHO Director-General, "SAGO will play a vital role in the next phase of studies into the origins of SARS-CoV-2, as well as the origins of future new pathogens."

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Rift Valley fever

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1997–98 El Niño event

The 1997–1998 El Niño was regarded as one of the most powerful El Niño–Southern Oscillation events in recorded history, resulting in widespread droughts, flooding and other natural disasters across the globe. It caused an estimated 16% of the world's reef systems to die, and temporarily warmed air temperature by 1.5 °C (2.7 °F) compared to the usual increase of 0.25 °C (0.45 °F) associated with El Niño events. The costs of the event were considerable, leading to global economic losses of US$5.7 trillion within five years. It led to a severe outbreak of Rift Valley fever after extreme rainfall in north-eastern Kenya and southern Somalia. It also led to record rainfalls in California during the water season of 1997–98 and one of Indonesia's worst droughts on record. 1998 ultimately became the warmest year in recorded history (up until then). In January 1997, probes gathering information on deep water temperatures discovered an area of unusually warm water, centered around 150 meters depth, across the western half of the Pacific Ocean . About 150 m (490 ft) below the surface, water temperatures were about 3 °C (5.4 °F) above normal, signifying that an El Niño-Southern Oscillation (ENSO) event was beginning. By this time, the Scripps Institution of Oceanography had forecast that an ENSO was likely to take place during the latter half of 1997. Throughout February, water temperatures began increasing over much of the Pacific as well as in shallower waters off the coast of Peru . The above-average water temperatures covered an area roughly 11,000 km (6,800 mi) across, almost stretching from New Guinea to South America . By April, the ENSO became fully established; a column of warm water extended to the surface in the middle of the Pacific Ocean and water anomalies exceeded 5 °C (9 °F) about 150 m (490 ft) below the ocean surface. At the surface off the coast of Peru, water temperatures averaged 3 °C (5.4 °F) above normal. Exceedingly warm waters became apparent by May, especially off the coast of South America where anomalies were reaching 7 °C (12.6 °F) above normal. Further north, sea surface temperatures along the Pacific coast of North America were increasing, with a large pool of water being 3 °C (5.4 °F) above normal. By September 1997, the ENSO became very powerful, with surface temperatures between South America and the International Dateline averaging 2-4 °C (3.6-7.2 °F) above normal, roughly a quarter of the planet's circumference. Additionally, the band of warmth along the Pacific coast of North America continued to expand, now stretching from Alaska to southern Mexico . A contrasting area of abnormally cool waters took shape near the coast of Australia by September as well, with waters 150 m (490 ft) below the surface averaging 4 °C (7.2 °F) below normal. Along the Pacific coast of the Americas , the volume of 21 to 30 °C (70 to 86 °F) water was roughly 30 times greater than that of all the water in the Great Lakes combined. The extra heat energy created by this anomaly was also about 93 times more than the energy produced by fossil fuels in the United States during 1995. By January 1998, sea surface temperatures off the coast of Peru continued to increase, reaching 11 °C (19.8 °F) above average. However, the region of cooler than average water in the western Pacific expanded, signifying that a La Niña would take shape in the latter part of 1998. Just two months later, the extent of above-average water temperatures sharply decreased as the El Niño weakened. The 1997–98 ENSO event finally ended during May 1998 as below-average water temperatures extended across much of the Pacific. The 1997–98 El Niño Event had various effects on tropical cyclone activity around the world, with more tropical cyclones than average occurring in the Pacific basins. This included the Southern Pacific basin between 160°E and 120°W, where 16 tropical cyclones in the South Pacific were observed during the 1997–98 season compared to an average of around 8. The area where most of the tropical cyclones developed was shifted eastwards, with parts of the Cook Islands and French Polynesia impacted as a result. In the West Pacific basin, the season saw a record of 11 super typhoons , with 10 of them reaching Category 5 intensity. In the east Pacific basin, the 1997 season featured two Category 5 hurricanes, Guillermo and Linda , the latter of which was the strongest on record before Patricia took that title during the 2015 season . The North Pacific basin broke the record for having the most tropical cyclones reaching Category 4 and 5 intensities with 17 that season. However, the 2015 season surpassed it with 21 tropical cyclones during the 2014–16 El Niño event .

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Rift Valley fever

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Rabies

Rabies is a viral disease that causes encephalitis in humans and other mammals . It was historically referred to as hydrophobia ("fear of water") due to the symptom of panic when presented with liquids to drink. Early symptoms can include fever and abnormal sensations at the site of exposure. These symptoms are followed by one or more of the following symptoms: nausea, vomiting, violent movements, uncontrolled excitement, fear of water, an inability to move parts of the body, confusion, and loss of consciousness . Once symptoms appear, the result is virtually always death. The time period between contracting the disease and the start of symptoms is usually one to three months but can vary from less than one week to more than one year. The time depends on the distance the virus must travel along peripheral nerves to reach the central nervous system . Rabies is caused by lyssaviruses , including the rabies virus and Australian bat lyssavirus . It is spread when an infected animal bites or scratches a human or other animals. Saliva from an infected animal can also transmit rabies if the saliva comes into contact with the eyes, mouth, or nose. Globally, dogs are the most common animal involved. In countries where dogs commonly have the disease, more than 99% of rabies cases are the direct result of dog bites . In the Americas , bat bites are the most common source of rabies infections in humans, and less than 5% of cases are from dogs. Rodents are very rarely infected with rabies. The disease can be diagnosed only after the start of symptoms. Animal control and vaccination programs have decreased the risk of rabies from dogs in a number of regions of the world. Immunizing people before they are exposed is recommended for those at high risk, including those who work with bats or who spend prolonged periods in areas of the world where rabies is common. In people who have been exposed to rabies, the rabies vaccine and sometimes rabies immunoglobulin are effective in preventing the disease if the person receives the treatment before the start of rabies symptoms. Washing bites and scratches for 15 minutes with soap and water, povidone-iodine , or detergent may reduce the number of viral particles and may be somewhat effective at preventing transmission. As of 2016 [ update ] , only fourteen people were documented to have survived a rabies infection after showing symptoms. However, research conducted in 2010 among a population of people in Peru with a self-reported history of one or more bites from vampire bats (commonly infected with rabies), found that out of 73 individuals reporting previous bat bites, seven people had rabies virus-neutralizing antibodies (rVNA). Since only one member of this group reported prior vaccination for rabies, the findings of the research suggest previously undocumented cases of infection and viral replication followed by an abortive infection. This could indicate that people may have an exposure to the virus without treatment and develop natural antibodies as a result. Rabies causes about 59,000 deaths worldwide per year, about 40% of which are in children under the age of 15. More than 95% of human deaths from rabies occur in Africa and Asia. Rabies is present in more than 150 countries and on all continents but Antarctica. More than 3 billion people live in regions of the world where rabies occurs. A number of countries, including Australia and Japan, as well as much of Western Europe, do not have rabies among dogs. Many Pacific islands do not have rabies at all. It is classified as a neglected tropical disease . The name rabies is derived from the Latin rabies , "madness". The Greeks derived the word lyssa , from lud or "violent"; this root is used in the genus name of the rabies virus, Lyssavirus . The period between infection and the first symptoms (incubation period) is typically one to three months in humans. This period may be as short as four days or longer than six years, depending on the location and severity of the wound and the amount of virus introduced. Initial symptoms of rabies are often nonspecific such as fever and headache. As rabies progresses and causes inflammation of the brain and meninges , symptoms can include slight or partial paralysis , anxiety , insomnia , confusion , agitation , abnormal behavior, paranoia , terror , and hallucinations . The person may also have fear of water. The symptoms eventually progress to delirium , and coma . Death usually occurs two to ten days after first symptoms. Survival is almost unknown once symptoms have presented, even with intensive care. Rabies has also occasionally been referred to as hydrophobia ("fear of water") throughout its history. It refers to a set of symptoms in the later stages of an infection in which the person has difficulty swallowing, shows panic when presented with liquids to drink, and cannot quench their thirst. Saliva production is greatly increased, and attempts to drink, or even the intention or suggestion of drinking, may cause excruciatingly painful spasms of the muscles in the throat and larynx . Since the infected individual cannot swallow saliva and water, the virus has a much higher chance of being transmitted, because it multiplies and accumulates in the salivary glands and is transmitted through biting. Hydrophobia is commonly associated with furious rabies, which affects 80% of rabies-infected people. This form of rabies causes irrational aggression in the host, which aids in the spreading of the virus through animal bites; [ medical citation needed ] a "foaming at the mouth" effect, caused by the accumulation of saliva, is also commonly associated with rabies in the public perception and in popular culture. The remaining 20% may experience a paralytic form of rabies that is marked by muscle weakness , loss of sensation, and paralysis ; this form of rabies does not usually cause fear of water. Rabies is caused by a number of lyssaviruses including the rabies virus and Australian bat lyssavirus . Duvenhage lyssavirus may cause a rabies-like infection. The rabies virus is the type species of the Lyssavirus genus , in the family Rhabdoviridae , order Mononegavirales . Lyssavirions have helical symmetry, with a length of about 180 nm and a cross-section of about 75 nm. These virions are enveloped and have a single-stranded RNA genome with negative sense . The genetic information is packed as a ribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. The RNA genome of the virus encodes five genes whose order is highly conserved: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L). To enter cells, trimeric spikes on the exterior of the membrane of the virus interact with a specific cell receptor, the most likely one being the acetylcholine receptor. The cellular membrane pinches in a procession known as pinocytosis and allows entry of the virus into the cell by way of an endosome . The virus then uses the acidic environment, which is necessary, of that endosome and binds to its membrane simultaneously, releasing its five proteins and single-strand RNA into the cytoplasm. Once within a muscle or nerve cell, the virus undergoes replication. The L protein then transcribes five mRNA strands and a positive strand of RNA all from the original negative strand RNA using free nucleotides in the cytoplasm. These five mRNA strands are then translated into their corresponding proteins (P, L, N, G and M proteins) at free ribosomes in the cytoplasm. Some proteins require post-translational modifications. For example, the G protein travels through the rough endoplasmic reticulum , where it undergoes further folding, and is then transported to the Golgi apparatus , where a sugar group is added to it ( glycosylation ). When there are enough viral proteins, the viral polymerase will begin to synthesize new negative strands of RNA from the template of the positive-strand RNA. These negative strands will then form complexes with the N, P, L and M proteins and then travel to the inner membrane of the cell, where a G protein has embedded itself in the membrane. The G protein then coils around the N-P-L-M complex of proteins taking some of the host cell membrane with it, which will form the new outer envelope of the virus particle. The virus then buds from the cell. From the point of entry, the virus is neurotropic , traveling along the neural pathways into the central nervous system . The virus usually first infects muscle cells close to the site of infection, where they are able to replicate without being 'noticed' by the host's immune system. Once enough virus has been replicated, they begin to bind to acetylcholine receptors at the neuromuscular junction. The virus then travels through the nerve cell axon via retrograde transport , as its P protein interacts with dynein , a protein present in the cytoplasm of nerve cells. Once the virus reaches the cell body it travels rapidly to the central nervous system (CNS), replicating in motor neurons and eventually reaching the brain. After the brain is infected, the virus travels centrifugally to the peripheral and autonomic nervous systems, eventually migrating to the salivary glands, where it is ready to be transmitted to the next host. : 317All warm-blooded species, including humans, may become infected with the rabies virus and develop symptoms. Birds were first artificially infected with rabies in 1884; however, infected birds are largely, if not wholly, asymptomatic, and recover. Other bird species have been known to develop rabies antibodies , a sign of infection, after feeding on rabies-infected mammals. The virus has also adapted to grow in cells of cold-blooded vertebrates. Most animals can be infected by the virus and can transmit the disease to humans. Worldwide, about 99% of human rabies cases come from domestic dogs. Other sources of rabies in humans include bats , monkeys , raccoons , foxes , skunks , cattle , wolves , coyotes , cats , and mongooses (normally either the small Asian mongoose or the yellow mongoose). Rabies may also spread through exposure to infected bears , domestic farm animals , groundhogs , weasels , and other wild carnivorans . However, lagomorphs , such as hares and rabbits , and small rodents , such as chipmunks , gerbils , guinea pigs , hamsters , mice , rats , and squirrels , are almost never found to be infected with rabies and are not known to transmit rabies to humans. Bites from mice, rats, or squirrels rarely require rabies prevention because these rodents are typically killed by any encounter with a larger, rabid animal, and would, therefore, not be carriers. The Virginia opossum (a marsupial, unlike the other mammals named in this paragraph, which are all eutherians / placental ), has a lower internal body temperature than the rabies virus prefers and therefore is resistant but not immune to rabies. Marsupials , along with monotremes ( platypuses and echidnas ), typically have lower body temperatures than similarly sized eutherians . The virus is usually present in the nerves and saliva of a symptomatic rabid animal. The route of infection is usually, but not always, by a bite. In many cases, the infected animal is exceptionally aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behavior. This is an example of a viral pathogen modifying the behavior of its host to facilitate its transmission to other hosts. After a typical human infection by bite, the virus enters the peripheral nervous system . It then travels retrograde along the efferent nerves toward the central nervous system . During this phase, the virus cannot be easily detected within the host, and vaccination may still confer cell-mediated immunity to prevent symptomatic rabies. When the virus reaches the brain , it rapidly causes encephalitis , the prodromal phase, which is the beginning of the symptoms. Once the patient becomes symptomatic, treatment is almost never effective and mortality is over 99%. Rabies may also inflame the spinal cord , producing transverse myelitis . Although it is theoretically possible for rabies-infected humans to transmit it to others by biting or otherwise, no such cases have ever been documented, because infected humans are usually hospitalized and necessary precautions taken. Casual contact, such as touching a person with rabies or contact with non-infectious fluid or tissue (urine, blood, feces), does not constitute an exposure and does not require post-exposure prophylaxis. But as the virus is present in sperm and vaginal secretions, it might be possible for rabies to spread through sex. There are only a small number of recorded cases of human-to-human transmission of rabies, and all occurred through organ transplants , most frequently with corneal transplantation , from infected donors. Rabies can be difficult to diagnose because, in the early stages, it is easily confused with other diseases or even with a simple aggressive temperament. The reference method for diagnosing rabies is the fluorescent antibody test (FAT), an immunohistochemistry procedure, which is recommended by the World Health Organization (WHO). The FAT relies on the ability of a detector molecule (usually fluorescein isothiocyanate) coupled with a rabies-specific antibody, forming a conjugate, to bind to and allow the visualisation of rabies antigen using fluorescent microscopy techniques. Microscopic analysis of samples is the only direct method that allows for the identification of rabies virus-specific antigen in a short time and at a reduced cost, irrespective of geographical origin and status of the host. It has to be regarded as the first step in diagnostic procedures for all laboratories. Autolysed samples can, however, reduce the sensitivity and specificity of the FAT. The RT PCR assays proved to be a sensitive and specific tool for routine diagnostic purposes, particularly in decomposed samples or archival specimens. The diagnosis can be reliably made from brain samples taken after death. The diagnosis can also be made from saliva, urine, and cerebrospinal fluid samples, but this is not as sensitive or reliable as brain samples. Cerebral inclusion bodies called Negri bodies are 100% diagnostic for rabies infection but are found in only about 80% of cases. If possible, the animal from which the bite was received should also be examined for rabies. Some light microscopy techniques may also be used to diagnose rabies at a tenth of the cost of traditional fluorescence microscopy techniques, allowing identification of the disease in less-developed countries. A test for rabies, known as LN34, is easier to run on a dead animal's brain and might help determine who does and does not need post-exposure prevention. The test was developed by the Centers for Disease Control and Prevention (CDC) in 2018. The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis , in particular infection with viruses such as herpesviruses , enteroviruses , and arboviruses such as West Nile virus . The most important viruses to rule out are herpes simplex virus type one, varicella zoster virus , and (less commonly) enteroviruses, including coxsackieviruses , echoviruses , polioviruses , and human enteroviruses 68 to 71. New causes of viral encephalitis are also possible, as was evidenced by the 1999 outbreak in Malaysia of 300 cases of encephalitis with a mortality rate of 40% caused by Nipah virus , a newly recognized paramyxovirus . Likewise, well-known viruses may be introduced into new locales, as is illustrated by the outbreak of encephalitis due to West Nile virus in the eastern United States. Almost all human exposure to rabies was fatal until a vaccine was developed in 1885 by Louis Pasteur and Émile Roux . Their original vaccine was harvested from infected rabbits, from which the virus in the nerve tissue was weakened by allowing it to dry for five to ten days. Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines. The human diploid cell rabies vaccine was started in 1967. Less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available. A recombinant vaccine called V-RG has been used in Belgium, France, Germany, and the United States to prevent outbreaks of rabies in undomesticated animals. Immunization before exposure has been used in both human and nonhuman populations, where, as in many jurisdictions, domesticated animals are required to be vaccinated. The Missouri Department of Health and Senior Services Communicable Disease Surveillance 2007 Annual Report states the following can help reduce the risk of contracting rabies: Vaccinating dogs, cats, and ferrets against rabies Keeping pets under supervision Not handling wild animals or strays Contacting an animal control officer upon observing a wild animal or a stray, especially if the animal is acting strangely If bitten by an animal, washing the wound with soap and water for 10 to 15 minutes and contacting a healthcare provider to determine if post-exposure prophylaxis is required 28 September is World Rabies Day , which promotes the information, prevention, and elimination of the disease. In Asia and in parts of the Americas and Africa, dogs remain the principal host. Mandatory vaccination of animals is less effective in rural areas. Especially in developing countries, pets may not be privately kept and their destruction may be unacceptable. Oral vaccines can be safely distributed in baits, a practice that has successfully reduced rabies in rural areas of Canada , France , and the United States . In Montreal , Quebec, Canada, baits are successfully used on raccoons in the Mount-Royal Park area. Vaccination campaigns may be expensive, but cost-benefit analysis suggests baits may be a cost-effective method of control. In Ontario , a dramatic drop in rabies was recorded when an aerial bait-vaccination campaign was launched. The number of recorded human deaths from rabies in the United States has dropped from 100 or more annually in the early 20th century to one or two per year due to widespread vaccination of domestic dogs and cats and the development of human vaccines and immunoglobulin treatments. Most deaths now result from bat bites, which may go unnoticed by the victim and hence untreated. Treatment after exposure can prevent the disease if given within 10 days. The rabies vaccine is 100% effective if given before symptoms of rabies appear. Every year, more than 15 million people get vaccinated after potential exposure. While this works well, the cost is significant. In the US it is recommended people receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a 14-day period. HRIG is expensive and makes up most of the cost of post-exposure treatment, ranging as high as several thousand dollars. In the UK, one dose of HRIG costs the National Health Service £1,000, although this is not flagged as a "high-cost medication". A full course of vaccine costs £120–180. As much as possible of HRIG should be injected around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site. People who have previously been vaccinated against rabies do not need to receive the immunoglobulin—only the postexposure vaccinations on days 0 and 3. The side effects of modern cell-based vaccines are similar to the side effects of flu shots. The old nerve-tissue-based vaccination required multiple injections into the abdomen with a large needle but is inexpensive. It is being phased out and replaced by affordable World Health Organization intradermal-vaccination regimens. In children less than a year old, the lateral thigh is recommended. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is effective in reducing the number of viral particles. Povidone-iodine or alcohol is then recommended to reduce the virus further. Awakening to find a bat in the room, or finding a bat in the room of a previously unattended child or mentally disabled or intoxicated person, is an indication for post-exposure prophylaxis (PEP). The recommendation for the precautionary use of PEP in bat encounters where no contact is recognized has been questioned in the medical literature, based on a cost–benefit analysis . However, a 2002 study has supported the protocol of precautionary administration of PEP where a child or mentally compromised individual has been alone with a bat, especially in sleep areas, where a bite or exposure may occur with the victim being unaware. Once rabies develops, death almost certainly follows. Palliative care in a hospital setting is recommended with administration of large doses of pain medication, and sedatives in preference to physical restraint. Ice fragments can be given by mouth for thirst, but there is no good evidence intravenous hydration is of benefit. A treatment known as the Milwaukee protocol, which involves putting a person into a chemically induced coma and using antiviral medications , has been proposed. It initially came into use in 2003, following Jeanna Giese, a teenage girl from Wisconsin , becoming the first person known to have survived rabies without preventive treatments before symptom onset. The protocol has been tried multiple times since, but has been assessed as an ineffective treatment, and concerns raised about the costs and ethics of its use. Treatment after exposure can prevent the disease if given within 10 days. The rabies vaccine is 100% effective if given before symptoms of rabies appear. Every year, more than 15 million people get vaccinated after potential exposure. While this works well, the cost is significant. In the US it is recommended people receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a 14-day period. HRIG is expensive and makes up most of the cost of post-exposure treatment, ranging as high as several thousand dollars. In the UK, one dose of HRIG costs the National Health Service £1,000, although this is not flagged as a "high-cost medication". A full course of vaccine costs £120–180. As much as possible of HRIG should be injected around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site. People who have previously been vaccinated against rabies do not need to receive the immunoglobulin—only the postexposure vaccinations on days 0 and 3. The side effects of modern cell-based vaccines are similar to the side effects of flu shots. The old nerve-tissue-based vaccination required multiple injections into the abdomen with a large needle but is inexpensive. It is being phased out and replaced by affordable World Health Organization intradermal-vaccination regimens. In children less than a year old, the lateral thigh is recommended. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is effective in reducing the number of viral particles. Povidone-iodine or alcohol is then recommended to reduce the virus further. Awakening to find a bat in the room, or finding a bat in the room of a previously unattended child or mentally disabled or intoxicated person, is an indication for post-exposure prophylaxis (PEP). The recommendation for the precautionary use of PEP in bat encounters where no contact is recognized has been questioned in the medical literature, based on a cost–benefit analysis . However, a 2002 study has supported the protocol of precautionary administration of PEP where a child or mentally compromised individual has been alone with a bat, especially in sleep areas, where a bite or exposure may occur with the victim being unaware. Once rabies develops, death almost certainly follows. Palliative care in a hospital setting is recommended with administration of large doses of pain medication, and sedatives in preference to physical restraint. Ice fragments can be given by mouth for thirst, but there is no good evidence intravenous hydration is of benefit. A treatment known as the Milwaukee protocol, which involves putting a person into a chemically induced coma and using antiviral medications , has been proposed. It initially came into use in 2003, following Jeanna Giese, a teenage girl from Wisconsin , becoming the first person known to have survived rabies without preventive treatments before symptom onset. The protocol has been tried multiple times since, but has been assessed as an ineffective treatment, and concerns raised about the costs and ethics of its use. Vaccination after exposure, PEP, is highly successful in preventing rabies. In unvaccinated humans, rabies is almost certainly fatal after neurological symptoms have developed. In 2010, an estimated 26,000 people died from rabies, down from 54,000 in 1990. The majority of the deaths occurred in Asia and Africa. As of 2015 [ update ] , India (approximately 20,847), followed by China (approximately 6,000) and the Democratic Republic of the Congo (5,600), had the most cases. A 2015 collaboration between the World Health Organization, World Organization of Animal Health (OIE), Food and Agriculture Organization of the United Nation (FAO), and Global Alliance for Rabies Control has a goal of eliminating deaths from rabies by 2030. India has the highest rate of human rabies in the world, primarily because of stray dogs, whose number has greatly increased since a 2001 law forbade the killing of dogs. Effective control and treatment of rabies in India is hindered by a form of mass hysteria known as puppy pregnancy syndrome (PPS). Dog bite victims with PPS, male as well as female, become convinced that puppies are growing inside them, and often seek help from faith healers rather than medical services. An estimated 20,000 people die every year from rabies in India, more than a third of the global total. Australia has an official rabies-free status, although Australian bat lyssavirus (ABLV), discovered in 1996, is a rabies-causing virus related to the rabies virus prevalent in Australian native bat populations. Canine-specific rabies has been eradicated in the United States, but rabies is common among wild animals, and an average of 100 dogs become infected from other wildlife each year. Due to high public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability of postexposure prophylaxis , incidence of rabies in humans is very rare in the United States. From 1960 to 2018, a total of 125 human rabies cases were reported in the United States; 36 (28%) were attributed to dog bites during international travel. Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats. The most recent rabies death in the United States was in November 2021, where a Texas child was bitten by a bat in late August 2021 but his parents failed to get him treatment. He died less than three months later. Either no or very few cases of rabies are reported each year in Europe; cases are contracted both during travel and in Europe. In Switzerland the disease was virtually eliminated after scientists placed chicken heads laced with live attenuated vaccine in the Swiss Alps . Foxes, proven to be the main source of rabies in the country, ate the chicken heads and became immunized. Italy, after being declared rabies-free from 1997 to 2008, has witnessed a reemergence of the disease in wild animals in the Triveneto regions ( Trentino-Alto Adige/Südtirol , Veneto and Friuli Venezia Giulia ), due to the spreading of an epidemic in the Balkans that also affected Austria. An extensive wild animal vaccination campaign eliminated the virus from Italy again, and it regained the rabies-free country status in 2013, the last reported case of rabies being reported in a red fox in early 2011. The United Kingdom has been free of rabies since the early 20th century except for a rabies-like virus (EBLV-2) in a few Daubenton's bats . There has been one fatal case of EBLV-2 transmission to a human. There have been four deaths from rabies, transmitted abroad by dog bites, since 2000. The last infection in the UK occurred in 1922, and the last death from indigenous rabies was in 1902. Sweden and mainland Norway have been free of rabies since 1886. Bat rabies antibodies (but not the virus) have been found in bats. On Svalbard, animals can cross the arctic ice from Greenland or Russia. Mexico was certified by the World Health Organization as being free of dog-transmitted rabies in 2019 because no case of dog-human transmission had been recorded in two years. India has the highest rate of human rabies in the world, primarily because of stray dogs, whose number has greatly increased since a 2001 law forbade the killing of dogs. Effective control and treatment of rabies in India is hindered by a form of mass hysteria known as puppy pregnancy syndrome (PPS). Dog bite victims with PPS, male as well as female, become convinced that puppies are growing inside them, and often seek help from faith healers rather than medical services. An estimated 20,000 people die every year from rabies in India, more than a third of the global total. Australia has an official rabies-free status, although Australian bat lyssavirus (ABLV), discovered in 1996, is a rabies-causing virus related to the rabies virus prevalent in Australian native bat populations.Canine-specific rabies has been eradicated in the United States, but rabies is common among wild animals, and an average of 100 dogs become infected from other wildlife each year. Due to high public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability of postexposure prophylaxis , incidence of rabies in humans is very rare in the United States. From 1960 to 2018, a total of 125 human rabies cases were reported in the United States; 36 (28%) were attributed to dog bites during international travel. Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats. The most recent rabies death in the United States was in November 2021, where a Texas child was bitten by a bat in late August 2021 but his parents failed to get him treatment. He died less than three months later. Either no or very few cases of rabies are reported each year in Europe; cases are contracted both during travel and in Europe. In Switzerland the disease was virtually eliminated after scientists placed chicken heads laced with live attenuated vaccine in the Swiss Alps . Foxes, proven to be the main source of rabies in the country, ate the chicken heads and became immunized. Italy, after being declared rabies-free from 1997 to 2008, has witnessed a reemergence of the disease in wild animals in the Triveneto regions ( Trentino-Alto Adige/Südtirol , Veneto and Friuli Venezia Giulia ), due to the spreading of an epidemic in the Balkans that also affected Austria. An extensive wild animal vaccination campaign eliminated the virus from Italy again, and it regained the rabies-free country status in 2013, the last reported case of rabies being reported in a red fox in early 2011. The United Kingdom has been free of rabies since the early 20th century except for a rabies-like virus (EBLV-2) in a few Daubenton's bats . There has been one fatal case of EBLV-2 transmission to a human. There have been four deaths from rabies, transmitted abroad by dog bites, since 2000. The last infection in the UK occurred in 1922, and the last death from indigenous rabies was in 1902. Sweden and mainland Norway have been free of rabies since 1886. Bat rabies antibodies (but not the virus) have been found in bats. On Svalbard, animals can cross the arctic ice from Greenland or Russia.Mexico was certified by the World Health Organization as being free of dog-transmitted rabies in 2019 because no case of dog-human transmission had been recorded in two years. Rabies has been known since around 2000 BC. The first written record of rabies is in the Mesopotamian Codex of Eshnunna ( c. 1930 BC ), which dictates that the owner of a dog showing symptoms of rabies should take preventive measures against bites. If another person were bitten by a rabid dog and later died, the owner was heavily fined. In Ancient Greece, rabies was supposed to be caused by Lyssa , the spirit of mad rage. Ineffective folk remedies abounded in the medical literature of the ancient world. The physician Scribonius Largus prescribed a poultice of cloth and hyena skin; Antaeus recommended a preparation made from the skull of a hanged man. Rabies appears to have originated in the Old World, the first epizootic in the New World occurring in Boston in 1768. Rabies was considered a scourge for its prevalence in the 19th century. In France and Belgium, where Saint Hubert was venerated, the " St Hubert's Key " was heated and applied to cauterize the wound. By an application of magical thinking , dogs were branded with the key in hopes of protecting them from rabies. It was not uncommon for a person bitten by a dog merely suspected of being rabid to commit suicide or to be killed by others. In ancient times the attachment of the tongue (the lingual frenulum , a mucous membrane) was cut and removed, as this was where rabies was thought to originate. This practice ceased with the discovery of the actual cause of rabies. Louis Pasteur's 1885 nerve tissue vaccine was successful, and was progressively improved to reduce often severe side-effects. In modern times, the fear of rabies has not diminished, and the disease and its symptoms, particularly agitation, have served as an inspiration for several works of zombie or similarly themed fiction, often portraying rabies as having mutated into a stronger virus which fills humans with murderous rage or incurable illness, bringing about a devastating, widespread pandemic. Rabies is infectious to mammals ; three stages of central nervous system infection are recognized. The clinical course is often shorter in animals than in humans, but result in similar symptoms and almost always death. The first stage is a one- to three-day period characterized by behavioral changes and is known as the prodromal stage . The second is the excitative stage, which lasts three to four days. This stage is often known as "furious rabies" for the tendency of the affected animal to be hyper-reactive to external stimuli and bite or attack anything near. In some cases, animals skip the excitative stage and develop paralysis, as in the third phase; the paralytic phase. This stage develops due to damage to motor neurons . Incoordination is seen, owing to rear limb paralysis , and drooling and difficulty swallowing is caused by paralysis of facial and throat muscles. Death is usually caused by respiratory arrest .

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Rift Valley fever

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ChAdOx1

ChAdOx1 is an adenoviral vector for vaccines that was developed by the Jenner Institute , University of Oxford . The vector is a chimpanzee adenovirus modified to avoid its replication. Adenoviruses are effective vectors for inducing and boosting cellular immunity to encoded recombinant antigens . However, the widespread seroprevalence of neutralizing antibodies to common human adenovirus serotypes limits their use. Simian adenoviruses do not suffer from the same disadvantages. Therefore, investigators have tested new vaccines using the chimp adenovirus ChAdOx1 as a vector. For example, a vaccine for influenza infection was designed using the vector expressing influenza antigens, nucleoprotein (NP), and matrix protein 1 (M1), creating a vaccine candidate named ChAdOx1 NP+M1. ChAdOx1 has been derived from a chimpanzee adenovirus (ChAd) serotype Y25 engineered by λ red recombination to exchange the native E4 orf 4, orf6 and orf6/7 genes for those from human adenovirus HAdV-C5. Serotype Y25 belongs to the species Human mastadenovirus E of genus Mastadenovirus . [ citation needed ]It has been demonstrated that the adenoviridae vector ChAdOx1 can be used to make vaccinations that are protective against Middle East Respiratory Syndrome (MERS) in mice and able to induce immune response against MERS in humans. The vector was also used to create a vaccine against Nipah which was effective in hamsters (but never proven in humans), in addition to a potential vaccine for Rift Valley Fever that was protective in sheep, goats, and cattle (but not proven in humans). The adenovirus expressing the antigen 85A (ChAdOx1 85A), is used as vector for a tuberculosis vaccine candidate. In 2017, the ChAdOx1 vector was used in a trial for a vaccine candidate against human malaria infection. The researchers studied two candidate vaccines ChAdOx1 LS2 along with MVA LS2. The former, encoding a malaria liver-stage dual antigen LS2 (LSA1 and LSAP2) fused with the transmembrane domain from shark invariant chain. And the latter, a Modified Vaccinia Ankara (MVA) vector encoding the LS2 fused to the C-terminal end of the leader sequence of tPA. The trial reached the phase I/IIa . There are also investigation lines that use the vector for vaccines against the Zika virus (ChAdOx1 ZIKV) and the Chikungunya virus (ChAdOx1 sCHIKV). The ChAdOx1 vector has been used as a platform for a vaccine against coronavirus disease since the beginning of the COVID-19 pandemic . Sarah Gilbert leads the work on this vaccine candidate alongside Andrew Pollard , Teresa Lambe , Sandy Douglas, Catherine Green and Adrian Hill . The COVID-19 vaccine , known now as ChAdOx1 nCoV-19 or AZD1222 , makes use of this vector, which stimulates an immune response against the coronavirus spike protein . Animal studies began in March 2020, and recruitment of 510 human participants for a phase I/II trial began on 27 March, and the results were presented in October. On 30 December 2020, the vaccine was approved for use in the UK's vaccination programme .

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Rift Valley fever

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Hantavirus pulmonary syndrome

Hantavirus pulmonary syndrome ( HPS ) is one of two potentially fatal syndromes of zoonotic origin caused by species of hantavirus . These include Black Creek Canal virus (BCCV), New York orthohantavirus (NYV), Monongahela virus (MGLV), Sin Nombre orthohantavirus (SNV), and certain other members of hantavirus genera that are native to the United States and Canada. Specific rodents are the principal hosts of the hantaviruses including the hispid cotton rat ( Sigmodon hispidus ) in southern Florida , which is the principal host of Black Creek Canal virus. The deer mouse ( Peromyscus maniculatus ) in Canada and the Western United States is the principal host of Sin Nombre virus . The white-footed mouse ( Peromyscus leucopus ) in the eastern United States is the principal host of New York virus. In South America , the long-tailed mouse ( Oligoryzomys longicaudatus ) and other species of the genus Oligoryzomys have been documented as the reservoir for Andes virus . Initially, HPS has an incubation phase of 2–4 weeks, in which patients remain asymptomatic. Subsequently, patients can experience 3–5 days of flu-like prodromal phase symptoms, including fever , cough, muscle pain , headache, lethargy, shortness of breath , nausea, vomiting and diarrhea. In the following 5–7 day cardiopulmonary phase, the patient's condition rapidly deteriorates into acute respiratory failure , characterized by the sudden onset of shortness of breath with rapidly evolving pulmonary edema , as well as cardiac failure , with hypotension, tachycardia and shock. In this phase, patients may develop acute respiratory distress syndrome . It is often fatal despite mechanical ventilation and intervention with diuretics . [ citation needed ] After the cardiopulmonary phase, patients can enter a diuretic phase of 2–3 days characterized by symptom improvement and diuresis . Subsequent convalescence can last months to years. As of 2017, patient mortality in the US from HPS is 36%. The virus can be transmitted to humans by a direct bite or inhalation of aerosolized virus, shed from stool, urine, or saliva from a natural reservoir rodent. In general, droplet and/or fomite transfer has not been shown in the hantaviruses in either the pulmonary or hemorrhagic forms. The preferred method for diagnosis of Hantavirus Pulmonary Syndrome is serological testing which identifies both acute (IgM) and remote infections (IgG); however, PCR may also be used to identify early infections. Rodent control in and around the home or dwellings remains the primary prevention strategy, as well as eliminating contact with rodents in the workplace and at campsites. Closed storage sheds and cabins are often ideal sites for rodent infestations. Airing out of such spaces prior to use is recommended. People are advised to avoid direct contact with rodent droppings and wear a mask while cleaning such areas to avoid inhalation of aerosolized rodent secretions. There is no cure or vaccine for HPS. Treatment involves supportive therapy, including mechanical ventilation with supplemental oxygen during the critical respiratory-failure stage of the illness. Although ribavirin can be used to treat hantavirus infections, it is not recommended as a treatment for HPS due to unclear clinical efficacy and likelihood of medication side effects. Early recognition of HPS and admission to an intensive care setting offers the best prognosis . Hantavirus pulmonary syndrome was first recognized during the 1993 outbreak in the Four Corners region of the southwestern United States . It was identified by Dr. Bruce Tempest. It was originally called Four Corners disease , but the name was changed to Sin Nombre virus after complaints by Native Americans that the name "Four Corners" stigmatized the region. It has since been identified throughout the United States. [ citation needed ]

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